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Vitamins C and E and Beta Carotene Supplementation and Cancer Risk: A Randomized Controlled Trial
Abstract
Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with antioxidants, may prevent cancer development. However, findings from randomized trials of the association between antioxidant use and cancer risk have been mostly negative.
From 8171 women who were randomly assigned in the Women's Antioxidant Cardiovascular Study, a double-blind, placebo-controlled 2 x 2 x 2 factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of alpha-tocopherol every other day), and beta carotene (50 mg every other day), 7627 women who were free of cancer before random assignment were selected for this study. Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index. Cox proportional hazards regression models were used to assess hazard ratios (represented as relative risks [RRs]) of common cancers associated with use of antioxidants, either individually or in combination. Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk. All statistical tests were two-sided.
During an average 9.4 years of treatment, 624 women developed incident invasive cancer and 176 women died from cancer. There were no statistically significant effects of use of any antioxidant on total cancer incidence. Compared with the placebo group, the RRs were 1.11 (95% confidence interval [CI] = 0.95 to 1.30) in the vitamin C group, 0.93 (95% CI = 0.79 to 1.09) in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in the beta carotene group. Similarly, no effects of these antioxidants were observed on cancer mortality. Compared with the placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the vitamin C group, 0.87 (95% CI = 0.65 to 1.17) in the vitamin E group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group. Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death.
Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality.
... A study performed in 1978 revealed that Vit-C therapy can notably prolong the survival rate of patients [11]. However, many RCTs prove the inconsistency of this fact [12,13] or neither approve nor disprove its effectiveness [14]. In terms of specific cancers, the results from one meta-analysis suggested that Vit-C intake can substantially decrease the mortality risk of breast cancer [15]. ...
... Nine thousand two hundred and fifty-seven records were searched, and 44 eligible trials were identified [4,5,7,12,13, (Figure 1). These 44 trials included 26540 participants. ...
... Forest plot of sepsis mortality, cardiac surgery mortality, non-cardiac surgery mortality, COVID-19 mortality, cancer mortality, and other mortality of trials evaluating vitamin C supplementation[4,5,7,12,13,27,28,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]47,50,[52][53][54][55][56][57][58][59][60][61][62][63][64]. ...
Mortality is the most clinically serious outcome, and its prevention remains a constant struggle. This study was to assess whether intravenous or oral vitamin C (Vit-C) therapy is related to reduced mortality in adults. Data from Medline, Embase, and the Cochrane Central Register databases were acquired from their inception to 26 October 2022. All randomized controlled trials (RCTs) involving intravenous or oral Vit-C against a placebo or no therapy for mortality were selected. The primary outcome was all-cause mortality. Secondary outcomes were sepsis, COVID-19, cardiac surgery, noncardiac surgery, cancer, and other mortalities. Forty-four trials with 26540 participants were selected. Although a substantial statistical difference was observed in all-cause mortality between the control and the Vit-C-supplemented groups (p = 0.009, RR 0.87, 95% CI 0.78 to 0.97, I2 = 36%), the result was not validated by sequential trial analysis. In the subgroup analysis, mortality was markedly reduced in Vit-C trials with the sepsis patients (p = 0.005, RR 0.74, 95% CI 0.59 to 0.91, I2 = 47%), and this result was confirmed by trial sequential analysis. In addition, a substantial statistical difference was revealed in COVID-19 patient mortality between the Vit-C monotherapy and the control groups (p = 0.03, RR 0.84, 95% CI 0.72 to 0.98, I2 = 0%). However, the trial sequential analysis suggested the need for more trials to confirm its efficacy. Overall, Vit-C monotherapy does decrease the risk of death by sepsis by 26%. To confirm Vit-C is associated with reduced COVID-19 mortality, additional clinical random control trials are required.
... Nevertheless, RCTs of cancer are costly and impractical to execute due to several reasons, such as large sample sizes and long follow up required as cancer cells can take decades to develop. Hitherto, only a few RCTs have reported results on the effect of vitamin C supplementation on digestive system cancers and those trials included few incident cancer cases and found no significant associations (Table 1) [13][14][15][16][17], albeit results for colorectal cancer were suggestive of a protective effect [16,17]. ...
... Nevertheless, RCTs of cancer are costly and impractical to execute due to several reasons, such as large sample sizes and long follow up required as cancer cells can take decades to develop. Hitherto, only a few RCTs have reported results on the effect of vitamin C supplementation on digestive system cancers and those trials included few incident cancer cases and found no significant associations (Table 1) [13][14][15][16][17], albeit results for colorectal cancer were suggestive of a protective effect [16,17]. ...
... A recent meta-analysis of prospective cohort studies showed that high intakes of dietary vitamin C (4 studies), supplemental vitamin C (2 studies), and dietary and supplemental vitamin C (1 study) were non-significantly associated with lower risk of colorectal cancer (relative risks of 0.86, 0.80 and 0.60, respectively, for the highest versus lowest exposure category) [7]. A meta-analysis of two RCTs [16,17] (Table 1) also suggested a reduction in colorectal cancer incidence in participants who received vitamin C supplements compared with the placebo group, but the precision of the estimate was low due to few cancer cases (relative risk 0.84, 95% CI 0.64-1.10) [7]. ...
Background & aims
Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers.
Methods
Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrumental variables. Effect size estimates for the genetic associations of the vitamin C-associated genetic variants with six major malignancies of digestive system were obtained from the FinnGen (N=309 154) and UK Biobank (N=367 542) studies. Results from the two studies were combined using meta-analysis.
Results
Genetically predicted higher circulating vitamin C showed a suggestive association with lower risk of small intestine and colorectal cancer after accounting for multiple testing. The odds ratio per 1 standard deviation increment in circulating vitamin C was 0.55 (95% confidence interval 0.32-0.94; P=0.029) for small intestine cancer and 0.84 (95% confidence interval 0.73-0.96; P=0.013) for colorectal cancer. There was a suggestive association between genetically predicted higher circulating vitamin C with lower risk of liver cancer in FinnGen but no association in the meta-analysis (odds ratio 0.69; 95% CI 0.36-1.32; P=0.265). Genetically predicted circulating vitamin C was not associated with cancers of the esophagus, stomach, or pancreas.
Conclusion
This Mendelian randomization study indicates that vitamin C might play a role in the prevention of small intestine and colorectal cancer.
... For the conducted meta-analyses and meta-regression, typical risk ratios (RRs) with 95% confidence intervals (CIs) were calculated based on data extracted from articles [14][15][16][17][18]. In the case of two papers [19,20], no exact data on the number of outcomes were found; in this case, the analysis was based on the RRs and 95% CIs taken directly from the articles. ...
... For example, no data on current/former smokers were available for two trials [17,20]. Second, in all trials [14][15][16][17][18][19][20], the intervention consisted of additional antioxidants with beta-carotene. Therefore, the obtained effect may not necessarily depend on supplementation, particularly with betacarotene; however, the use of meta-analysis should have weakened this disadvantage. ...
... Beta-carotene was supplemented every day in five of the eight trials [14,16,19,20], and on alternate days in the remaining three [15,17,18]. The dose of beta-carotene varied from 15 to 30 mg daily. ...
Lung cancer is one of the most common neoplasms globally, with about 2.2 million new cases and 1.8 million deaths annually. Although the most important factor in reducing lung cancer risk is lifestyle change, most patients favour the use of supplements, for example, rather than quitting smoking or following a healthy diet. To better understand the efficacy of such interventions, a systematic review was performed of data from randomized controlled trials concerning the influence of beta-carotene supplementation on lung cancer risk in subjects with no lung cancer before the intervention. The search corpus comprised a number of databases and eight studies involving 167,141 participants, published by November 2021. The findings indicate that beta-carotene supplementation was associated with an increased risk of lung cancer (RR = 1.16, 95% CI = 1.06–1.26). This effect was even more noticeable among smokers and asbestos workers (RR = 1.21, 95% CI = 1.08–1.35) and non-medics (RR = 1.18, 95% CI = 1.07–1.29). A meta-regression found no relationship between the beta-carotene supplementation dose and the size of the negative effect associated with lung cancer risk. Our findings indicate that beta-carotene supplementation has no effect on lung cancer risk. Moreover, when used as the primary chemoprevention, beta-carotene may, in fact, increase the risk of lung cancer.
... Furthermore, it is challenging to establish a clear protective effect of a specific compound in the development of chronic diseases within a complex diet influenced by many other risk factors. In such cases, conflicting results may also arise [79,80]. Although the studies we included adjusted for age and gender as confounding factors, there is still a possibility of inadequate control for other confounding factors. ...
Background
Gastric cancer is characterized by high invasiveness, heterogeneity, and late diagnosis, leading to high incidence and mortality rates. It is a significant public health concern globally. Early prevention is crucial in reducing the occurrence of gastric cancer, and dietary prevention, particularly focusing on carotenoids, has been considered a convenient and effective approach. However, the association between carotenoid intake and gastric cancer incidence remains controversial.
Methods
A systematic search was conducted in PubMed, Ovid Embase, Web of Science, and Cochrane databases from inception to January 5, 2023. Two reviewers independently screened search results, extracted relevant data, and evaluated study quality. Statistical analysis was performed using the "metan" command in STATA 16 software. Random-effects or fixed-effects models were chosen based on the magnitude of heterogeneity among studies.
Results
This study included a total of 35 publications, consisting of 23 case–control studies and 12 cohort studies. Meta-analysis of case–control studies showed that alpha-carotene (OR = 0.71, 95% CI: 0.55–0.92), beta-carotene (OR = 0.62, 95% CI: 0.53–0.72), and lutein (OR = 0.82, 95% CI: 0.69–0.97) significantly reduced the risk of gastric cancer, while beta-cryptoxanthin (OR = 0.88, 95% CI: 0.75–1.04) and lycopene (OR = 0.86, 95% CI: 0.73–1.00) showed no significant correlation. Meta-analysis of cohort studies indicated no significant associations between any of the five carotenoids and gastric cancer incidence (alpha-carotene: RR = 0.81, 95% CI: 0.54–1.23; beta-carotene: RR = 0.86, 95% CI: 0.64–1.16; beta-cryptoxanthin: RR = 0.86, 95% CI: 0.64–1.16; lutein: RR = 0.94, 95% CI: 0.69–1.29; lycopene: RR = 0.89, 95% CI: 0.69–1.14).
Conclusions
The relationship between carotenoids and gastric cancer incidence may vary depending on the type of study conducted. Considering that evidence from cohort studies is generally considered stronger than evidence from case–control studies, and high-quality randomized controlled trials show no significant association between carotenoids and gastric cancer incidence, current evidence does not support the supplementation of carotenoids for gastric cancer prevention. Further targeted research is needed to explore the association between the two.
... For example, studies by Yong et al (6) in 1997, Voorrips et al in 2000 (19) and Yuan et al (20) in 2003 reported that vitamin C intake reduced the risk of lung cancer by 34, 23 and 19%, respectively. Additionally, it has been reported that supplementary vitamin C intake reduces the risk of lung cancer (10,21,22). However, other observational studies have reported that there is no association between vitamin C (dietary and/or supplementary) intake and the risk of lung cancer (19,20,(23)(24)(25). ...
Previous cohort studies reported inconsistent findings regarding the association between dietary or supplementary vitamin C intake and lung cancer risk. These associations were investigated by conducting a meta-analysis of cohort studies. The PubMed and EMBASE databases were utilized, using keywords related to the topic from inception to April 15, 2022. Pooled effect sizes, such as relative risk (RR) or hazard ratio (HR) with 95% confidence intervals (CIs), were calculated using a random-effects model. A total of 20 cohort studies from 13 articles were included in the final analysis. In a meta-analysis of all studies, there was no significant association between dietary or supplementary vitamin C intake and lung cancer risk (RR/HR, 0.90; 95% CI, 0.80–1.01; I²=56.4%; n=20). In the subgroup meta-analysis by the source of vitamin C, dietary vitamin C intake decreased the risk of lung cancer (RR/HR, 0.82; 95% CI, 0.73–0.92; I²=42.5%; n=14), whereas there was no association between supplementary vitamin C intake and lung cancer risk (RR/HR, 1.01; 95% CI, 0.84–1.22; n=4). The present meta-analysis of cohort studies found that dietary vitamin C intake is beneficial for preventing lung cancer, whereas its supplementary intake does not have a beneficial effect.
... antioxidants/). Some randomized, placebo-controlled trials offer a little support that taking vitamin C, vitamin E, betacarotene, or other single antioxidants provides substantial protection against heart disease, cancer, or other chronic conditions in humans (Lee et al. 2005;Cook et al. 2007;Lin et al. 2009;Goodman et al. 2011). Many observational studies, including case-control studies and cohort studies, investigating the potential role of dietary antioxidant supplements in reducing risks of cancer in humans have yielded mixed results (Milman et al. 2007). ...
... A balance between oxidants and antioxidants is necessary for a healthy biological system (Bouayed and Bohn 2010). To counteract the damaging effects of reactive species, the body has several antioxidant mechanisms, including enzymes such as superoxide dismutase, catalase and glutathione peroxidase, as well as antioxidants such as vitamin C, vitamin E and beta-carotene (Lin et al. 2009;Adwas et al. 2019). Antioxidants play a critical role in maintaining homeostasis within the body by neutralizing harmful oxidizing agents and preventing oxidative stress (OS). ...
Aging accompanied by several age-related complications, is a multifaceted inevitable biological progression involving various genetic, environmental, and lifestyle factors. The major factor in this process is oxidative stress, caused by an abundance of reactive oxygen species (ROS) generated in the mitochondria and endoplasmic reticulum (ER). ROS and RNS pose a threat by disrupting signaling mechanisms and causing oxidative damage to cellular components. This oxidative stress affects both the ER and mitochondria, causing proteopathies (abnormal protein aggregation), initiation of unfolded protein response, mitochondrial dysfunction, abnormal cellular senescence, ultimately leading to inflammaging (chronic inflammation associated with aging) and, in rare cases, metastasis. RONS during oxidative stress dysregulate multiple metabolic pathways like NF-κB, MAPK, Nrf-2/Keap-1/ARE and PI3K/Akt which may lead to inappropriate cell death through apoptosis and necrosis. Inflammaging contributes to the development of inflammatory and degenerative diseases such as neurodegenerative diseases, diabetes, cardiovascular disease, chronic kidney disease, and retinopathy. The body’s antioxidant systems, sirtuins, autophagy, apoptosis, and biogenesis play a role in maintaining homeostasis, but they have limitations and cannot achieve an ideal state of balance. Certain interventions, such as calorie restriction, intermittent fasting, dietary habits, and regular exercise, have shown beneficial effects in counteracting the aging process. In addition, interventions like senotherapy (targeting senescent cells) and sirtuin-activating compounds (STACs) enhance autophagy and apoptosis for efficient removal of damaged oxidative products and organelles. Further, STACs enhance biogenesis for the regeneration of required organelles to maintain homeostasis. This review article explores the various aspects of oxidative damage, the associated complications, and potential strategies to mitigate these effects.
Graphical abstract
... Additionally, a seminal article was published by Peto and colleagues, entitled "Can dietary carotene materially reduce human cancer rates?", which drew more attention to the field [32]. However, when the supplementation of individual nutrients such as alpha-tocopherol, beta-carotene, vitamin C, selenium, or B vitamins was tested in randomized controlled trials, no reduction in cancer risk or cancerrelated mortality was observed [33][34][35][36][37] and, in some cases, there was an increase in cancer incidence [38][39][40]. In this example, more recent meta-analyses of this body of work have concluded that β-carotene supplementation does not impact cancer incidence (no harm or benefit), but it may negatively impact lung cancer risk for smokers [41]. ...
Simple Summary
Diet plays an important role in modifying cancer risk and may improve outcomes for patients during and after cancer treatment. The goals of this bibliometric review were to characterize studies, highlight emerging trends, and identify gaps in the literature regarding diet and cancer. We found that while previous publications have focused on the impact of high-fat diets and alcohol on common cancers such as breast, colorectal, and liver, there are far fewer publications describing the role of diet in less prevalent cancers. Areas of emerging interest include studies on nutrient timing, spices, and pre- and probiotics.
Abstract
Diet plays a critical role for patients across the cancer continuum. The World Cancer Research Fund International and the American Cancer Society have published evidence supporting the role of nutrition in cancer prevention. We conducted an analysis of the literature on dietary nutrients and cancer to uncover opportunities for future research. The objective of the bibliometric analysis was to describe trends in peer-reviewed publications on dietary components and cancer and to highlight research gaps. PubMed was queried for manuscripts with diet- and cancer-related keywords and Medical Subject Headings (MeSH) terms. Metadata covering 99,784 publications from 6469 journals were analyzed to identify trends since 1970 on diet topics across 19 tumor types. Publications focused largely on breast, colorectal, and liver cancer, with fewer papers linking diet with other cancers such as brain, gallbladder, or ovarian. With respect to “unhealthy” diets, many publications focused on high-fat diets and alcohol consumption. The largest numbers of publications related to “healthy” diets examined the Mediterranean diet and the consumption of fruits and vegetables. These findings highlight the need for additional research focused on under-investigated cancers and dietary components, as well as dietary studies during cancer therapy and post-therapy, which may help to prolong survivorship.
... For example, a study found that a higher intake of alpha-tocopherol is associated with a reduced risk of breast cancer among postmenopausal women [129]. However, other studies have found no significant association between alpha-tocopherol intake and breast cancer risk [130,131]. For example, a study found no evidence that alpha-tocopherol supplementation reduced breast cancer risk among women with a high risk of developing the disease [132]. ...
Breast cancer is one of the most common types of cancer in women worldwide, and its incidence is increasing. Diet has been identified as a modifiable risk factor for breast cancer, but the complex interplay between diet, metabolism, and cancer development is not fully understood. Nutritional metabolomics is a rapidly evolving field that can provide insights into the metabolic changes associated with dietary factors and their impact on breast cancer risk. The review’s objective is to provide a comprehensive overview of the current research on the application of nutritional metabolomics in understanding the relationship between diet and breast cancer. The search strategy involved querying several electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar. The search terms included combinations of relevant keywords such as “nutritional metabolomics”, “diet”, “breast cancer”, “metabolites”, and “biomarkers”. In this review, both in vivo and in vitro studies were included, and we summarize the current state of knowledge on the role of nutritional metabolomics in understanding the diet–breast cancer relationship, including identifying specific metabolites and metabolic pathways associated with breast cancer risk. We also discuss the challenges associated with nutritional metabolomics research, including standardization of analytical methods, interpretation of complex data, and integration of multiple-omics approaches. Finally, we highlight future directions for nutritional metabolomics research in studying diet–breast cancer relations, including investigating the role of gut microbiota and integrating multiple-omics approaches. The application of nutritional metabolomics in the study of diet–breast cancer relations, including 2-amino-4-cyano butanoic acid, piperine, caprate, rosten-3β,17β-diol-monosulfate, and γ-carboxyethyl hydrochroman, among others, holds great promise for advancing our understanding of the role of diet in breast cancer development and identifying personalized dietary recommendations for breast cancer prevention, control, and treatment.
... Additionally, regular use of nutritional supplementation was associated with reducing risk of CG and non-cardia CG, regardless of lifestyle [46][47][48]. However, use of high doses of anti-inflammatory nutrients, such as β-carotene, vitamin C, and vitamin E, for cancer prevention purposes in generally healthy populations has not shown beneficial effects on incidence and mortality, regardless of cancer type [49]. In this study, we observed a more pro-inflammatory dietary pattern in the Brazilian population, with lower consumption of the anti-inflammatory nutrients. ...
Background:
Few studies have evaluated the association between diet-related inflammation and gastric adenocarcinoma (GA) and evidence is scarce in Brazil. This study evaluated the association between a pro-inflammatory diet and GA.
Methods:
A multicenter case-control study was conducted in Brazil. A total of 1645 participants-492 cases, 377 endoscopy controls, and 776 hospital controls-were included. Energy-adjusted Dietary Inflammatory Index (E-DIITM) scores were derived from a validated food frequency questionnaire. We used binary and multinomial logistic regression models for the analysis of total GA, and its subtypes (cardia and non-cardia, intestinal, and diffuse histological subtypes).
Results:
In cases versus endoscopy controls, a pro-inflammatory diet, estimated by higher E-DII scores, was associated with a higher risk GA (ORQ4vsQ1: 2.60, 1.16-5.70), of non-cardia GA (OR: 2.90, 1.06-7.82), and diffuse subtype (OR: 3.93, 1.59-9.70). In cases versus hospital controls, higher E-DII scores were associated with a higher risk of GA (OR: 2.70, 1.60-4.54), of cardia GA (OR: 3.31, 1.32-8.24), non-cardia GA (OR: 2.97, 1.64-5.39), and both intestinal (OR: 2.82, 1.38-5.74) and diffuse GA (OR: 2.50, 1.54-5.11) subtypes.
Conclusions:
This study provides evidence that a pro-inflammatory diet is associated with an increased risk of GA in Brazil. E-DII requires the inclusion of sodium due to its importance in carcinogenesis.
... As a defensive response, the cells activate defense systems that resist the production of antioxidants, including SOD and GSH. Currently, the mechanism based on inducing an increase in oxidative stress as an anticancer effect is used in many therapies [79][80][81][82][83][84][85][86]. The obtained results suggest that, in the case of a potential therapy that induces oxidative stress in breast cancer tumors, the MGN complex seems to be the most promising. ...
One of the components of bee venom is melittin (M), which has strong lysing properties on membranes. M has high toxicity to cancer cells, but it also affects healthy cells, making it necessary to use methods for targeted delivery to ensure treatment. This research is a continuation of previous studies using graphene nanomaterials as M carriers to breast cancer cells. The studies described below are conducted on a more organized biological structure than what is found in vitro cells, namely, cancerous tumors grown on a chicken embryo chorioallantoic membrane. Caspase 3 and 8 levels are analyzed, and the level of oxidative stress markers and changes in protein expression for cytokines are examined. The results show that M complexes with nanomaterials reduce the level of oxidative stress more than M alone does, but the use of graphene (GN) as a carrier increases the level of DNA damage to a greater extent than the increase caused by M alone. An analysis of cytokine levels shows that the use of the M and GN complex increases the level of proteins responsible for inhibiting tumor progression to a greater extent than the increase occasioned by a complex with graphene oxide (GO). The results suggest that the use of GN as an M carrier may increase the toxic effect of M on structures located inside a cell.
... Although the protective effects of the above nutrients were recorded in many previous studies and confirmed in the current study, one randomized controlled trial and metaanalyses did not advocate for the high-dose use of β-carotene, vitamin C, and vitamin E supplementation for cancer prevention purposes in the generally healthy population, as no beneficial effects on total cancer incidence and mortality were shown [20,21]. A recent Swedish study illustrated the potential biological basis behind the scenes [22]. ...
Abstract
Previous studies provided inconsistent results on the effects of antioxidant nutrient intake on lung cancer prevention. We aimed to evaluate the association between antioxidant consumption from food and supplemental sources and lung cancer incidence. Data were obtained from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. A total of 98,451 participants were included in the data analysis. We used a multivariable Cox proportional hazards regression model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between antioxidant intake and lung cancer risk. Dose-response assessments for individual nutrients were conducted. We also selected the model for the best combination of antioxidants for reducing lung cancer risk using machine learning methods. After the median follow-up of 12.2 years, 1642 new cases were identified. Intake of the calculated HRs indicated a trend for a higher quartile of food-based Composite Dietary Antioxidant Index (fCDAI) associated with a lower lung cancer risk after adjusting for covariates (HRQ4vs.Q1 = 0.64, 95% CI: 0.52, 0.79; P for trend < 0.001). Protective effects of dietary antioxidant intake were observed across all individual antioxidant micronutrients except magnesium. Random forests model suggested the dietary intake group of α-carotene, magnesium, vitamin C, vitamin E, lycopene, selenium, lutein, and zeaxanthin, and β-carotene had the most favorable effects on lung cancer prevention. Higher consumption of antioxidants from food sources has a protective effect against lung cancer, while no effects were shown in the supplemental group. It is recommended to consume a combination of various antioxidants due to the potential benefits from the interaction, while more research should be performed to investigate the underlying mechanisms of antioxidant synergic effects on lung cancer risk reduction.
... Moreover, it was why, for instance, vitamins were not a good idea. Because it essentially promotes cell proliferation, several studies [4,5] have shown that giving patients vitamin supplements increase cancer. In reality, 'it is similar to spraying fertilizers on an open field; we want crops to grow, but a lot of weeds sprout. ...
Cancer is not a rare condition; it impacts around one in ten of us, a statistic we must seriously consider. Cancer and cardiovascular disease have long been the leading causes of death.[1,2] If we go past 50–70 years, heart attacks and strokes were the leading causes of death among Indians; cancer was a rather remote cause. However, the mortality rate from cardiovascular disease has been decreasing rapidly, and cancer has increased rapidly.[3] This is due to the complexity of the condition of cancer and the way that we perceive it. What exactly it is, we are unsure. So for such a widespread illness, it is ambiguous why we acquire this cancerous condition. As we think about it, it could not make sense for the spite to grow as it is an essential component of us. For instance, if we develop breast cancer or lung cancer, the cancerous cell was originally derived from our natural cells.
For example, when we have a cancerous breast cell derived from normal breast tissue, but after it evolves, it grows or does not grow, depending on the availability of the growth factors. Normal breast or lung cells work together as a team and always assist the body, but cancerous cells are not motivated to work as a team; instead, they are concerned with ensuring their existence so they can surpass their neighboring cells. They keep expanding and will eventually obliterate their surroundings. Later, they begin to move about, which is bad for the entire body. It benefits the
cancerous cells themselves by dispersing throughout the body. As a result, it is almost an alien invader that has developed from us.
The main risk factors for cancer are genetics and smoking; however, there are many additional risk factors (carcinogens). Similar to how smoking increases our chance of developing lung cancer, even though we can smoke indefinitely without developing the disease, there are other factors that we know very little about. We need to understand more about those factors. While genetics play a factor, I believe one of the biggest mistakes we have made over the years is to place so much emphasis on it, leading us to believe that a random mutation causes cancer. So the idea about cancer is that cancer is like a seed. If we have a genetic risk factor, we tend to develop cancer. Each human cell and the cells of all multicellular organisms contain the cancerous seed. We will maximize our chance of getting cancer if we create the ideal conditions for that seed to sprout. The cancer issue is that we don’t fully comprehend what it is as a disease. From this
perspective, I will now discuss the concept of cancer as a disease and its causation.
... What is more, beneficial effect of vitamin C in reference to human diseases (cancer, atherosclerosis, diabetes, neurodegenerative disease) remains equivocal [217], and a shortage of clinical trials impedes drawing clear conclusions about therapeutic role of ascorbic acid administration [238]. Furthermore, it was also reported that supplementation with antioxidant nutrients (vitamin C, vitamin E or β-carotene) offered no prevention against cancer incidence [239], and there is no certainty that possible cancer-preventive ability of anti-oxidant molecules, such as β-carotene, can be strictly due to free radical quenching mechanism [240]. In addition to mentioned discrepancies, it should be also noted that β-carotene and vitamin C can possess pro-oxidant activity [217,240]. ...
Prolonged elevated oxidative stress (OS) possesses negative effect on cell structure and functioning, and is associated with the development of numerous disorders. Naturally occurred anti-oxidant compounds reduce the oxidative stress in living organisms. In this review, antioxidant properties of β-carotene, tocopherols and ascorbic acid are presented based on in vitro, in vivo and populational studies. Firstly, environmental factors contributing to the OS occurrence and intracellular sources of Reactive Oxygen Species (ROS) generation, as well as ROS-mediated cellular structure degradation, are introduced. Secondly, enzymatic and non-enzymatic mechanism of anti-oxidant defence against OS development, is presented. Furthermore, ROS-preventing mechanisms and effectiveness of β-carotene, tocopherols and ascorbic acid as anti-oxidants are summarized, based on studies where different ROS-generating (oxidizing) agents are used. Oxidative stress biomarkers, as indicators on OS level and prevention by anti-oxidant supplementation, are presented with a focus on the methods (spectrophotometric, fluorometric, chromatographic, immuno-enzymatic) of their detection. Finally, the application of Raman spectroscopy and imaging as a tool for monitoring the effect of anti-oxidant (β-carotene, ascorbic acid) on cell structure and metabolism, is proposed. Literature data gathered suggest that β-carotene, tocopherols and ascorbic acid possess potential to mitigate oxidative stress in various biological systems. Moreover, Raman spectroscopy and imaging can be a valuable technique to study the effect of oxidative stress and anti-oxidant molecules in cell studies.
... Antioxidants inhibit cellular damage by donating an electron to reactive oxygen species, effectively neutralizing them and reducing their ability to create damage [107]. The vitamin antioxidants include vitamin E, vitamin C, and beta-carotene [108]. As the body cannot manufacture these antioxidants, it is important to have a diet rich in these nutrients. ...
Background and Objectives: Alzheimer’s disease (AD) is the most common form of dementia, with the risk of developing it attributed to non-modifiable and modifiable factors. Currently, there is no cure for AD. A plant-based diet may protect against cognitive decline, due to the effects of plant-based nutrients such as vitamins, antioxidants, and fiber. The aim of the review is to summarize current literature on plant-based nutrients and their impact on cognition. Materials and Methods: A search was conducted on PubMed for clinical and murine studies, using combinations of the following words: “Alzheimer’s disease”, “dementia”, “cognition”, “plant-based diet”, “mild cognitive impairment”, “vitamin B”, “vitamin C”, “vitamin E, “beta carotene”, “antioxidants”, “fiber”, “vitamin K”, “Mediterranean diet”, “vitamin D”, and “mushrooms”. Results and Conclusions: A diet rich in vitamin B and antioxidants can benefit the cognitive functions of individuals as shown in randomized clinical trials. Vitamin K is associated with improved cognition, although large randomized controlled trials need to be done. Fiber has been shown to prevent cognitive decline in animal studies. Vitamin D may contribute to cognitive health via anti-inflammatory processes. Several medical organizations have recommended a plant-based diet for optimizing cognitive health and potentially helping to prevent dementia.
... β-carotene (BC) is an active vitamin A precursor and well known-antioxidant found in abundance in many fruits and vegetables with deep yellow, orange, or green colors. Increased plasma concentrations of BC and due to high dietary intakes of BC have been shown to decrease the incidence of several cancers, such as lung cancer, non-Hodgkin lymphoma, and epithelial cell cancer [9,10]. Previously, the protective effect of BC against colon cancer has been reported in the 1,2-dimethylhydrazine (DMH)-induced colon cancer model in vivo [11]. ...
Background/objectives:
Colorectal cancer (CRC) is the third most common cancer worldwide and has a high recurrence rate, which is associated with cancer stem cells (CSCs). β-carotene (BC) possesses antioxidant activity and several anticancer mechanisms. However, no investigation has examined its effect on colon cancer stemness.
Materials/methods:
CD133+CD44+ HCT116 and CD133+CD44+ HT-29 cells were isolated and analyzed their self-renewal capacity by clonogenic and sphere formation assays. Expressions of several CSCs markers and Wnt/β-catenin signaling were examined. In addition, CD133+CD44+ HCT116 cells were subcutaneously injected in xenograft mice and analyzed the effect of BC on tumor formation, tumor volume, and CSCs markers in tumors.
Results:
BC inhibited self-renewal capacity and CSC markers, including CD44, CD133, ALDH1A1, NOTCH1, Sox2, and β-catenin in vitro. The effects of BC on CSC markers were confirmed in primary cells isolated from human CRC tumors. BC supplementation decreased the number and size of tumors and delayed the tumor-onset time in xenograft mice injected with CD133+CD44+ HCT116 cells. The inhibitory effect of BC on CSC markers and the Wnt/β-catenin signaling pathway in tumors was confirmed in vivo as well.
Conclusions:
These results suggest that BC may be a potential therapeutic agent for colon cancer by targeting colon CSCs.
... In addition, given that oxidative stress induced by cancer may enhance the consumption of VitC as well, findings were prone to reverse causality (8). Several randomized controlled trials (RCTs) focusing on this issue did not support the protective role of VitC in the development of cancers, whereas the sample size of incident cancer cases was limited (9,10). Simultaneously, RCTs investigating the effect of VitC intake and EC risk are time-consuming and expensive, largely infeasible in a primary prevention condition. ...
Background
Observational studies indicated that circulating vitamin C (VitC) levels may be correlated with the risk of endometrial cancer (EC). However, the causal effects and direction between them were still unclear.
Methods
In this study, 11 single nucleotide polymorphisms (SNPs) robustly correlated with plasma VitC levels were extracted from the latest genome-wide association study (GWAS), containing 52,018 individuals. Genetic data of EC were obtained from the Endometrial Cancer Association Consortium (ECAC) (12,906 cases and 108,979 controls). An inverse-variance weighted method was utilized as the primary analysis of Mendelian randomization (MR), supplemented by the weighted median, MR Pleiotropy Residual Sum and Outlier test (MR-PRESSO), and MR-Egger methods. Additional sensitivity analyses excluding 3 SNPs with secondary phenotypes were conducted to rule out the possible pleiotropic effects. Potential impacts of several risk factors of EC, such as obesity, body mass index (BMI), hypertension, and diabetes on VitC levels, were assessed. We additionally evaluated the effects of VitC on LDL cholesterol levels, HDL cholesterol levels, and triglycerides levels to probe into the possible mediators in the VitC-EC pathway.
Results
Genetically predicted higher plasma VitC levels (per 1 SD increase, approximately 20 μmol/L) were causally associated with an increased risk of EC overall [odds ratio ( OR ) 1.374, 95% CI 1.128–1.674, p = 0.0016], supported by complementary sensitivity analyses. In the subgroup analyses, genetically predicted higher levels of VitC were associated with a tendency of increased risks of both endometrioid ( OR SD 1.324, 95% CI 0.959–1.829, p = 0.0881) and non-endometrioid histology ( OR SD 1.392, 95% CI 0.873–2.220, p = 0.1647) while without statistical significance. The association remained significant after the exclusion of the three pleiotropic SNPs ( OR SD 1.394, 95% CI 1.090–1.784, p = 0.0082). The confounders and mediators were unlikely to affect the VitC-EC relationship. The causal effect of EC on VitC levels was not supported ( OR 1.001, 95% CI 0.998–1.004, p = 0.4468).
Conclusions
This bi-directional MR study demonstrated a causal risk role of higher circulating VitC at physiological levels on an increased risk of EC, which was independent of confounders and mediators. Further studies are warranted to elucidate the possible mechanisms.
... In this context, there are two therapeutic approaches, one of which is based on antioxidant administration, which could reduce ROS levels required for the proliferation of cancer cells, making them susceptible to cellular apoptosis. However, this approach has raised numerous questions on this topic, and the results have been evasive [293]. ...
Oxidative stress is the subject of numerous studies, most of them focusing on the negative effects exerted at both molecular and cellular levels, ignoring the possible benefits of free radicals. More and more people admit to having heard of the term “oxidative stress”, but few of them understand the meaning of it. We summarized and analyzed the published literature data in order to emphasize the importance and adaptation mechanisms of basal oxidative stress. This review aims to provide an overview of the mechanisms underlying the positive effects of oxidative stress, highlighting these effects, as well as the risks for the population consuming higher doses than the recommended daily intake of antioxidants. The biological dose–response curve in oxidative stress is unpredictable as reactive species are clearly responsible for cellular degradation, whereas antioxidant therapies can alleviate senescence by maintaining redox balance; nevertheless, excessive doses of the latter can modify the redox balance of the cell, leading to a negative outcome. It can be stated that the presence of oxidative status or oxidative stress is a physiological condition with well-defined roles, yet these have been insufficiently researched and explored. The involvement of reactive oxygen species in the pathophysiology of some associated diseases is well-known and the involvement of antioxidant therapies in the processes of senescence, apoptosis, autophagy, and the maintenance of cellular homeostasis cannot be denied. All data in this review support the idea that oxidative stress is an undesirable phenomenon in high and long-term concentrations, but regular exposure is consistent with the hormetic theory.
... The detailed mechanisms involved in this process include the quenching of free radicals and ROS, inhibiting lipid peroxidation, and regulating cell growth and apoptosis [65]. However, other studies did not observe any effects or even observed harmful effects after the use of carotenoid supplementation [79,80]. Many factors may account for these findings, such as the baseline characteristics of participants and carotenoid interactions. ...
Cancer is one of the greatest causes of death worldwide. With the development of surgery, radiotherapy, and medical agents, the outcomes of cancer patients have greatly improved. However, the underlying mechanisms of cancer are not yet fully understood. Recently, natural products have been proven to be beneficial for various conditions and have played important roles in the development of novel therapies. A substantial amount of evidence indicates that bioactive compounds could improve the outcomes of cancer patients via various pathways, such as endoplasmic reticulum stress, epigenetic modification, and modulation of oxidative stress. Here, we review the current evidence of bioactive compounds in natural products for the treatment of cancer and summarize the underlying mechanisms in this pathological process.
... Interestingly, some clinical studies using mineral supplements have not shown a strong relationship between isolated nutrients and the incidence of HNC; this may indicate that a single, isolated food ingredient will not produce the synergistic effect of the numerous chemopreventive compounds present in whole, natural, unprocessed foods. The use of concentrates containing the right proportion of fruit and vegetables in patients with HNC may be an alternative and sufficient intervention to increase the intake of CTDs, vitamins, minerals, and phytochemicals [18,19]. Chainani-Wu reports that vegetables contain high levels of micronutrients with anticancer properties, such as carotenes, lycopene, and other antioxidant vitamins; in some cases, the combination of several nutritious compounds increases their the clinical chemopreventive effect [174]. ...
Head and neck cancer (HNC) is one of the most common cancers in the world according to GLOBCAN. In 2018, it was reported that HNC accounts for approximately 3% of all human cancers (51,540 new cases) and is the cause of nearly 1.5% of all cancer deaths (10,030 deaths). Despite great advances in treatment, HNC is indicated as a leading cause of death worldwide. In addition to having a positive impact on general health, a diet rich in carotenoids can regulate stages in the course of carcinogenesis; indeed, strong epidemiological associations exist between dietary carotenoids and HNS, and it is presumed that diets with carotenoids can even reduce cancer risk. They have also been proposed as potential chemotherapeutic agents and substances used in chemoprevention of HNC. The present review discusses the links between dietary carotenoids and HNC. It examines the prospective anticancer effect of dietary carotenoids against intracellular cell signalling and mechanisms, oxidative stress regulation, as well as their impact on apoptosis, cell cycle progression, cell proliferation, angiogenesis, metastasis, and chemoprevention; it also provides an overview of the limited preclinical and clinical research published in this arena. Recent epidemiological, key opinion-forming systematic reviews, cross-sectional, longitudinal, prospective, and interventional studies based on in vitro and animal models of HNC also indicate that high carotenoid content obtained from daily supplementation has positive effects on the initiation, promotion, and progression of HNC. This article presents these results according to their increasing clinical credibility.
... Lin et al. [31] followed up 7627 women who were randomly assigned in the Women's Antioxidant Cardiovascular Study, a double-blind, placebo-controlled 2 × 2 × 2 factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of α-tocopherol every other day), and beta carotene (50 mg every other day) and were free of cancer before random assignment. The authors revealed that supplementation with vitamin C, vitamin E, or beta carotene offered no overall benefits in the primary prevention of total cancer incidence or mortality. ...
Vitamin C (L-ascorbic acid) works as a strong reductant, radical scavenger, and protector of cell membranes against primary peroxidative damage in tissues and in the extracellular fluid. L-ascorbic acid is involved in the synthesis of collagen and many other biologically relevant substances, enzyme activity, xenobiotic detoxification, and prevention of forming carcinogenic nitrosamines. It also plays a role in the immune system. Numerous data indicate that cancer patients suffer from vitamin C deficiency. Studies show that people with a low vitamin C intake have an increased risk of head and neck cancers as well as lung, gastric, pancreatic, cervical, rectal, or breast cancer. On the other hand, there is no clinical evidence to support the thesis that antioxidant supplements (including vitamin C) prevent cancer. Observational trials investigating high doses of intravenous L-ascorbic acid in previously treated cancer patients have shown that it allows an increase in quality of life and may improve physical, mental, and emotional functions, as well as reducing adverse effects of standard anticancer treatment, including fatigue, nausea, vomiting, and appetite loss. So far, there were a few randomized controlled trials and they have not reported any statistically significant improvements in the overall or progression-free survival with vitamin C, as compared to the control arm. However, preclinical data indicating a role of L-ascorbic acid in modulation of immune response and its involvement in epigenome remodeling suggest its new potential clinical applications in cancer patients, especially in combination with immunotherapy. It seems reasonable to further investigate the value of vitamin C as a supportive treatment or in combination with anticancer targeted therapy.
Fat-soluble vitamins have a pivotal role in in maintaining good vision and overall eye health. Profound importance of vitamin A in lowering risk of cataracts and age-related macular degeneration (ARMD) has been illustrated. Also, plausible role of fat-soluble vitamins in risk attenuation in cardiac diseases has been studied. This chapter also discusses the role of Vitamin D in the immune system and its potential impact on infectious diseases. It highlights that Vitamin D has a significant influence on both innate and adaptive immunity, affecting various immune cells. Vitamin D fosters immune tolerance by promoting regulatory T cells (Tregs) and suppresses inflammation by altering the type of T cells produced. It also enhances the function of immune cells like macrophages and dendritic cells. Moreover, Vitamin D is linked to infectious diseases, and there’s evidence suggesting it may play a role in combating conditions such as tuberculosis, respiratory infections, and influenza. However, randomized controlled trials have produced inconsistent results regarding the prophylactic use of Vitamin D for infectious diseases. The importance of avoiding Vitamin D toxicity has been discussed. Further research is needed to fully understand its role in infectious diseases. Finally, the chapter emphasizes the importance of informed decision-making when it comes to vitamin supplementation and dispelling common myths and misconceptions.
Introduction : Breast cancer is still the most common type of cancer, and surgery is still an alternative available. Postoperative care for breast cancer is an action that must be evaluated from a variety of perspectives. Methods : The information retrieval feature of the PubMed and Cambridge Core literature search engines was used to find review of literature articles for this journal. The periodicals on which the literature was predicated were obtained. Result Vitamin C has various functions in cases of breast cancer. A special review in this paper is in terms of wound healing and anti-pain modulation in postoperative breast cancer. The existence of this is considered significant and can be used as postoperative therapy. Conclusion : Vitamin C involvement in postoperative therapy for breast cancer is expected to have benefits in terms of wound healing as well as modulation of anti-pain interventions. Furthermore, vitamin C therapy is not permitted as an adjunctive treatment or to lower the risk of breast cancer or to inhibit post-surgical complications within those cases.
During normal metabolism, the body produces unstable molecules, the most common of which are the reactive oxygen species (ROS). Increased number of ROS, called oxidative stress, is capable to damage cells. To be able to combat the adverse effects of free radicals, human body triggers the massive production of different antioxidants or accelerates their intake from foods. Scientific studies have demonstrated that long intense exercise such as endurance training, may cause an overwhelming of body's antioxidant defenses, leading to excessive oxidative stress and harmful outcomes. On the other hand regular exercise in intensity and duration has a wide range of beneficial effects on the body, by producing healthy amounts of oxidative stress. Contrary to what is believed until now, oxidative stress is beneficial in small amounts. In fact it's essential, because prompts the body cells to become stronger over time by increasing antioxidants and thus provide protection against potential injury or cellular damage. The beneficial consequences of regular exercise and harmful outcomes of exhaustive exercise due to amount of ROS production fit well with the concept of hormesis. It states that exposure to a low dose of a noxious or toxic agent can bring about results believed beneficial to the long-term welfare of the organisms. According to literature, physical inactivity combined with poor nutrition, excessive smoking and alcohol consumption leads to impairment in physiological functions and reduces the whole body resistance to oxidative stress, and can be regarded as one of the end points of the exercise associated hormesis curve. Moreover, it seems that physical inactivity through molecular pathways could facilitate the incidence of oxidative stress-related diseases. Therefore it seems that the human being is not designed to be inactive for survival.
Context
β-Carotene, which is derived from most fruits and vegetables, is the most common type of carotenes. Existing studies have demonstrated that β-carotene is associated with some positive health outcomes. However, results about the effects of supplemental β-carotene on cancer are inconsistent.
Objective
To determine the association between supplemental β-carotene intake and the risk of cancers.
Data sources
Eight databases (PubMed, Web of Science, Embase, Cochrane, China National Knowledge Infrastructure, Wangfang, China Science and Technology Journal Database, and Chinese Biomedical Literature Database) were systematically searched until September 2022.
Data extraction
Only reports from randomized controlled trials in which an association between supplemental β-carotene intake and the risk of cancer was found were included in the meta-analysis.
Data analysis
A total of 18 eligible studies based on 8 different randomized controlled trials were included in the meta-analysis, with varying sample sizes from 391 to 39 876 participants. There was no significant association between supplemental β-carotene intake and overall cancer incidence rate after synthesizing all the results (risk ratio [RR]: 1.02; 95% confidence interval [CI], 0.99–1.05). Results from subgroup analysis indicated that intake of supplemental β-carotene significantly increased the risk of lung cancer (RR: 1.19; 95%CI: 1.08–1.32), whereas no significant associations were observed for other site-specific cancers. In addition, smokers and the subgroup of participants with only low-dose β-carotene intake had a risk increment of cancer if they took supplemental β-carotene (RR: 1.16; 95%CI: 1.05–1.29).
Conclusion
β-Carotene supplementation has no beneficial or harmful effect on cancer incidence; moreover, it might have potentially harmful effects on lung cancer, especially for people who smoke. On the basis of the evidence from this study, supplemental intake of β-carotene is not recommended for preventing cancer, and the establishment of a tolerable upper intake level of β-carotene should be considered.
Application of sustainable materials in the production of Smart Packaging (SPM) has recently garnered attention around the world. This is because of its ability to control the packaging system and then act on fresh foods to preserve quality and enhance their shelf-life. In this paper, two methods of SPM production using mechanical and biochemical approaches were reviewed. The mechanical approach is essentially the application of extrusion and injection molding techniques to form granules that are later transformed into sheets by casting into prepared molds. The biochemical approach involves the production of nanocomposites from a mixture of sustainable plant or animal products, like bamboo or keratin from chicken feathers, a starch and plasticizer to form the package. A novel SPM, that can provide protection from in-situ interference, was proposed for food preservation by incorporating Aerotolerant anaerobes, like Cutibacterium acnes, into the matrix of the package during production. This technique can enhance the performance of the SPMs to control the gas atmosphere within the packaging system.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Historically, sperm have been seen as simply a mechanism of transferring a haploid set of chromosomes to the oocyte. However, data from assisted reproduction therapies (ART) have demonstrated that in many couples the sperm appears to be responsible for abnormal embryogenesis. Recent advances in genetic and epigenetic techniques have identified key mechanisms by which the sperm, and the DNA carried by the sperm, can affect early embryonic development. Paternal Influences on Human Reproductive Success examines the genetic and epigenetic influences on embryogenesis, as well as practical clinical factors related to the male contribution to reproductive success. It also provides 'cutting edge' data and analysis of recent evaluations of the role of advanced paternal age, environmental influences and lifestyle factors on male reproductive fitness, making this an invaluable text for physicians treating patients for infertility, recurrent pregnancy loss, and developmental anomalies, as well as basic scientists studying embryogenesis and spermatogenesis.
Prevention strategies aim to change environmental and lifestyle risk factors that contribute to the development of cancer. Screening detects abnormalities before they become clinically apparent, allowing intervention either before cancer develops or at an early stage when treatment is most likely to be effective. Despite reliable data on factors that reduce the risk of neoplasms, in routine clinical practice, the effectiveness of cancer prevention is still not high enough. This determines the high importance of the topic of this review, which summarizes the current scientific data on risk factors for the development of oncopathology and ways to influence them. Such risk factors as lifestyle, alcohol and tobacco use, physical activity, nutrition and other environmental factors are considered. A large role is given to infections, which is also considered in this review. The article highlights the intake of vitamins and microelements for the purpose of cancer prevention, as well as the influence of certain drugs taken to treat non-oncological diseases on the development of oncopathology. The purpose of the review is to present an analysis of current literature data on the methods of cancer prevention.
Although a large number of observational studies suggest a beneficial role for antioxidants in different diseases, the data from intervention trials are still scarce and inconclusive. In this article we address the possible role of vitamins C and E in aging and in different conditions associated with oxidative stress. The data obtained through meta-analyses show that although both vitamins can reduce fasting blood glucose and HbA1c levels in metabolically compromised subjects, the effect is not clinically significant. In different situations, high doses of these antioxidants can blunt the positive effects of diet and exercise and their supplementation pose a greater risk of developing cancer. We can conclude that more studies are still necessary to generate evidence-based guidelines and that, in any case, an adequate intake of these molecules from the diet should be recommended to maintain an adequate antioxidant status for optimal health.
Background
Aging is a phenomenon universally involving all organisms, genetically determined, and epigenetically influenced by the environment. Numerous observational studies have shown the positive impact of non-pharmacological approaches started in younger age on chronic conditions affecting the elderly health and survival. This meta-analysis aimed to investigate the effect of beta-carotene on the total and cause-specific mortality as reported by randomized controlled trials (RCTs).
Methods
We searched Medline, Scopus, Web of Science, and CENTRAL Cochrane from inception to September 2021. Studies were eligible if enrolled adults with any health condition, compared beta-carotene supplements at any dose with placebo or no intervention, provided information on deaths from any cause, and were RCTs, in English. The risk of bias was assessed by the Cochrane risk of bias tool and the GRADE. Risk ratios and their 95% confidence intervals were used and a P -value less than 0.05 was considered statistically significant.
Results
Among 3,942 articles searched, 44 articles on 31 RCTs, which included 216,734 total subjects, 108,622 in beta-carotene supplement groups, and 108,112 in the placebo or no-intervention groups, were involved in the final analyses. In a random-effects meta-analysis of all 31 trials, beta-carotene supplements were found to have no preventive effect on mortality (risk ratio 1.02, 95% confidence interval 0.98–1.05, I ² = 42%). Further, the analysis showed no preventive effect on cancer, cardiovascular, cerebrovascular, and other mortality causes. Instead, beta-carotene supplementation significantly increased the risk of lung cancer mortality (RR 1.14, 95% CI 1.02, 1.27, I ² = 3%) but decreased the risk of human immunodeficiency virus-related mortality (RR 0.55, 95% CI 0.33, 0.92, I ² = 0).
Conclusion
More studies should be performed to better define the role of beta-carotene on survival, to confirm or deny our results. Therefore, the possible beneficial or harmful effects of the beta-carotene supplementation on mortality must not be overstated.
Systematic Review Registration
[ https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=259354 ], identifier [CRD42021259354].
Background:
The objective of this study was to update the association between multivitamin supplementation and total or cause-specific mortality in a population with a high prevalence of undernutrition in China.
Methods:
The Linxian Dysplasia Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial in which 3318 persons aged 40-69 years with esophageal squamous dysplasia were assigned to receive daily multivitamin supplementation or a placebo for 6 years and were followed for 29 years. The primary outcome was esophageal/gastric cardia cancer mortality. The data were analyzed with Cox proportional hazards regression models. Subgroup analyses were performed by common characteristics such as age and gender.
Results:
The cumulative total mortality was 83.5%. Multivitamin supplementation did not affect total or cause-specific mortality in the participants as a whole (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03). Subgroup analyses showed that no association between multivitamin supplementation and all-cause mortality was observed in men (HR, 0.90; 95% CI, 0.81-1.01), women (HR, 1.01; 95% CI, 0.91-1.12), younger participants (HR, 0.97; 95% CI, 0.87-1.08), or older participants (HR, 0.94; 95% CI, 0.85-1.04). Significant reductions in heart disease mortality (HR, 0.64; 95% CI, 0.47-0.87) and cerebrovascular disease mortality (HR, 0.74; 95% CI, 0.56-1.00) were seen in older men. In a subgroup of younger men and a subgroup of moderate or severe dysplasia, subjects receiving multivitamin supplementation had a lower risk of esophageal/cardia cancer mortality (HR for younger men, 0.76; 95% CI, 0.58-0.99; HR for moderate or severe dysplasia, 0.76; 95% CI, 0.58-1.00). No association between multivitamin supplementation and any cause-specific mortality was observed in a mild dysplasia population.
Conclusions:
Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial. In light of this and previous trials, multivitamin supplements should be used thoughtfully to improve health status of populations with esophageal squamous dysplasia.
Lay summary:
Multivitamin supplementation is common, yet its effect on mortality is unclear. The aim of this study was to update the long-term effects of multivitamin supplementation on total and cause-specific mortality during nearly 35 years of follow-up in the Linxian Dysplasia Nutrition Intervention Trial in China. Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial, and this indicates that multivitamin supplements should be used thoughtfully to improve health status.
This chapter covers metabolic syndrome, obesity and cancer risk, including epidemiology and pathophysiology of metabolic syndrome, obesity, cancer, hyperglycaemis, dyslipidaemia, hypertension, insulin resistance and metabolic syndrome in different cancer types.KeywordsMetabolic syndromeObesityCancer risk
Loss of E-cadherin (ECAD), often caused by epigenetic inactivation, is closely associated with tumor metastasis. However, how ECAD is regulated in response to oxidative stress during tumorigenesis is largely unknown. Here we identify RNF25 as a new E3 ligase of ECAD, whose activation by oxidative stress leads to ECAD protein degradation in hepatocellular carcinoma (HCC). Loss of ECAD activates YAP, which in turn promotes the transcription of RNF25, thus forming a positive feedback loop to sustain the ECAD downregulation. YAP activation mitigates oxidative stress in detached HCC cells by upregulating antioxidant genes, protecting detached HCC cells from ferroptosis, resulting in anoikis resistance. Mechanistically, we found that protein kinase A (PKA) senses oxidative stress by redox modification in its β catalytic subunit (PRKACB) at Cys200 and Cys344, which increases its kinase activity towards RNF25 phosphorylation at Ser450, facilitating RNF25-mediated degradation of ECAD. Moreover, RNF25 expression is associated with HCC metastasis and depletion of RNF25 is sufficient to diminish HCC invasion and metastasis in vitro and in vivo. Together, these results identify a dual role of RNF25 as a critical regulator of ECAD protein turnover, promoting both anoikis resistance and metastasis, and PKA is a necessary redox sensor to enable this process. Our study provides mechanistic insight into how tumor cells sense oxidative stress signals to spread while escaping cell death.
Oxidative stress can cause cancer. Our aim was to establish whether antioxidant supplements reduce the incidence of gastrointestinal cancer and mortality.
With the Cochrane Collaboration methodology, we reviewed all randomised trials comparing antioxidant supplements with placebo for prevention of gastrointestinal cancers. We searched electronic databases and reference lists (February, 2003). Outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were analysed with fixed-effect and random-effects model meta-analyses and were reported as relative risk with 95% CIs.
We identified 14 randomised trials (n=170,525). Trial quality was generally high. Heterogeneity of results was low to moderate. Neither the fixed-effect (relative risk 0.96, 95% CI 0.88-1.04) nor random-effects meta-analyses (0.90, 0.77-1.05) showed significant effects of supplementation with beta-carotene, vitamins A, C, E, and selenium (alone or in combination) versus placebo on oesophageal, gastric, colorectal, pancreatic, and liver cancer incidences. In seven high-quality trials (n=131727), the fixed-effect model showed that antioxidant significantly increased mortality (1.06, 1.02-1.10), unlike the random-effects meta-analysis (1.06, 0.98-1.15). Low-quality trials showed no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high-quality and low-quality trials was significant (Z=2.10, p=0.04 by test of interaction). beta-carotene and vitamin A (1.29, 1.14-1.45) and beta-carotene and vitamin E (1.10, 1.01-1.20) significantly increased mortality, whereas beta-carotene alone only tended to increase mortality (1.05, 0.99-1.11). In four trials (three with unclear or inadequate methodology), selenium showed significant beneficial effect on the incidence of gastrointestinal cancer.
We could not find evidence that antioxidant supplements can prevent gastrointestinal cancers; on the contrary, they seem to increase overall mortality. The potential preventive effect of selenium should be studied in adequate randomised trials.
Dietary factors are thought to have an important role in gastric and esophageal carcinogenesis, but evidence from cohort studies for such a role is lacking. We examined the risks of gastric cancer and esophageal adenocarcinoma associated with meat consumption within the European Prospective Investigation Into Cancer and Nutrition (EPIC) cohort.
Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders.
We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo.
A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years.
After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Vitamin C is marketed as a dietary supplement, partly because of its `antioxidant' properties. However, we report here that vitamin C administered as a dietary supplement to healthy humans exhibits a pro-oxidant, as well as an antioxidant, effect in vivo.
Increased reactive oxygen species generation by the leukocytes of the obese may be responsible for increased oxidative injury to lipids and proteins and, hence, atherosclerosis. We have investigated whether reactive oxygen species generation by leukocytes and other indexes of oxidative damage in the body fall with short-term dietary restriction and weight loss. Nine nondiabetic obese subjects (body mass index, 32.5-64.4 kg/m(2)), not taking any antioxidants, were put on a 1000-Cal diet. Fasting blood samples were taken at 0, 1, 2, 3, and 4 weeks and at 12 weeks after the cessation of dietary restriction. Blood samples were also obtained at 1 and 2 h after administration of 75 g oral glucose at 0 and 4 weeks. Mononuclear cells (MNC) and polymorphonuclear leukocytes (PMN) were isolated, and reactive oxygen species generation was measured. Plasma concentrations of thiobarbituric acid-reactive species (TBARS), 13-hydroxyoctadecadienoic acid (13-HODE), 9-hydroxyoctadecadienoic acid (9-HODE), carbonylated proteins, o-tyrosine, and m-tyrosine as indexes of oxidative damage to lipids, proteins and amino acids, respectively, were measured. Antioxidant vitamins were measured as indexes of antioxidant reserves. Plasma tumor necrosis factor-alpha concentrations were also measured. Mean weight loss was 2.4 +/- 0.6 kg at week 1, 2.5 +/- 1.7 kg at week 2, 3.9 +/- 0.8 kg at week 3, and 4.5 +/- 2.8 kg at week 4 (P < 0.05). Reactive oxygen species generation by PMN fell from 236.4 +/- 95.8 to 150.9 +/- 69.0, 125.9 +/- 24.3, 96.0 +/- 39.9, and 103.1 +/- 35.7 mV at weeks 1, 2, 3, and 4, respectively (P < 0.001). It increased 3 months after the cessation of dietary restriction to 270.0 +/- 274.3 mV. Reactive oxygen species generation by MNC fell from 187.8 +/- 75.0 to 101.7 +/- 64.5, 86.9 +/- 42.8, 63.8 +/- 14.3, and 75.1 +/- 32.2 mV and increased thereafter to 302.0 +/- 175.5 mV at 1, 2, 3, 4, and 16 weeks, respectively (P < 0.005). Reactive oxygen species generation by PMN and MNC increased in response to glucose; the relative increase was greater at 4 weeks than that at week 0 due to a fall in the basal levels of reactive oxygen species generation. Consistent with the fall in reactive oxygen species generation, there was a reduction in plasma TBARS from 1.68 +/- 0.17 micromol/L at week 0 to 1.47 micromol/L at 4 weeks (P < 0.05). The 13-HODE to linoleic acid ratio fell from a baseline of 100% to 56.4 +/- 36.1% at 4 weeks (P < 0.05), and the 9-HODE to linoleic acid ratio fell from a baseline of 100% to 60.5 +/- 37.7% at 4 weeks (P < 0.05). Carbonylated proteins fell from 1.39 +/- 0.27 microgram/mg protein at week 0 to 1.17 +/- 0.12 microgram/mg protein at week 4 (P < 0.05); o-tyrosine fell from 0.42 +/- 0.03 mmol/mol phenylalanine at week 0 to 0.36 +/- 0.02 mmol/mol phenylalanine at 4 weeks (P < 0.005), and m-tyrosine fell from 0.45 +/- 0.04 mmol/mol phenylalanine at week 0 to 0.40 +/- 0.03 mmol/mol phenylalanine at 4 weeks (P < 0.05). The basal concentrations of TBARS, 9-HODE, 13-HODE, carbonylated proteins, o-tyrosine, and m-tyrosine in the obese were significantly greater than those in normal subjects. On the other hand, tumor necrosis factor-alpha concentrations did not change during this 4-week period, nor was there any change in antioxidant vitamins. This is the first demonstration of 1) an increase in reactive oxygen species-induced damage in lipids, proteins, and amino acids in the obese compared with normal subjects; and 2) a decrease in reactive oxygen species generation by leukocytes and oxidative damage to lipids, proteins, and amino acids after dietary restriction and weight loss in the obese over a short period.
Case-control studies have suggested that a diet rich in fresh fruit and vegetables protects from the risk of most common epithelial cancers, including those of the digestive tract, and also several nondigestive neoplasms; however, selections in cohort studies have been generally weaker.
To review the relation between frequency of consumption of vegetables and fruit, estimated intake of selected antioxidants and the risk of cancer at different sites.
Systematic overview of data, with specific focus on a network of case-control studies conducted in Italy from 1983 to 1999.
The relative risks (RR) of digestive tract neoplasms were reduced in subjects reporting highest vegetable intake. A protective effect of vegetables was also observed for hormone-related neoplasms. Fruit was related to a reduced RR of cancers of the upper digestive tract, stomach and urinary tract. With reference to the role of selected antioxidants, beta-carotene, vitamins C and E showed a significant inverse relation with oral and pharyngeal, esophageal and breast cancer risk. Against colorectal cancer, the most consistent protective effects were provided by carotene, riboflavin and vitamin C, but inverse relations were observed also for calcium and vitamin D.
Fruit and vegetable consumption in Mediterranean populations appears to provide protection against several types of neoplasms.
Intakes of vitamins A, C, and E, folate, and carotenoids have been hypothesized to reduce the risk of breast cancer. However, previous epidemiological studies on these nutrients and breast cancer risk have been inconclusive, and have included primarily postmenopausal women. We examined the intake of these nutrients in relation to breast cancer risk among 90,655 premenopausal women ages 26-46 years in 1991 in the Nurses' Health Study II. Nutrient intake was assessed with a validated food-frequency questionnaire at baseline in 1991 and in 1995. During 8 years of follow-up from 1991 to 1999, we documented 714 incident cases of invasive breast cancer. Overall, none of the vitamins and carotenoids was strongly related to a reduced risk of breast cancer. However, intake of vitamin A, including preformed vitamin A and carotenoids, was associated with a reduced risk of breast cancer among smokers; participants in the highest quintile of total vitamin A intake had a multivariate relative risk of 0.28 (95% confidence interval 0.12-0.62; P, test for trend <0.001; P, test for interaction <0.001) compared with those in the lowest quintile of intake. We found no evidence that higher intakes of vitamins C and E, and folate in early adult life reduce risk of breast cancer. However, intake of vitamin A may be related to a reduced risk of breast cancer among smokers.
Several studies have reported that even a moderate daily dose of supplementary vitamin C (200 mg) induces the formation of genotoxins from lipid hydroperoxides, thereby resulting in DNA damage and initiation of carcinogenesis. However, other reports questioned the experimental designs used and suggested that the chemopreventive effects of vitamin C may be linked to the inhibition of tumor promotion as well as to the blocking of tumor initiation. In this article, we discuss issues of contention and some controversies related to the potential chemopreventive effects of vitamin C in carcinogenesis.
The British Nutrition Foundation was recently commissioned by the Food Standards Agency to conduct a review of the government's research programme on Antioxidants in Food. Part of this work involved an independent review of the scientific literature on the role of antioxidants in chronic disease prevention, which is presented in this paper.
There is consistent evidence that diets rich in fruit and vegetables and other plant foods are associated with moderately lower overall mortality rates and lower death rates from cardiovascular disease and some types of cancer. The 'antioxidant hypothesis' proposes that vitamin C, vitamin E, carotenoids and other antioxidant nutrients afford protection against chronic diseases by decreasing oxidative damage.
Although scientific rationale and observational studies have been convincing, randomised primary and secondary intervention trials have failed to show any consistent benefit from the use of antioxidant supplements on cardiovascular disease or cancer risk, with some trials even suggesting possible harm in certain subgroups. These trials have usually involved the administration of single antioxidant nutrients given at relatively high doses. The results of trials investigating the effect of a balanced combination of antioxidants at levels achievable by diet are awaited.
The suggestion that antioxidant supplements can prevent chronic diseases has not been proved or consistently supported by the findings of published intervention trials. Further evidence regarding the efficacy, safety and appropriate dosage of antioxidants in relation to chronic disease is needed. The most prudent public health advice remains to increase the consumption of plant foods, as such dietary patterns are associated with reduced risk of chronic disease.
The effects of vitamin C (ascorbic acid), vitamin E (alpha-tocopherol), and beta-carotene as antioxidants and their cooperative action against the oxidation of lipid in solution, membranes, and lipoproteins have been studied and reviewed. Ascorbic acid and alpha-tocopherol act as potent, and probably the most important, hydrophilic and lipophilic antioxidants, respectively. They function at their own site individually and furthermore act synergistically. beta-Carotene has lower reactivity toward radicals than does alpha-tocopherol and acts as a weak antioxidant in solution. It is more lipophilic than alpha-tocopherol and is assumed to be present at the interior of membranes or lipoproteins, which enables it to scavenge radicals within the lipophilic compartment more efficiently than does alpha-tocopherol. The cooperative interaction between vitamin C and vitamin E may be quite probable, that of vitamin C and beta-carotene is improbable, whereas that between vitamin E and beta-carotene may be possible.
OBJECTIVE: To estimate the association between antioxidant use and primary cancer incidence and mortality and to evaluate these effects across specific antioxidant compounds, target organs, and participant subgroups. METHODS: Multiple electronic databases (MEDLINE, Cochrane Controlled Clinical Trials Register, EMBASE, Science Citation Index) were searched from their dates of inception until August 2005 to identify eligible randomized clinical trials. Random effects meta-analyses estimated pooled relative risks (RRs) and 95% confidence intervals (CIs) that described the effect of antioxidants vs placebo on cancer incidence and cancer mortality. RESULTS: Twelve eligible trials, 9 of high methodological quality, were identified (total subject population, 104,196). Antioxidant supplementation did not significantly reduce total cancer incidence (IRR, 0.99; 95% CI, 0.94-1.04) or mortality (RR, 1.03; 95% CI, 0.92-1.15) or any site-specific cancer incidence. Beta carotene supplementation was associated with an increase in the incidence of cancer among smokers (RR, 1.10; 95% CI, 1.03-1.10) and with a trend toward increased cancer mortality (RR, 1.16; 95% CI, 0.98-1.37). Selenium supplementation was associated with reduced cancer incidence in men (RR, 0.77; 95% CI, 0.64-0.92) but not in women (IRR, 1.00; 95% CI, 0.89-1.13, value for interaction, P<.001) and with reduced cancer mortality (RR, 0.78; 95% CI, 0.65-0.94). Vitamin E supplementation had no apparent effect on overall cancer incidence (RR, 0.99; 95% CI, 0.941.04) or cancer mortality (RR, 1.04; 95% CI, 0.97-1.12). CONCLUSION: Beta carotene supplementation appeared to increase cancer incidence and cancer mortality among smokers, whereas vitamin E supplementation had no effect. Selenium supplementation might have anticarcinogenic effects in men and thus requires further research.
Several studies have reported that even a moderate daily dose of supplementary vitamin C (200 mg) induces the formation of genotoxins from lipid hydroperoxides, thereby resulting in DNA damage and initiation of carcinogenesis. However, other reports questioned the experimental designs used and suggested that the chemopreventive effects of vitamin C may be linked to the inhibition of tumor promotion as well as to the blocking of tumor initiation. In this article, we discuss issues of contention and some controversies related to the potential chemopreventive effects of vitamin C in carcinogenesis.
It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes. METHODS: 20,536 UK adults (aged 40-80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. FINDINGS: There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo-allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non-vascular (568 [5.5%] vs 549 [5.3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10.4%] vs 1047 [10.2%]), non-fatal or fatal stroke (511 [5.0%] vs 518 [5.0%]), or coronary or non-coronary revascularisation (1058 [10.3%] vs 1086 [10.6%]). For the first occurrence of any of these "major vascular events", there were no material differences either overall (2306 [22.5%] vs 2312 [22.5%]; event rate ratio 1.00 [95% CI 0.94-1.06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause. INTERPRETATION: Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.
Background There is conflicting evidence on the benefits of foods rich in vitamin E (alpha-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction. Methods From October, 1993, to September, 1995, 11324 patients surviving recent (less than or equal to 3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (Ig daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). Findings Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relative risk decrease 10% [95% CI 1-18] by two-way analysis, 15% [2-26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3-24] two-way, 20% [6-33] four-way) and cardiovascular death (17% [3-29] two-way, 30% [13-44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1-26]) and for fatal events (20% [5-33]). Interpretation Dietary supplementation with n-3 PUFA led to a clinically important and satistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.
Background. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. Methods. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. Results. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha- tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. Conclusions. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
Background:
It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes.
Methods:
20,536 UK adults (aged 40-80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.
Findings:
There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo-allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non-vascular (568 [5.5%] vs 549 [5.3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10.4%] vs 1047 [10.2%]), non-fatal or fatal stroke (511 [5.0%] vs 518 [5.0%]), or coronary or non-coronary revascularisation (1058 [10.3%] vs 1086 [10.6%]). For the first occurrence of any of these "major vascular events", there were no material differences either overall (2306 [22.5%] vs 2312 [22.5%]; event rate ratio 1.00 [95% CI 0.94-1.06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause.
Interpretation:
Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.
Objective.
—To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.Design.
—A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.Setting.
—Seven dermatology clinics in the eastern United States.Patients.
—A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.Interventions.
—Oral administration of 200 μg of selenium per day or placebo.Main Outcome Measures.
—The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.Results.
—After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR, 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.Conclusions.
—Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.
Aspirin is known to be effective in treatment of acute myocardial infarction and in secondary prevention of cardiovascular disease in both men and women (BMJ 2002;324:71–86). In addition, trials have indicated that low-dose aspirin is effective in primary prevention of myocardial infarction in men without a significant effect on ischemic stroke. There are, however, few data with respect to aspirin use and primary prevention of cardiovascular disease in women. In this article, 39,876 women 45 years of age or older and considered healthy at study entrance were randomized to receive 100 mg of aspirin or placebo on alternate days. They were followed up for 10 years for a first major cardiovascular event (death from cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke). In follow-up, there were 477 major cardiovascular events in the aspirin group and 522 in the placebo group. This 9% reduction in risk with aspirin was not significant (relative risk [RR], 0.91; 95% confidence interval [CI], 0.80–1.03; P = .13). There was a 17% reduction in risk of stroke in the aspirin patients vs those treated with placebo (RR, 0.83; 95% CI, 0.69–0.99; P = .04). This resulted from a 24% reduction in risk of ischemic stroke (RR, 0.76; 95% CI, 0.63–0.93; P = .009). There was a nonsignificant increase in risk of hemorrhagic stroke in the aspirin group (RR, 1.24; 95% CI, 0.82–1.87; P = .31). Aspirin had no significant effect on risk of fatal or nonfatal myocardial infarction. Gastrointestinal bleeding leading to transfusion was more frequent in the aspirin than in the placebo group (RR, 1.40; 95% CI, 1.07–1.83; P = .02). Subgroup analysis indicated that the most consistent benefit for aspirin occurred in women 65 years of age or older at study entry. In these women, the risk of major cardiovascular events was reduced by 26% in the aspirin group (P = .008), and the risk of ischemic stroke was reduced by 30% (P = .05). Also, myocardial infarction was decreased by aspirin use (P = .04).
Background:Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and β-carotene might be associated with reduced risk of colorectal cancer.
Methods:We tested the effects of α-tocopherol and β-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50–69-year-old male cigarette smokers. Participants were randomly assigned to receive α-tocopherol (50 mg), β-carotene (20 mg), both agents, or a placebo daily for 5–8 years. Incident colorectal cancers (n = 135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models.
Results:Colorectal cancer incidence was somewhat lower in the α-tocopherol arm compared to the no α-tocopherol arm, but this finding was not statistically significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55–1.09; log-rank test p = 0.15). β-Carotene had no effect on colorectal cancer incidence (RR=1.05, 95% CI 0.75–1.47; log-rank test p = 0.78). There was no interaction between the two substances.
Conclusion:Our study found no evidence of a beneficial or harmful effect for β-carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.
Despite convincing in vitro evidence, a vitamin C–E interaction has not been confirmed in vivo. This study was designed to examine the effects of supplementation with either vitamin C or E on their respective plasma concentrations, other antioxidants, lipids and some haemostatic variables. Fasting blood was collected before and after intervention from thirty healthy adults in a double-blinded crossover study. Baselines for measured variables were established after 2 weeks of placebo supplementation, followed by daily supplementation with 73·5 mg RRR-α-tocopherol acetate or 500 mg ascorbic acid, and placebo, for 6 weeks. A 2 month washout preceded supplement crossover. Mean values showed that plasma lipid standardised α-tocopherol increased with ascorbic acid supplementation: from 4·09 (SEM 0·51) TO 4·53 (sem 0·66) μmol/mmol total cholesterol plus triacylglycerol (P < 0·05), and plasma ascorbic acid increased from 62·8 (sem 14·9) to 101·3 (sem 22·2) μmol/l (P < 0·005). Supplementation with (RRR)-α-tocopherol acetate increased plasma α-tocopherol from 26·8 (sem 3·9) to 32·2 (sem 3·8) μmol/l (P < 0·05), and lipid-standardised α-tocopherol from 4·12 (sem 0·48) to 5·38 (sem 0·52) μmol/mmol (P < 0·001). Mean plasma ascorbic acid also increased with vitamin E supplementation, from 64·4 (sem 13·3) to 76·4 (sem 18·4) μmol/l (P < 0·05). Plasma ferric reducing (antioxidant) power and glutathione peroxidase (U/g haemoglobin) increased in both groups, while urate, total cholesterol and triacylglycerol levels decreased (P < 0·05 throughout). Results are supportive of an in vivo interaction between vitamins C and E.
On page 845 in the first paragraph of the “All Randomized Trials” subsection, the sentence that read “Heterogeneity was not significant (I²=18.6%, P=.10)” should have read “Heterogeneity was significant (I²=18.9%, P=.10).” In the following sentence that begins “Adjusted-rank correlation test (P=.08), but not the regression asymmetry test (P=.26), suggested the bias among trials,” the respective P values should have read “(P=.09)” and “(P=.24).” In the second paragraph of the same subsection, the portion of the sentence that begins on page 845: “Univariate meta-regression analyses revealed significant influences of dose of beta carotene (RR, 1.004; 95% CI, 1.001-1.007; P=.012),” the P value should have been equal to “.014.” In the latter part of the same sentence that falls on page 847, the P value for the dose of selenium that read “P=.002” should have read “P=.001.” In the following part of the sentence, the upper confidence limit that read “1.29” should have read “1.30.” In the third paragraph of the same subsection, on page 847, the P value for the “multivariate meta-regression” for dose of selenium that read “P=.005” should have read “P=.004,” the lower confidence limit for low-bias risk trials that read “1.05” should have read “1.04,” and the P value for the low-bias risk trials in the same sentence that read “P=.005” should have read “P=.006.”
In Table 5 on page 853, the RR (95% CI) in the “Beta carotene given singly” row that read “1.06 (1.01-1.11)” should have read “1.05 (1.00-1.11)” and the I² value that read “5.4” should have read “11.8.” In the “Beta carotene given in combination with other antioxidant supplements” row, the I² value that read “55.6” should have read “55.5.” In the “Beta carotene given singly or in combination with other antioxidant supplements” row, the CI range that read “(0.96-1.08)” should have read “(0.95-1.07)” and the I2 value that read “52.2” should have read “52.5.” In the “Beta carotene given singly or in combination with other antioxidant supplements after exclusion of high-bias risk and selenium trials” row, the I² value that read 36.8” should have read “34.4” In the “Vitamin E given singly” row, the number of study participants that read “47 007” should have read “41 341.” In the “Vitamin E given in combination with other antioxidant supplements” row, the RR that read “1.01” should have read “1.00” and the I² value that read “17.2” should have read “16.9.” In the “Vitamin E given singly or in combination with other antioxidant supplements” row, the I²value that read “2.8” should have read “2.4.” In the “Vitamin E given singly or in combination with other antioxidant supplements after exclusion of high-bias risk and selenium trials” row, the list of references should have included reference 87 and excluded 95.
Objective:
To evaluate the evidence of the supplements vitamin C and vitamin E for treatment and prevention of cancer.
Methods:
Systematic review of trials and meta-analysis. DATA SOURCES AND MAIN RESULTS: Thirty-eight studies showed scant evidence that vitamin C or vitamin E beneficially affects survival. In the ATBC Cancer Prevention Study Group, no statistically significant effect of treatment was seen for any cancer individually, and our pooled relative risk (regardless of tumor type) for alpha-tocopherol alone was 0.91 (95% confidence interval [CI]: 0.74, 1.12). All cause mortality was not significant. In the Linxian General Population Trial, the relative risks for cancer death for vitamin C (combined with molybdenum) was 1.06 (95% CI: 0.92, 1.21) and for vitamin E (combined with beta-carotene and selenium) was 0.87 (95% CI: 0.76, 1.00). We identified only 3 studies that reported statistically significant beneficial results: vitamin C (in combination with BCG) was found to be beneficial in a single trial of bladder cancer and vitamin E (in combination with omega-3 fatty acid) increased survival in patients with advanced cancer. In the ATBC trial, in analyses of 6 individual cancers, the prevention of prostate cancer in subjects treated with alpha-tocopherol was statistically significant (RR=0.64, 95% CI: 0.44, 0.94).
Conclusions:
The systematic review of the literature does not support the hypothesis that the use of supplements of vitamin C or vitamin E in the doses tested helps prevent and/or treat cancer in the populations tested. There were isolated findings of benefit, which require confirmation.
The effects of co-supplementing healthy volunteers with iron (14 mg/day ferrous sulphate) and vitamin C (either 60 mg/day or 260 mg/day as ascorbic acid) on levels of oxidative DNA damage in white blood cells were studied. The subjects were divided into two groups: one group of 20 volunteers with a higher mean initial level of plasma vitamin C (71.9 ± 14.0 μmol/l) and a second group of 18 volunteers with a lower mean level (50.4 ± 25.8 μmol/l). In the first group there was a significant rise in several oxidative DNA base damage products and in total oxidative DNA damage in DNA extracted from white blood cells, but not in 8-hydroxyguanine, after 6 weeks of supplementation. However, after 12 weeks levels returned approximately to normal. In the group with the lower initial level of plasma ascorbate, presupplemental levels of oxidative DNA damage were higher and decreased on supplementation with iron and ascorbate. Since oxidative DNA damage has been suggested as a risk factor for the development of cancer, the implications of increased levels in well-nourished subjects after iron/ascobate supplementation are disturbing in view of the frequent use of dietary supplements containing both iron salts and ascorbate.
Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality.
To perform a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials.
135,967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d).
PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and meta-analyses. No language restrictions were applied.
3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available.
9 of 11 trials testing high-dosage vitamin E (> or =400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons (95% CI, 3 to 74 per 10,000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was -16 per 10,000 persons (CI, -41 to 10 per 10,000 persons; P > 0.2). A dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d.
High-dosage (> or =400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult.
High-dosage (> or =400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.
The evidence on whether antioxidant supplements prevent gastrointestinal cancers is contradictory.
To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.
Using the Cochrane Collaboration methodology, we reviewed the randomized trials comparing antioxidant supplements with placebo or no intervention on the occurrence of gastrointestinal cancers. We searched electronic databases and reference lists until October, 2007. Our outcome measures were gastrointestinal cancers, overall mortality and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence intervals (CI) based on random-effects and fixed-effect models meta-analyses.
We identified 20 randomized trials (211,818 participants) assessing beta-carotene, vitamin A, vitamin C, vitamin E, and selenium. The trial quality was generally high. The antioxidant supplements were without a significant effect on the occurrence of gastrointestinal cancers (RR 0.94, 95% CI 0.83-1.06, I(2) = 54.0%). The heterogeneity seemed to be explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96-1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43-0.80, test of interaction P < 0.0005) and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). Antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97-1.07, I(2) = 53.5%) but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02-1.07).
We could not find evidence that the studied antioxidant supplements prevented gastrointestinal cancers. On the contrary, they seem to increase overall mortality.
The main human cancers are associated with complex life-style related causative, enhancing, and inhibiting factors. Tobacco smoking or chewing exposes humans to genotoxic carcinogens and to promoting substances. Likewise, Western dietary traditions involve certain carcinogens and promoters, whereas Oriental traditions implicate other carcinogens and promoters. Importantly, in virtually all situations regular intake of fruits and vegetables appreciably lowers the risk of cancer. This paper reviews the causes of the main human cancers and analyzes the mechanisms of the protective effects of fruits and vegetables. Prevention of human cancer requires the definition of optimal levels of recommended daily allowances of micronutrients.
The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens.
Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a
major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be
related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body's
defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing
such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.
The effects of vitamin C (ascorbic acid), vitamin E (alpha-tocopherol), and beta-carotene as antioxidants and their cooperative action against the oxidation of lipid in solution, membranes, and lipoproteins have been studied and reviewed. Ascorbic acid and alpha-tocopherol act as potent, and probably the most important, hydrophilic and lipophilic antioxidants, respectively. They function at their own site individually and furthermore act synergistically. beta-Carotene has lower reactivity toward radicals than does alpha-tocopherol and acts as a weak antioxidant in solution. It is more lipophilic than alpha-tocopherol and is assumed to be present at the interior of membranes or lipoproteins, which enables it to scavenge radicals within the lipophilic compartment more efficiently than does alpha-tocopherol. The cooperative interaction between vitamin C and vitamin E may be quite probable, that of vitamin C and beta-carotene is improbable, whereas that between vitamin E and beta-carotene may be possible.
Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers, including cancers of the esophagus and stomach. Vitamins and minerals in these foods may contribute to the reduced cancer risk. The people of Linxian County, China, have one of the world's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients.
We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian.
Individuals of ages 40-69 were recruited in 1985 from four Linxian communes. Mortality and cancer incidence during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period. The subjects were randomly assigned to intervention groups according to a one-half replicate of a 2(4) factorial experimental design. This design enabled testing for the effects of four combinations of nutrients: (A) retinol and zinc; (B) riboflavin and niacin; (C) vitamin C and molybdenum; and (D) beta carotene, vitamin E, and selenium. Doses ranged from one to two times U.S. Recommended Daily Allowances.
A total of 2127 deaths occurred among trial participants during the intervention period. Cancer was the leading cause of death, with 32% of all deaths due to esophageal or stomach cancer, followed by cerebrovascular disease (25%). Significantly (P = .03) lower total mortality (relative risk [RR] = 0.91; 95% confidence interval [CI] = 0.84-0.99) occurred among those receiving supplementation with beta carotene, vitamin E, and selenium. The reduction was mainly due to lower cancer rates (RR = 0.87; 95% CI = 0.75-1.00), especially stomach cancer (RR = 0.79; 95% CI = 0.64-0.99), with the reduced risk beginning to arise about 1-2 years after the start of supplementation with these vitamins and minerals. No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc, riboflavin and niacin, or vitamin C and molybdenum. Patterns of cancer incidence, on the basis of 1298 cases, generally resembled those for cancer mortality.
The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults, particularly with the combination of beta carotene, vitamin E, and selenium, may effect a reduction in cancer risk in this population.
The results on their own are not definitive, but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements.
Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation.
In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene.
Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points.
In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.
OBJECTIVE AND CONCLUSIONS: This article gives an overview of observational and experimental epidemiological studies relating beta-carotene to risk of cancer and cardiovascular disease. Observational epidemiological studies have consistently shown that a diet rich in beta-carotene-rich fruits and vegetables or high blood levels of beta-carotene are associated with a reduced risk of cancer at a number of common sites, such as lung and stomach. For other cancer sites, such as prostate and breast, the observational evidence is not very consistent or absent altogether. For cardiovascular disease, observational studies are less numerous but do point to a protective effect of high beta-carotene intake. The associations from observational epidemiology may indeed be ascribed to beta-carotene, since a number of plausible preventive mechanisms have been demonstrated for cancer as well as cardiovascular disease. However, observational epidemiology cannot resolve the question whether other constituents from fruits and vegetables or other factors may explain the findings from the case-control and cohort studies. The results of intervention studies undertaken so far are disappointing and do not indicate a preventive potential for beta-carotene. Further intervention trials with longer follow-up may be needed to elucidate whether beta-carotene is protective against certain forms of cancer and against cardiovascular disease.
Free radical-induced oxidative damage is thought to be involved in the pathogenesis of diseases associated with cigarette smoking. We examined the production of 8-epi-prostaglandin (PG) F2 alpha, a stable product of lipid peroxidation in vivo, and its modulation by aspirin and antioxidant vitamins in chronic cigarette smokers.
We performed the following studies: (1) a cross-sectional comparison of smokers and control subjects, (2) an examination of the dose-response relationship, (3) an exploration of the effect of smoking cessation (3 weeks) and nicotine patch supplementation, (4) the effect of aspirin consumption, and (5) the effects of 5 days' dosing with vitamin E (100 and 800 U), vitamin C (2 g), and their combination. 8-epi-PGF2 alpha excretion (in pmol/mmol, mean +/- SEM) was 176.5+/-30.6 in heavy smokers, 92.7+/-4.8 (P<.05) in moderate smokers, and 54.1+/-2.7 (P<.005) in nonsmokers. Urinary levels fell from 145.5+/-24.9 to 114.6+/-27.1 (week 2, P<.05) and 112.6+/-24.9 (week 3, P<.05) on cessation of smoking. Aspirin treatment failed to suppress urinary levels of 8-epi-PGF2 alpha despite a significant reduction in urinary 11-dehydro-TxB2 production and suppression of 8-epi-PGF2 alpha and TxB2 in serum. Vitamin C (pre, 194.6+/-40.9; post, 137.2+/-34.1; P<.05) and a combination of vitamin C and E (pre, 171.0+/-39.8; post, 133.5+/-29.6 P<.05) suppressed urinary 8-epi-PGF2 alpha, whereas vitamin E alone had no effect.
Urinary 8-epi-PGF2 alpha may represent a noninvasive, quantitative index of oxidant stress in vivo. Elevated levels of 8-epi-PGF2 alpha in smokers may be modulated by quitting cigarettes and switching to nicotine patches or by antioxidant vitamin therapy.
To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.
A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.
Seven dermatology clinics in the eastern United States.
A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.
Oral administration of 200 microg of selenium per day or placebo.
The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.
After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.
Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made
The present study was designed to investigate whether acute ethanol intoxication increases the production of active oxidants, and subsequently promotes apoptosis of hepatocytes. Hepatocytes were isolated from male Wistar rats, and cultured in the presence or absence of ethanol. The fluorescence in situ nick end labeling method and an enzyme-linked immunosorbent assay (ELISA) system to quantify fragmented DNA were used to estimate apoptotic change in hepatocytes. Nuclear morphological alterations and membrane barrier dysfunction of hepatocytes were assessed by staining with Hoechst 33342 and propidium iodide (PI). Intracellular glutathione level was determined as the fluorescence of monochlorobimane (MCLB), which forms conjugate with glutathione to become fluorescent. Ethanol (100 mmol/L) increased the amount of fragmented DNA and the number of apoptotic hepatocytes in vivo as well as in vitro. These ethanol-induced alterations in hepatocytes were attenuated by simultaneous incubation with either 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, or dimethylthiourea, an intracellular oxidant scavenger. Diethyl maleic acid (DMA), a glutathione depletor, enhanced the induction of apoptotic change, and decreased membrane barrier function in ethanol-treated hepatocytes, whereas ethanol per se did not increase the number of PI-positive hepatocytes. Furthermore, combination of ethanol and DMA but not ethanol alone decreased the hepatocyte MCLB fluorescence. Taken together, the present study suggests that active oxidants produced during ethanol metabolism mediate fragmentation of DNA in hepatocytes, and that intracellular antioxidants such as glutathione play a critical role in the cytoprotective mechanisms of hepatocyte against lethal cell death, ie, apoptosis, induced by ethanol.
In observational studies, individuals with high intakes of fruits and vegetables containing beta-carotene experience lower risks of developing cancer. However, the few randomized trials of beta-carotene supplementation show no overall benefits; some even suggest harm. This trial was designed to test the effects of beta-carotene supplementation in women.
The Women's Health Study is a randomized, double-blind, placebo-controlled trial originally testing aspirin, vitamin E, and beta-carotene in the prevention of cancer and cardiovascular disease among 39 876 women aged 45 years or older. The beta-carotene component was terminated early after a median treatment duration of 2.1 years (range = 0.00-2. 72 years). Statistical tests were two-sided.
Among women randomly assigned to receive beta-carotene (50 mg on alternate days; n = 19 939) or placebo (n =19 937), there were no statistically significant differences in incidence of cancer, cardiovascular disease, or total mortality after a median of 4.1 years (2.1 years' treatment plus another 2.0 years' follow-up). There were 378 cancers in the beta-carotene group and 369 cancers in the placebo group (relative risk [RR] = 1.03; 95% confidence interval [CI] = 0.89-1. 18). There were no statistically significant differences for any site-specific cancer or during years 1 and 2 combined and years 3 and up combined. For cardiovascular disease, there were no statistically significant differences for myocardial infarction (42 in the beta-carotene group versus 50 in the placebo group), stroke (61 versus 43), deaths from cardiovascular causes (14 versus 12), or the combined end point of these three events (116 versus 102; among women with more than one event, only the first was counted). Deaths from any cause were similar in the two groups (59 versus 55). Among smokers at baseline (13% of all women), there were no statistically significant differences in overall incidence of cancer (RR = 1.11; 95% CI = 0.78-1.58) or cardiovascular disease (RR = 1.01; 95% CI = 0. 62-1.63).
Among apparently healthy women, there was no benefit or harm from beta-carotene supplementation for a limited period on the incidence of cancer and of cardiovascular disease.
A meta-analysis was carried out, in order to summarise published data on the relationship between breast cancer, fruit and vegetable consumption and/or the intake of beta-carotene and vitamin C. Relative risks were extracted from 26 published studies from 1982 to 1997. Random and fixed effects models were used. Between studies, heterogeneity was found for vegetables, fruit, vitamin C but not for beta-carotene. Summary relative risk (RR) estimates based upon a random effects model, except for beta-carotene, for 'high consumption' compared with 'low consumption', derived from the studies satisfying the inclusion criteria were as follows: vegetable consumption: RR=0.75 (95% CI (confidence interval) 0.66-0.85) from 17 studies; fruit consumption: RR=0.94 (95% CI 0.79-1.11) from 12 studies; vitamin C: RR=0.80 (95% CI 0.68-0.95) from 9 studies; beta-carotene: RR=0.82 (95% CI 0.76-0.91) from 11 studies. This analysis confirms the association between intake of vegetables and, to a lesser extent, fruits and breast cancer risk from published sources. Increasing vegetable consumption might reduce the risk of breast cancer.
Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and beta-carotene might be associated with reduced risk of colorectal cancer.
We tested the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50-69-year-old male cigarette smokers. Participants were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5-8 years. Incident colorectal cancers (n = 135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models.
Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm compared to the no alpha-tocopherol arm, but this finding was not statistically significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55-1.09; log-rank test p = 0.15). Beta-carotene had no effect on colorectal cancer incidence (RR = 1.05, 95% CI 0.75-1.47; log-rank test p = 0.78). There was no interaction between the two substances.
Our study found no evidence of a beneficial or harmful effect for beta-carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.
Cellular oxidants, called reactive oxygen species (ROS), are constantly produced in animal and human cells. Excessive ROS can induce oxidative damage in cell constituents and promote a number of degenerative diseases and aging. Cellular antioxidants protect against the damaging effects of ROS. However, in moderate concentrations, ROS are necessary for a number of protective reactions. Thus, ROS are essential mediators of antimicrobial phagocytosis, detoxification reactions carried out by the cytochrome P-450 complex, and apoptosis which eliminates cancerous and other life-threatening cells. Excessive antioxidants could dangerously interfere with these protective functions, while temporary depletion of antioxidants can enhance anti-cancer effects of apoptosis. Experimental data are presented supporting these notions. The human population is heterogeneous regarding ROS levels. Intake of exogenous antioxidants (vitamins E, C, beta-carotene and others) could protect against cancer and other degenerative diseases in people with innate or acquired high levels of ROS. However, abundant antioxidants might suppress these protective functions, particularly in people with a low innate baseline level of ROS. Screening human populations for ROS levels could help identify groups with a high level of ROS that are at a risk of developing cancer and other degenerative diseases. It also could identify groups with a low level of ROS that are at a risk of down-regulating ROS-dependent anti-cancer and other protective reactions. Screening populations could provide a scientifically grounded application of antioxidant supplements, which could significantly contribute to the nation's health.
Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFkappaB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.
The evidence for a potential benefit of antioxidant vitamins and folic acid in cardiovascular disease (CVD) prevention is derived from laboratory, clinical, and observational epidemiological studies but remains inconclusive. Large-scale randomized trials with clinical end points are necessary to minimize confounding and provide unbiased estimates of the balance of benefits and risks, yet data from such trials are scarce, especially among women.
The Women's Antioxidant Cardiovascular Study (WACS) is a randomized, double-blind, placebo-controlled trial testing whether antioxidant vitamins and a folic acid/vitamin B(6)/vitamin B(12) combination prevent future cardiovascular events among women with preexisting CVD or >or=3 CVD risk factors. This paper describes the design of the trial and baseline characteristics of participants, evaluates the success of randomization, and addresses the generalizability of future findings.
In a factorial design, 8171 U.S. female health professionals aged >or=40 years were randomized to vitamin E, vitamin C, beta-carotene, or placebos. Of these women, 5442 were also subsequently randomized to folic acid/vitamin B(6)/vitamin B(12) or placebo. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The clinical profile of participants was similar to that observed in another large trial of women with CVD.
The similar distribution of known potential confounders across treatment groups provides reassurance that unmeasured or unknown potential confounders are also equally distributed. Although a definitive conclusion regarding generalizability requires additional trials in diverse populations, there is little biological basis for supposing that the benefit-risk balance differs in other high-risk women.
DNA methylation is an important epigenetic mechanism of transcriptional control. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of cancer. Aberrant methylation of DNA (global hypomethylation accompanied by region-specific hypermethylation) is frequently found in tumor cells. Global hypomethylation can result in chromosome instability, and hypermethylation has been associated with the inaction of tumor suppressor genes. Preclinical and clinical studies suggest that part of the cancer-protective effects associated with several bioactive food components may relate to DNA methylation patterns. Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interaction of nutrients and DNA methylation because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B(12), vitamin B(6), methionine, and choline. However, looking at individual nutrients may be too simplistic. Dietary methyl (folate, choline, and methionine) deficiency in combination causes decreased tissue S-adeno-sylmethionine, global DNA hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Other dietary components such as vitamin B(12), alcohol, and selenium may modify the response to inadequate dietary folate.