Content uploaded by Henry I. Jacoby
Author content
All content in this area was uploaded by Henry I. Jacoby on Jul 01, 2015
Content may be subject to copyright.
The Effect of MGN-3 on Cisplatin and Doxorubicin Induced Toxicity in the Rat
Abstract
MGN-3 (BioBran(r)) is derived from rice bran and is produced by the partial hydrolysis of the water soluble hemicellulose fraction of rice bran by carbohydrases derived from Lentius edodes mycelia. It is a biological response modifier producing an increase in natural killer cell activity in immunocompromised patient. The aim of the study was to evaluate orally administered MGN-3 against gross pathological changes and weight loss produced by a single intraperitoneal dose of cisplatin or doxorubicin by daily oral dosing of 5 or 50 mg/kg MGN-3. Male Sprague-Dawley rats received either vehicle or MGN-3 prior to and after a single dose of cis-platinum or doxorubicin. Rats were observed for clinical signs daily for 11 days and body weights were recorded every other day. All animals were euthanized and necropsied on Day 11. Lethality was observed only in rats receiving cisplatin (50% with cisplatin alone reduced to 10% in rats receiving MGN-3 5 mg/kg, and 40% after MGN-3 50 mg/kg). Rats receiving MGN-3 ...
... RBAC was also shown to work synergistically with other natural anti-cancer substances, such as Baker's yeast [51] and curcumin [53]. It also enhanced the effectiveness of chemotherapeutic agents, including cisplatin [37,54], daunorubicin [54,55] and paclitaxel [56,57] as well as radiotherapy [48,58]. ...
... RBAC was also shown to work synergistically with other natural anti-cancer substances, such as Baker's yeast [51] and curcumin [53]. It also enhanced the effectiveness of chemotherapeutic agents, including cisplatin [37,54], daunorubicin [54,55] and paclitaxel [56,57] as well as radiotherapy [48,58]. ...
Rice bran arabinoxylan compound (RBAC) is derived from defatted rice bran hydrolyzed with Lentinus edodes mycelial enzyme. It has been marketed as a functional food and a nutraceutical with health-promoting properties. Some research has demonstrated this rice bran derivative to be a potent immunomodulator, which also possesses anti-inflammatory, antioxidant, and anti-angiogenic properties. To date, research on RBAC has predominantly focused on its immunomodulatory action and application as a complementary therapy for cancer. Nonetheless, the clinical applications of RBAC can extend beyond cancer therapy. This article is a narrative review of the research on the potential benefits of RBAC for cancer and other health conditions based on the available literature. RBAC research has shown it to be useful as a complementary treatment for cancer and human immunodeficiency virus infection. It can positively modulate serum glucose, lipid and protein metabolism in diabetic patients. Additionally, RBAC has been shown to ameliorate irritable bowel syndrome and protect against liver injury caused by hepatitis or nonalcoholic fatty liver disease. It can potentially ease symptoms in chronic fatigue syndrome and prevent the common cold. RBAC is safe to consume and has no known side effects at the typical dosage of 2–3 g/day. Nevertheless, further research in both basic studies and human clinical trials are required to investigate the clinical applications, mechanisms, and effects of RBAC.
... A recent review by Egashira [17] also concurred that RBAC prevented liver damage in hepatitis by inhibiting the NK-κB and JNK/MAPK expression. Other notable beneficial actions of RBAC include antiinflammation [48,90,96,126,[139][140][141][142], antioxidant [85,98,120,[142][143][144][145], radioprotection [116,142,143], chemoprevention [118,121,122], antiallergy [96,98,123,126,146], antibacterial [84,86,94], antifatigue [131,147], antiflu [147][148][149], gastroprotection [129,[147][148][149][150], and antihyperlipidemia [151,152]. ...
Rice bran arabinoxylan compound (RBAC) is a polysaccharide modified by Lentinus edodes mycelial enzyme widely used as a nutraceutical. To explore translational research on RBAC, a scoping review was conducted to synthesise research evidence from English (MEDLINE, ProQuest, CENTRAL, Emcare, CINAHL+, Web of Science), Japanese (CiNii, J-Stage), Korean (KCI, RISS, ScienceON), and Chinese (CNKI, Wanfang) sources while combining bibliometrics and network analyses for data visualisation. Searches were conducted between September and October 2022. Ninety-eight articles on RBAC and the biological activities related to human health or disease were included. Research progressed with linear growth (median = 3/year) from 1998 to 2022, predominantly on Biobran MGN-3 (86.73%) and contributed by 289 authors from 100 institutions across 18 countries. Clinical studies constitute 61.1% of recent articles (2018 to 2022). Over 50% of the research was from the USA (29/98, 29.59%) and Japan (22/98, 22.45%). A shifting focus from immuno-cellular activities to human translations over the years was shown via keyword visualisation. Beneficial effects of RBAC include immunomodulation, synergistic anticancer properties, hepatoprotection, antiinflammation, and antioxidation. As an oral supplement taken as an adjuvant during chemoradiotherapy, cancer patients reported reduced side effects and improved quality of life in human studies, indicating RBAC's impact on the psycho-neuro-immune axis. RBAC has been studied in 17 conditions, including cancer, liver diseases, HIV, allergy, chronic fatigue, gastroenteritis, cold/flu, diabetes, and in healthy participants. Further translational research on the impact on patient and community health is required for the evidence-informed use of RBAC in health and disease.
... Biobran does not exhibit hyporesponsiveness [35], making it a unique and attractive agent for long-term preventive and/or therapeutic purposes. Biobran has also been shown to be a completely safe and nontoxic agent, its biosafety has been demonstrated in many studies [35,73,74], it has been shown to reduce chemotoxic effects in animals [75,76] and to improve quality of life parameters in cancer patients [42,77], and it has not shown any adverse side effects in humans or animals after long periods of treatment [35,78,79]. ...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), poses a serious global public health threat for which there is currently no satisfactory treatment. This study examines the efficacy of Biobran/MGN-3 against SARS-CoV-2. Biobran is an arabinoxylan rice bran that has been shown to significantly inhibit the related influenza virus in geriatric subjects. Here, Biobran’s anti-SARS-CoV-2 activity was assessed using MTT and plaque reduction assays, RT-PCR, ELISA techniques, and measurements of SARS-CoV-2-related gene expression and protein levels. For Vero E6 cells infected with SARS-CoV-2, Biobran reduced the viral load by 91.9% at a dose of 100 μg/mL, it reduced viral counts (PFU/mL) by 90.6% at 50 μg/mL, and it exhibited a significant selectivity index (EC50/IC50) of 22.5. In addition, Biobran at 10 μg/mL inhibited papain-like proteinase (PLpro) by 87% and ACE2 SARS-CoV-2 S-protein RBD by 90.5%, and it significantly suppressed SARS-CoV-2 gene expression, down-regulating E-gene and RdRp gene expression by 93% each at a dose of 50 μg/mL and inhibiting the E-protein by 91.3%. An in silico docking study was also performed to examine the protein–protein interaction (PPI) between SARS-CoV-2 RBD and DC-SIGN as well as between serine carboxypeptidase and papain-like protease PLpro. Serine carboxypeptidase, an active ingredient in Biobran, was found to interfere with the binding of SARS-CoV-2 to its receptor DC-SIGN on Vero cells, thus preventing the cell entry of SARS-CoV-2. In addition, it impairs the viral replication cycle by binding to PLpro. We conclude that Biobran possesses potent antiviral activity against SARS-CoV-2 in vitro and suggest that Biobran may be able to prevent SARS-CoV-2 infection. This warrants further investigation in clinical trials.
... These results are in agreement with earlier studies showing that Biobran provides protection against irradiation-induced BW loss [33] and acts as an adjuvant for chemotherapeutic drugs to maintain BW when combined with chemotherapy drugs such as paclitaxel, cisplatin or doxorubicin. [16,34,35]. The beneficial role of Biobran has been further confirmed in clinical trials of patients with hepatocellular carcinoma showing that Biobran treatment reduces cancer recurrence and prolongs life expectancy following chemotherapy [36]. ...
This study examines the ability of arabinoxylan rice bran (MGN-3/Biobran) to enhance the anti-cancer effects of fractionated X-ray irradiation of Ehrlich solid tumor-bearing mice. Swiss albino mice bearing tumors were exposed to the following: (i) Biobran treatment (40 mg/kg/day, intraperitoneal injections) beginning on day 11 post-tumor cell inoculation until day 30; (ii) ionizing radiation (Rad) 2 Gy at three consecutive doses on days 12, 14 and 16; or (iii) Biobran + Rad. Final tumor weight was suppressed by 46% for Biobran, 31% for Rad and 57% for the combined treatment (Biobran + Rad) relative to control untreated mice. Biobran and Rad also arrested the hypodiploid cells in the sub-G1-phase, signifying apoptosis by +102% and +85%, respectively, while the combined treatment induced apoptosis by +123%, with similar results in the degree of DNA fragmentation. Furthermore, Biobran + Rad upregulated the relative gene expression and protein level of p53 and Bax in tumor cells, down-regulated Bcl-2 expression, and increased the Bax/Bcl-2 ratio and caspase-3 activity, with the combined treatment greater than for either treatment alone. Additionally, the combined treatment modulated the decrease in body weight, the increase in liver and spleen weight, and the elevation of liver enzymes aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase to be within normal values. We conclude that Biobran enhances radiation therapy-induced tumor regression by potentiating apoptosis and minimizing toxicities related to radiation therapy, suggesting that Biobran may be useful in human cancer patients undergoing radiotherapy and warranting clinical trials.
Biobran/MGN-3, a unique natural product extracted from rice bran, can strengthen immune health by enhancing the activity of natural killer (NK) cells. NK cells play a crucial role in the first line of defense against cancer and viral infections, but they are suppressed during aging, and low NK cell activity is linked with cancer. Over the last 25 years, studies have shown that Biobran/MGN-3 can enhance this suppression of NK cell activity and furthermore that it has superior effects in comparison with other biological response modifiers (BRMs). Biobran/MGN-3 has been shown to restore the aging-induced NK cell immune suppression of aged mice to normal levels, and it enhanced NK cell activity in human geriatric subjects participating in a randomized, double-blind, placebo-controlled clinical trial. In addition, Biobran/MGN-3 has been shown to exert significant anticancer effects in several studies of mice and rats bearing tumor as well as in human clinical trials against several types of malignancies by a mechanism that involved enhancement of NK cell activity. The molecular mechanisms underlying Biobran/MGN-3’s effect on NK cell activity involve increasing the granular content of NK cells and increasing the expression of key cell surface receptors such as adhesion molecule ICAM-1 and the activation-associated receptors CD25 and CD69. Biobran/MGN-3 has no toxicity or side effects, and unlike many other BRMs, its long-term effects are not limited by hyporesponsiveness. This report describes the superiority of Biobran/MGN-3 as a BRM that enhances NK cell activity, followed by evidence showing how Biobran/MGN-3 can improve lives by reversing aging-induced and cancer-induced NK cell suppression.KeywordsBiobran/MGN-3CancerAgingBiological response modifierImmunomodulatorICAM-1
Baker's yeast, Saccharomyces cerevisiae, has been shown to sensitize a variety of breast cancer cell (BCC) lines to paclitaxel chemotherapy in vitro. The present study evaluated the ability of S. cerevisiae to sensitize BCCs to paclitaxel in animals bearing Ehrlich ascites carcinoma (EAC). Mice bearing EAC were intratumorally injected with dead S. cerevisiae (1x10 ⁷ cells/ml) in the presence or absence of low- and high-dose paclitaxel [paclitaxel-L, 2 mg/kg body weight (BW) and paclitaxel-H, 10 mg/kg BW, respectively]. At 30 days post tumor inoculation, co-treatment with yeast plus paclitaxel-L showed improvements over paclitaxel-H alone, as measured by tumor weight (-64 vs. -53%), DNA damage (+79 vs. +62%), tumor cell apoptosis (+217 vs. +177%), cell proliferation (-56 vs. -42%) and Ki-67 marker (+95 vs. +40%). Histopathology and ultra-structural examinations showed that yeast plus paclitaxel-L enhanced apoptosis in EAC more than paclitaxel-H alone and caused comparable tumor necrosis. We conclude that baker's yeast may be used with low-dose chemotherapy to achieve the same potency as high-dose chemotherapy in mice bearing EAC. This suggests that baker's yeast may be an anticancer adjuvant and may have clinical implications for the treatment of breast cancer.
Introduction:
Conventional cancer treatment, including surgery, chemotherapy, and radiotherapy, may not be sufficient to eradicate all malignant cells and prevent recurrence. Intensive treatment often leads to a depressed immune system, drug resistance, and toxicity, hampering the treatment outcomes. BioBran/MGN-3 Arabinoxylan is a standardized arabinoxylan concentrate which has been proposed as a plant-based immunomodulator that can restore the tumor-induced disturbance of the natural immune system, including natural killer cell activity to fight cancer, complementing conventional therapies.
Objectives:
To comprehensively review the available evidence on the effects and efficacies of MGN-3 as a complementary therapy for conventional cancer treatment.
Methods:
Systematic search of journal databases and gray literature for primary studies reporting the effects of MGN-3 on cancer and cancer treatment.
Results:
Thirty full-text articles and 2 conference abstracts were included in this review. MGN-3 has been shown to possess immunomodulating anticancer effects and can work synergistically with chemotherapeutic agents, in vitro. In murine models, MGN-3 has been shown to act against carcinogenic agents, and inhibit tumor growth, either by itself or in combination with other anticancer compounds. Fourteen successful MGN-3 treated clinical cases were found. Eleven clinical studies, including 5 nonrandomized, pre-post intervention studies and 6 randomized controlled trials (RCTs) were located. Reported effects include enhanced immunoprofile, reduced side effects, improved treatment outcomes; one RCT established significantly increased survival rates. There are no reports on adverse events on MGN-3. Most of the clinical trials are small studies with short duration.
Conclusion:
There is sufficient evidence suggesting MGN-3 to be an effective immunomodulator that can complement conventional cancer treatment. However, more well-designed RCTs on MGN-3 are needed to strengthen the evidence base.
In this study, we examine the ability of arabinoxylan rice bran (MGN-3/Biobran) to enhance the apoptotic effect of paclitaxel (Taxol) at low concentration [2 mg/kg body weight (BW)] in animals bearing Ehrlich ascites carcinoma (EAC) cells and elucidate its mechanisms of action. On Day 8 following tumor cells inoculation, mice bearing tumors were administered MGN-3 alone (40 mg/kg BW), paclitaxel alone, or MGN-3 plus paclitaxel. On Day 30 post-tumor inoculation, we observed significant suppression of tumor volume (TV) with paclitaxel alone (59%), MGN-3 alone (77%), and MGN-3 plus paclitaxel (88%). Inhibition of tumor growth post-treatment with both agents, as compared with either treatment alone, was associated with a decrease in cell proliferation, a marked increase in the sub-G0/G1 population, an increase in DNA damage and apoptosis of tumor cells, and a significant maximization of the apoptosis index (AI)/proliferation index (PrI) ratio. Histopathological and electron microscopy examination of the combined treatment group showed an increase in the degenerative regions of the solid tumor tissue and abundant apoptotic cells. These data suggest that MGN-3 supplementation enhances tumor cell demise in the presence of a low dose of chemotherapeutic agent via apoptotic mechanism.
In the current study, we investigated the chemopreventive activity of arabinoxylan rice bran, MGN-3/Biobran, against chemical induction of glandular stomach carcinogenesis in rats. Gastric cancer was induced by carcinogen methylnitronitrosoguanidine (MNNG), and rats received MNNG alone or MNNG plus Biobran (40 mg/kg body weight) for a total of 8 months. Averaged results from 2 separate readings showed that exposure to MNNG plus Biobran caused gastric dysplasia and cancer (adenocarcinoma) in 4.5/12 rats (9/24 readings, 37.5%), with 3.5/12 rats (7/24 readings, 29.2%) showing dysplasia and 1/12 rats (8.3%) developing adenocarcinoma. In contrast, in rats treated with MNNG alone, 8/10 (80%) developed dysplasia and adenocarcinoma, with 6/10 rats (60%) showing dysplasia and 2/10 rats (20%) developing adenocarcinoma. The effect of combining both agents was also associated with significant suppression of the expression of the tumor marker Ki-67 and remarkable induction in the apoptotic gastric cancer cells via mitochondrial-dependent pathway as indicated by the upregulation in p53 expression, Bax expression, downregulation in Bcl-2 expression, an increase in Bax/Bcl-2 ratio, and an activation of caspase-3. In addition, Biobran treatment induced cell-cycle arrest in the subG1 phase, where the hypodiploid cell population was markedly increased. Moreover, Biobran treatment protected rats against MNNG-induced significant decrease in lymphocyte levels. We conclude that Biobran provides protection against chemical induction of glandular stomach carcinogenesis in rats and may be useful for the treatment of human patients with gastric cancer.
MGN-3, an arabinoxylan extracted from rice bran that is treated enzymatically with an extract from Shiitaki mushrooms, is an effective biological response modifier that increases NK cell activity, and potentiates the activity of conventional chemotherapeutic agents. In this study, we investigated the effect of MGN-3 on death receptor-induced apoptosis in the human leukemic HUT 78 cell line. HUT 78 cells were pre-treated with MGN-3, and then were incubated with the agonistic antibody against death receptor (Fas, CD95). Apoptosis was determined by the propidium iodide technique using FACScan. Activation of caspase 3, caspase 8, and caspase 9 was determined by flow cytometry. Mitochondrial membrane potential was measured with DIOC6 dye using FACScan. Expression of CD95 and Bcl-2 were measured by flow cytometry. In a dose-dependent manner, MGN-3 enhanced anti-CD95 anti body-induced apoptosis. Increased cell death was correlated with increased depolarization of mitochondrial membrane potential and increased activation of caspase 3, caspase 8, and caspase 9. MGN-3 treatment had no effect on the level of expression of CD95, but it caused down regulation of Bcl-2 expression. These results suggest that MGN-3 increases the susceptibility of cancer cells to undergo apoptosis mediated by death ligands, which may be relevant for anti-cancer activities.
Dose-limiting toxicity secondary to antineoplastic chemotherapy is due to the inability of cytotoxic drugs to differentiate between normal and malignant cells. The consequences of this may include impairment of patient quality of life, because of toxicity, and reduced tumour control because of the inability to deliver adequate dose-intensive therapy against the cancer. Specific examples of toxicity against normal tissues include cisplatin-related neurotoxicity and nephrotoxicity, myelotoxicity secondary to treatment with alkylating agents and carboplatin, oxazaphosphorine-induced haemorrhagic cystitis, and cumulative dose-related cardiac toxicity secondary to anthracycline treatment. Chemoprotectants have been developed as a means of ameliorating the toxicity associated with cytotoxic agents by providing site-specific protection for normal tissues, without compromising antitumour efficacy. Clinical trials with toxicity protectors must include sufficient dose-limiting events for study, and assessment of both toxicity (allowing for measurement of efficacy of protection) and antitumour effect. Several chemoprotective compounds have now been extensively investigated, including dexrazoxane, amifostine, glutathione, mesna and ORG 2766. Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy. Numerous studies have demonstrated that sulfur-containing nucleophiles, including amifostine, glutathione, and mesna can specifically bind cisplatin- or alkylating agent—generated free radicals or alkylating agent metabolites to reduce the incidence of cisplatin-associated neurotoxicity and nephrotoxicity, or alkylating agent-associated myelosuppression and urothelial toxicity. These studies, in the majority of instances, have not revealed any evidence of reduction in antitumour efficacy. Further randomised trials are required to identify the optimal role of chemo-protectants when used alone or in combination with other toxicity modifiers including haemopoietic growth factors.
The mechanisms mediating the protective effects of amifostine on cisplatin-induced toxicity were investigated in tumor-bearing nude mice by quantitative immunohistochemistry for analysis of cisplatin-DNA adduct levels in tumors and kidneys. The mice were treated with cisplatin 5 or 10 mg/kg i.p. with or without amifostine 200 mg/kg 30 min prior to cisplatin. Toxicity was noted in terms of mortality and changes in body weight. Mortality was similar in the four treatment groups, regardless of cisplatin dose or whether amifostine was added or not. At a cisplatin dose of 5 mg/kg, amifostine did not affect the moderate decrease in body weight. Cisplatin 10 mg/kg alone gave a significant loss of body weight, with the nadir on day 7. By adding amifostine to 10 mg/kg cisplatin the weight loss was much less pronounced. Tumor growth was significantly more retarded among animals treated with 10 mg/kg cisplatin alone compared with amifostine+cisplatin 10 mg/kg. There was no difference in tumor growth retardation between cisplatin 5 mg/kg alone or in combination with amifostine. The most likely explanation was that the pronounced tumor growth retardation with 10 mg/kg cisplatin alone was due to the decline in the general condition of the animals rather than increased antitumoral activity per se. Analysis of cisplatin-DNA adducts in tumors showed no difference whether cisplatin 10 mg/kg was combined with amifostine or not. In kidneys there were significantly fewer tubular cells with very high adduct levels in animals pretreated with amifostine.
MGN-3 an arabinoxylane from rice bran that has been enzymatically modified with extract from Hyphomycetes mycelia, was tested for anti-HIV activity in vitro. MGN-3 activity against HIV-1 (SF strain) was examined in primary cultures of peripheral blood mononuclear cells. MGN-3 inhibited HIV-1 replication by: (1) inhibition of HIV-1 p24 antigen production in a dose dependent manner--MGN-3 concentrations of 12.5, 25, 50, and 100 micrograms/ml showed 18.3, 42.8, 59, and 75% reduction in p24 antigen, respectively; and (2) inhibition of syncytia formation maximized (75%) at concentrations of 100 micrograms/ml. Further studies showed that ingestion of MGN-3 at concentration of 15 mg/kg/day resulted in a significant increase in T and B cell mitogen response at 2 months after treatment: 146% for PHA, 140% for Con A, and 136.6% for PWM mitogen. We conclude that MGN-3 possesses potent anti-HIV activity and in the absence of any notable side effects, MGN-3 shows promise as an agent for treating patients with AIDS.
Platinum-type drugs have proven to be valuable in the treatment of a variety of solid tumors, beginning with the commercial approval of cisplatin 18 years ago. There are several clinically important toxicities commonly associated with the administration of these drugs. Despite the extensive use of cisplatin and carboplatin, the fundamental chemical transformations and mechanisms that underlie their antitumor and toxic effects have not been fully characterized. Several first-generation protective thiols have been clinically studied in an attempt to reduce the toxicity of platinum-type drugs; while some of these agents appear to protect against certain toxicities, nearly all platinum-protecting drugs have their own intrinsic toxicities, which can be additive to the toxicity of platinum-type drugs. Tumor protection by platinum-protecting drugs is an additional untoward effect that is associated with certain types of agents and must be addressed with care. Recent advances in theoretical and laboratory methods and the use of supercomputers have extended our understanding of the possible major mechanisms underlying platinum drug antitumor activity and toxicity; we present strong evidence that there are two classes of chemical species of platinum drug. One class appears to predominantly account for the antitumor activity, and the other class of chemical species produces many of the toxic effects of platinum drugs. We have discovered a new nontoxic, second-generation platinum-protecting agent, known as BNP7787, which appears to selectively inactivate and eliminate toxic platinum species. BNP7787 has recently entered phase I clinical testing in cancer patients.
1. Dexrazoxane (ICRF-187) is the only clinically approved drug for use in cancer patients to prevent anthracycline mediated cardiotoxicity. 2. The mode of action appears to be mainly due to the potential of the drug to remove iron from iron/anthracycline complexes and thus reduce free radical formation by these complexes. 3. Dexrazoxane also influences cell biology by its ability to inhibit topoisomerase II and its effects on the regulation of cellular iron homeostasis. 4. Although the cardioprotective effect of dexrazoxane in cancer patients undergoing chemotherapy with anthracyclines is well documented, the potential of this drug to modulate topoisomerase II activity and cellular iron metabolism may hold the key for future applications of dexrazoxane in cancer therapy, immunology, or infectious diseases.
Anticancer treatment is generally associated with toxicity to health issues. One of the reasons for this unpleasant association is that anticancer agents have been mostly selected on the basis of an empirically established toxicity towards cancer cell lines and rapidly growing tumours in animal models, and not on the basis of a sophisticated intervention in tumour-specific biology. This strategy of drug development unavoidably produces drugs with toxicity towards normal cells and tissues which also have a high cell turnover and share many characteristics with tumour cells. Therefore it is a continuing challenge to design therapy which is both effective and also has high specificity for the biology of cancer and/or is efficiently targeted to tumour tissue.
This article describes the mechanisms of cytotoxicity of standard chemo- and radiotherapy and discussed the possibilities of currently available cytoprotective agents to reduce or prevent these toxicities. These agents should ideally be selective for normal cells versus cancer cells, be effective in reducing or preventing toxicity, have no negative impact on anticancer therapy and have minimal adverse effects. None of the agents described in this article fulfils these criteria completely and therefore we cannot recommend these agents for standard use in daily anti-cancer practice. Nevertheless, there are encouraging data concerning the beneficial effects of dexrazoxane for anthracycline-induced cardiomyopathy and amifostine for platinum- and radiotherapy-induced toxicity. These date warrant further studies.
Patients receiving systemic cancer chemotherapy must often have their dose intensity of therapeutic agents reduced, because a broad range of organs are adversely affected. Therefore, research and the development of agents protecting the normal tissues from the toxicity of antineoplastic therapy, without reducing the antitumour efficacy, are very important. Amifostine, a prodrug that forms an activated free thiol, when dephosphorylated by alkaline phosphatase, appears selective in its entry in non-malignant cells, and exerts a protective effect from toxicity induced by chemo- or radiotherapy on normal tissues, through free radical scavenging, hydrogen donation and inhibition of DNA damage. Studies in vitro and experimental models have confirmed the protective properties of amifostine in normal cells. In clinical trials pretreatment with amifostine reduced the frequency of cyclophosphamide induced neutropenia and nephro-, oto- and neurotoxicity of platinum compounds. In some cases the use of amifostine have also potentiated the effects of several drugs, such as alkylating agents and, in recent studies, taxanes. The main potentially dose-limiting adverse effect is hypotension, that is often asymptomatic. Amifostine is thus usefully employed in order to obtain a better quality of life in patients receiving oncologic treatments.
Recently, we presented evidence for the role of MGN-3, an enzymatically modified arabinoxylan extracted from rice bran, in potent activation of human natural killer (NK) cell function in vivo and in vitro. In the current study, we examined the mechanism by which MGN-3 elevated NK cytotoxic activity. We did this by testing the action of MGN-3 on the levels of both tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) secretions and MGN-3 function on the expression of key cell surface receptors. Peripheral blood lymphocytes were treated with MGN-3 at concentrations of 0.1 mg/ml and 1 mg/ml, and supernatants were subjected to enzyme-linked immunosorbent assay. Results showed that MGN-3 is a potent TNF-alpha inducer. The effect was dose-dependent. MGN-3 concentration at 0.1 and 1 mg/ml increased TNF-alpha production by 22.8- and 47. 1-fold, respectively. MGN-3 also increased production of IFN-gamma but at lower levels as compared to TNF-alpha With respect to key cell surface receptors, MGN-3 increases the expression of CD69, an early activation antigen at 16 hours after treatment. Furthermore, the interleukin-2 receptor CD25 and the adhesion molecule ICAM-1 (CD54) were upregulated after treatment with MGN-3. Treating highly purified NK cells with MGN-3 also resulted in increased levels of TNF-alpha and IFN-gamma secretion in conjunction with augmentation of NK cell cytotoxic function. Furthermore, addition of MGN-3 to interleukin-2-activated NK cells resulted in a synergistic induction of TNF-alpha and IFN-gamma secretion. Overall, our data suggest that MGN-3, a novel biological response modifier, can be used as a safe alternative or as an adjuvant to the existing immunotherapeutic modalities.