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Chlorine dioxide solution in metastatic uncurable cancer: case series

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Abstract

Immunotherapy has recently yielded tremendous progress in the fight against malignancies. Its precise mechanism of action remains controversial. Activated leukocytes release reactive oxygen species which kill cancer cells. In the body, chlorine dioxide, orally ingested degrades into free radicals such as found in neutrophils. Chlorine dioxide is a potent oxidant with in vitro anticancer activity. Its precise mechanism of action has not been thoroughly explored, but it is proposed that it acts through the redox imbalance of cancer cells. Six patients were treated for metastatic cancer (breast, kidney, prostate, lymphoma, uterus and melanoma), on a compassionate basis. We report lasting tumor response with a combination of oral, enema and/or intravenous chlorine dioxide, without any side effects. This preliminary work suggest that chlorine dioxide and free radicals might be the mediators for immunotherapies. Chlorine dioxide is both a promising and unexpensive anticancer agent. Rigorous clinical trials are needed to confirm these preliminary results. Keywords : Chlorine dioxide , cancer, immunotherapy, Warburg effect, reactive oxygen species, intermittent fasting, ketogenic diet.

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Reactive oxygen species (ROS), a group of highly reactive ions and molecules, are increasingly being appreciated as powerful signaling molecules involved in the regulation of a variety of biological processes. Indeed, their role is continuously being delineated in a variety of pathophysiological conditions. For instance, cancer cells are shown to have increased ROS levels in comparison to their normal counterparts. This is partly due to an enhanced metabolism and mitochondrial dysfunction in cancer cells. The escalated ROS generation in cancer cells contributes to the biochemical and molecular changes necessary for the tumor initiation, promotion and progression, as well as, tumor resistance to chemotherapy. Therefore, increased ROS in cancer cells may provide a unique opportunity to eliminate cancer cells via elevating ROS to highly toxic levels intracellularly, thereby, activating various ROS-induced cell death pathways, or inhibiting cancer cell resistance to chemotherapy. Such results can be achieved by using agents that either increase ROS generation, or inhibit antioxidant defense, or even a combination of both. In fact, a large variety of anticancer drugs, and some of those currently under clinical trials, effectively kill cancer cells and overcome drug resistance via enhancing ROS generation and/or impeding the antioxidant defense mechanism. This review focuses on our current understanding of the tumor promoting (tumorigenesis, angiogenesis, invasion and metastasis, and chemoresistance) and the tumor suppressive (apoptosis, autophagy, and necroptosis) functions of ROS, and highlights the potential mechanism(s) involved. It also sheds light on a very novel and an actively growing field of ROS-dependent cell death mechanism referred to as ferroptosis.
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The use of a family of chemical agents, releasing active species of oxygen, effective against infectious microorganisms and viruses is described with emphasis on Chlorine Dioxide (CLO2), one of the oxides of chlorine. Also discussed are ozone, hypochlorite, periodate and the known mechanisms of action by which certain white blood cells attach and eradicate infectious microorganisms and primitive bacteria also known as viruses. Explanation of the biochemical mechanisms of acid of CLO 2 as an antimicrobial agent, is presented. Particular attention is given to Candida albicans, cytomegalovirus, polio virus, Herpes I and II, HTLV-III and Pseudomonas responding to the clinical application of CLO2. It is implied that these biochemical mechanisms are so fundamental that the development of resistant strains of bacteria and/or yeast would not occur with other anti-infectious agents. Limited lists of health abnormalities that respond to CLO2 are discussed.
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Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.
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An AIE-based fluorescent nanoprobe (MTPE-M) has been developed and used for ratiometric detection of hypochlorite with high selectivity and sensitivity. More importantly, its application in live cells and zebrafish for ratiometric imaging of endogenous ClO(-) has also been achieved.
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Dimethyl sulfoxide (CAS # 67-68-5) is a colorless organosulfur compound and is important as a polar aprotic solvent. It is readily absorbed by animals and humans by dermal and oral routes and enhances absorption of many other chemicals by those routes. In humans, it is an irritant of the eyes, skin, and respiratory system. In animals, reported effects include renal and hepatic lesions, corneal injury (opacities), teratogenicity, and repeated dermal application results in irritation and urticaria.
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Cancer cells are characterized by altered glucose metabolism known as the Warburg effect in which aerobic glycolysis is increased. Glucose is converted to lactate even under sufficient oxygen tension. Interfering with this process may be a potential effective strategy to cause cancer cell death because these cells rely heavily on glucose metabolism for survival and proliferation. 2-Deoxy-D-glucose (2DG), a glucose analog, targets glucose metabolism to deplete cancer cells of energy. In addition, 2DG increases oxidative stress, inhibits N-linked glycosylation, and induces autophagy. It can efficiently slow cell growth and potently facilitate apoptosis in specific cancer cells. Although, 2DG itself has limited therapeutic effect in many types of cancers, it may be combined with other therapeutic agents or radiotherapy to exhibit a synergistic anticancer effect. In this review, we describe the Warburg effect and discuss 2DG and its underlying mechanisms and potential application for cancer treatment.
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The effects of pH on the inorganic products formed during the reaction of chlorine dioxide with an etherified lignin model compound have been studied. Analyses of the inorganic species produced during the reaction at pH 8 revealed that 2 mol of chlorite are liberated for every 1 mol of oxidized nonphenolic lignin model compound formed, consistent with two consecutive one-electron-transfer processes. In contrast, the low-pH reactions produced mostly ring oxidation products and chlorinated organic material, accompanied by increased levels of hypochlorous acid. The transient hypochlorous acid rapidly reacted with chlorite to generate chloride ions, with a maximum chloride formation at pH 4. Chlorate formation was shown to increase with increasing reaction pH. These results are in contrast to those previously reported for reactions with wood pulps and are explained on the basis of the slow reaction kinetics of nonphenolic lignin moieties as compared to phenolic ones, thereby enabling hypochlorous acid to react with chlorine dioxide to produce chlorate.
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In this paper, the disinfection effects of chlorine dioxide (ClO2) on some main bacteria in water and the influence of ClO2 on the inactivation of some microorganisms studied under various conditions such as the dose of disinfectant and the contact time, pH value, etc. were researched and reported, and it was compared with that of liquid chlorine. The results showed that the killing effect of the ClO2 on bacteria is similar to or better than that of liquid chlorine, the bacteria were effectively killed off by using ClO2 in a relatively wider range of pH value. Moreover, the investigation of the bactericidal mechanism of ClO2 was tentatively undertaken. Then, we concluded that ClO2 is an excellent disinfectant to substitute for the liquid chlorine.
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Oxychlorine compounds, such as hypochlorous acid (HOCl) and chlorine dioxide (ClO2), have potent antimicrobial activity. Although the biochemical mechanism of the antimicrobial activity of HOCl has been extensively investigated, little is known about that of ClO2. Using bovine serum albumin and glucose-6-phosphate dehydrogenase of Saccharomyces cerevisiae as model proteins, here I demonstrate that the antimicrobial activity of ClO2 is attributable primarily to its protein-denaturing activity. By solubility analysis, circular dichroism spectroscopy, differential scanning calorimetry, and measurement of enzymatic activity, I demonstrate that protein is rapidly denatured by ClO2 with a concomitant decrease in the concentration of ClO2 in the reaction mixture. Circular dichroism spectra of the ClO2-treated proteins show a change in ellipticity at 220 nm, indicating a decrease in alpha-helical content. Differential scanning calorimetry shows that transition temperature and endothermic transition enthalpy of heat-induced unfolding decrease in the ClO2-treated protein. The enzymatic activity of glucose-6-phosphate dehydrogenase decreases to 10% within 15 s of treatment with 10 microM ClO2. Elemental analyses show that oxygen, but not chlorine, atoms are incorporated in the ClO2-treated protein, providing direct evidence that protein is oxidized by ClO2. Furthermore, mass spectrometry and nuclear magnetic resonance spectroscopy show that tryptophan residues become N-formylkynurenine and tyrosine residues become 3,4-dihydroxyphenylalanine (DOPA) or 2,4,5-trihydroxyphenylalanine (TOPA) in the ClO2-treated proteins. Taking these results together, I conclude that microbes are inactivated by ClO2 owing to denaturation of constituent proteins critical to their integrity and/or function, and that this denaturation is caused primarily by covalent oxidative modification of their tryptophan and tyrosine residues.
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A low serum 25-hydroxyvitamin D [25(OH)D] level is a risk factor for many diseases, including musculoskeletal diseases, many types of cancer, cardiovascular diseases, diabetes mellitus, infectious diseases, autoimmune diseases, and brain diseases. This report estimates the reduction in mortality rates for the five Nordic countries for an increase in population mean serum 25-hydroxyvitamin D level to 105 nmol/L. Serum vitamin D dose-incidence/prognosis relationships can be developed with significant levels of reliability for most vitamin D-sensitive diseases on the basis of ecological, cross-sectional, and observational studies, randomized controlled trials, and meta-analysis of such studies. These dose-response relations are used to estimate the population-wide benefit of raising mean serum 25(OH)D concentration to 105 nmol/L for the five Nordic countries. From this study, the reductions in mortality rates possible by raising population mean serum 25(OH)D levels to 105 nmol/L are: Denmark, 17% (estimated range,11%-24%); Finland, 24% (17%-32%); Iceland, 24% (17%-32%); Norway, 18% (11%-26%); and Sweden, 18% (8%-25%). Reaching these levels would require changes in health policies with respect to solar ultraviolet-B (UVB) irradiance, vitamin D fortification of food, availability of vitamin D and calcium supplements, and attitude toward use of UVB lamps. Adverse effects of oral vitamin D intake are limited, and those from UVB irradiance are minor compared with the benefits.
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An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.
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The purpose of this review is to summarize ecological studies of solar ultraviolet B (UVB), vitamin D and cancer since 2000. The journal literature is surveyed and summarized. The ecological approach has been the primary tool used during the past two decades to extend the applicability of the UVB-vitamin D-cancer theory to include at least 18 types of cancer. Many of these studies were conducted in the United States, which has the advantages of availability of reliable age-standardized cancer incidence and mortality rate data for geographic areas at various spatial resolutions, and an asymmetric solar UVB dose pattern, with higher UVB irradiance in the west and lower in the east, at any particular latitude. In addition, indices for other cancer risk-modifying factors are readily available including those for smoking, alcohol consumption, ethnic background, urban/rural residence, socioeconomic status, air pollution, and in limited fashion, diet. The ecological approach has also been used to identify latitudinal variations in cancer mortality rates in Australia, China, Japan, and Spain, and in multicountry studies. It has been used to investigate the relative roles of solar UVB and dietary factors on a global scale. The ecological approach has also been applied to cancer survival. Studies in Norway and England found that individuals diagnosed with cancer in summer or fall, when serum 25-hydroxyvitamin D levels are highest, had a milder clinical course and longer survival than those diagnosed in winter or spring. These findings provide strong evidence that vitamin D status plays an important role in controlling the outcome of cancer. Support for the UVB-vitamin D-cancer theory is now scientifically strong enough to warrant use of vitamin D in cancer prevention, and as a component of treatment. More research studies would help to explore whether there are benefits beyond the substantial effects that have been observed.
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The effects of chlorine dioxide (ClO2), sodium hypochlorite (NaOCl), and hydrogen peroxide (H2O2) on cell death and the cell cycle of human gingival fibroblast (HGF) cells were examined. The inhibition of HGF cell growth was evaluated using a Cell Counting Kit-8. The cell cycle was assessed with propidium iodide-stained cells (distribution of cells in G0/G1, S, and G2/M phases) using flow cytometry. The patterns of cell death (necrosis and apoptosis) were analyzed using flow cytometry with annexin V-FITC/PI staining. The lethal doses for 50% of the cells (LD50) of ClO2, NaOCl, and H2O2 were 0.16, 0.79, and 0.11 mM, respectively. All three dental disinfectants induced G0/G1 cell cycle arrest. H2O2 induced apoptosis at concentrations of 0.05 and 0.1 mM, while NaOCl and ClO2 did not induce significant apoptosis at any concentration examined. These results suggest that ClO2 is sufficient for use as a dental disinfectant compared with H2O2 or NaOCl.