“Antioxidants Accelerate Lung Cancer Progression in Mice”
Sayin, and colleagues suggest in a January 2014 paper published in Science Translational Medicine that mutant mice, which are genetically modified to be susceptible lung cancer and undergo tumor initiation through inhalation of a genetically modified virus, have worse outcomes when given a synthetic vitamin E analog or N-acetylcysteine. It is unclear how this study relates to antioxidant intake in normal mice, let alone the human experience. This data is inconsistent with research demonstrating antioxidant supplementation reduces cancer risk in humans. For example, a major study (Physician’s Health Study II) reported in 2012 that daily supplementation with a multivitamin containing a variety of antioxidants significantly reduced cancer risk. 1
However, the media is releasing shocking headlines related to antioxidants and cancer based on this one mutant mouse study. There are several problems with extrapolating the data from this article to the human experience. Also, a substantial body of evidence demonstrates antioxidants are cancer preventive.11-32
The mice used in this study were genetically modified to be susceptible to lung tumors. Also, the mice were given a genetically modified virus via inhalation to initiate lung tumorigenesis. Considerable differences in human and mouse physiology means that research on genetically modified mice may not reflect outcomes in humans.35
Synthetic Vitamin E Used
A synthetic vitamin E analog was used rather than the more biologically active natural vitamin E. This synthetic form of vitamin E is not equivalent in chemical structure or biological activity to natural vitamin E.2 The pharmacology of synthetic vitamin E is quite different from that of natural vitamin E; it demonstrates an entirely different dose-response curve, and is an entirely different drug by modern pharmacological standards.3
Also, only the alpha form was used; it is clear from the developing research that a variety of tocopherols, including gamma, should be used in dietary supplementation for optimal results. Using a single tocopherol form, such as this synthetic vitamin E analog, has the potential to reduce other important tocopherol forms that may inhibit tumorigenesis such as gamma tocopherol.4-6
Doses not reflective of typical supplement use
The high-end concentration of synthetic vitamin E used in the in vitro model was supraphysiologic at 100 µM; compare to normal vitamin E plasma concentrations in the range 8-28 µM. Using 20 µM as an typical vitamin E concentration in plasma,7 this means that the in vitro portion of the study used a concentration 5 times higher.
Also, the mutant mouse portion of the study used a very crude and imprecise method of dosing the animals via water and food supply. The level of NAC in drinking water was 1 gram/liter. Since an adult mouse weighs on average about 25 grams, and since the average mouse ingests about 20 ml of water daily, and further correcting for interspecies differences in body surface area and differences in bodyweight between an average mouse and an average 80 kg human, this yields a rough estimate for a human equivalent dose of more than 5.2 grams of NAC. This dose of NAC is much higher than a typical dose of NAC used as a dietary supplement,more than quintuple, in fact.
Results do not apply to a healthy population
The failure of the mainstream media to thoroughly explain Sayin’s research will undoubtedly cause many healthy individuals who use vitamin E and N-acetylcysteine to worry that they might be increasing their lung cancer risk by doing so. This is absolutely not what was examined in this research.
The scientists looked at what would happen when mutant mice with artificially-induced lung cancer were given synthetic vitamin E and N-acetylcysteine. No aspect of the animal experiment provides any evidence that these nutrients cause cancer under normal conditions. Similarly, the work on cell culture in this study also does not suggest that vitamin E or N-acetylcysteine initiate lung cancer under normal conditions.
Preclinical research with very limited relevance to humans
Cancer occurs when genes that control cellular growth and death cycles become mutated or dysfunctional.36 A number of specific genes are known to be important drivers in specific types of cancer if they become mutated. These are called proto-oncogenes. Once a cell acquires (or inherits) a mutation in a proto-oncogene,irregular cell growth may occur.37However, this does not necessarily mean that a single genetic mutation will cause overt cancer. Typically, a driver mutation in a proto-oncogene initiates a cascade of cellular dysfunction causing mutations in numerous other genes involved in cell growth. Eventually, this leads to cancer. In some cancers this takes decades, whereas in others, such as aggressive cancers of the blood,cancer can erupt within weeks.38
The researchers utilized mice developed to harbor specific mutations that can be “activated” upon exposure to a specialized viral inducer.Once the mice harboring these mutations are exposed to the viral tumor inducer,they develop lung cancer soon after. This model diverges considerably with the development of lung cancer among humans, which typically takes decades of chemical insult. Although animal models are tools essential for the advancement of science, they only offer small clues about variables that might be relevant to human diseases. Animal models allow researchers to develop hypotheses, which then need to be tested in humans. Very often, an effect consistently observed in an animal model fails to translate to human beings.39
The mass media tends to over-emphasize and misconstrue this type of preclinical research, resulting is misinformation spreading like wildfire among the public. Animal models are interesting, but conclusions about interventions in humans must be based upon research conducted in humans.
Results do not apply to other forms of antioxidants
Different antioxidant ingredients have different biologic effects and it cannot be assumed that all antioxidants will have the same effects.40 For example, if we were to believe the outrageous media headlines about antioxidants and cancer, we would avoid antioxidant-rich vegetables and berries due to concerns about cancer risk. This is obviously preposterous and illustrates the risk of extrapolating this data to other antioxidants and tohuman populations.
Results are inconsistent with previous research
Previous studies show that antioxidants are protective against chemically induced lung cancer.8-10For example, NAC prevented the induction of lung tumors when supplemented to the diet of mice both before and after injection of a carcinogen. The researchers also noted that their results “…rule out that NAC may behave as a tumor promoter…”8 Previous research also demonstrates that NAC has an impressive array of mechanisms and protective effects on cancer development including:10Previous studies show that antioxidants are protective against chemically induced lung cancer.8-10For example, NAC prevented the induction of lung tumors when supplemented to the diet of mice both before and after injection of a carcinogen. The reseachers also noted that their results “…rule out that NAC may behave as a tumor promoter…”8 Previous research demonstrates that NAC has an impressive array of mechanisms and protective effects on cancer development including:10
· Inhibition of genotoxicity and cell transformation
· Positive effects on gene expression and signal transduction pathways (eg, an increase in p53 expression, modulation of TNF-alpha, and decrease the activity of transforming growth factor- beta[TGF-beta])
· Modulation of apoptosis
· Inhibition of tumor promotion and progression
· Inhibition of cell proliferation
· Inhibition of invasion and metastasis of cancer cells
Furthermore, scientific publications and clinical trials examining actual human data, as opposed to conjecture and hypothetical commentary,demonstrate the benefits of antioxidants in cancer. The author appears to ignore existing research that does not support his hypothesis. Although more work needs to be done, a significant body of published scientific literature demonstrates antioxidants increase survival, tumor response, or both. For example:
· A systematicreview conducted by Block, et al. in 2007 of only randomized, controlled clinical trials that reported survival and/or tumor response had the following conclusion: “None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls…”11
· A review article published in 2007 by Simone, et al. concludes, “Since the 1970s, 280 peer-reviewed in vitro and in vivostudies, including 50 human studies involving 8,521 patients, 5,081 of whom were given nutrients, have consistently shown that non-prescription antioxidants and other nutrients do not interfere with therapeutic modalities for cancer. Furthermore, they enhance the killing of therapeutic modalities for cancer, decrease their side effects, and protect normal tissue. In 15 human studies, 3,738 patients who took non-prescription antioxidants and other nutrients actually had increased survival.12
· In a 2004 review article by Prasad et al., the authors propose “that an active nutritional protocol that includes high doses of multiple dietary antioxidants and their derivatives(vitamin C, alpha-tocopheryl succinate, and natural beta-carotene), but not endogenously made antioxidants (glutathione- and antioxidant enzyme-elevating agents), when administered as an adjunct to radiation therapy, chemotherapy, or experimental therapy, may improve its efficacy by increasing tumor response and decreasing toxicity. Experimental data and limited human studies suggest that use of these nutritional approaches may improve oncologic outcomes and decrease toxicity.”13
· Several individual studies suggest antioxidant nutrients such as tea polyphenols, curcumin, quercetin, selenium, and others have synergistic effects with conventional oncology treatments(chemotherapy/radiation). 14-17
· A 2007 article by Simone, et al. provides an extensive list of studies demonstrating the benefits of antioxidant nutrients in cancer chemotherapy and radiation.12 See the table below titled “The Effects of Nutrients on Patients Receiving Systemic Treatment and/or Radiation Treatment.” For example,
o A randomized, double-blind, placebo-controlled trial assessed the efficacy of glutathione (GSH) in the prevention of cisplatin induced neurotoxicity. The authors found an improved response rate (76% [20%complete response] in the GSH group and 52% [12% complete response] in the placebo group). The trial also confirmed preliminary reports about the lack of reduction in activity of cytotoxic drugs induced by GSH.18
o In a study of 50 consecutive patients with untreated stage III or stage IV ovarian cancer, patients were treated with 2c ycles of cisplatin, carboplatin and glutathione (2,500 mg before chemotherapy). Fifty-four percent of patients had a complete response, there were fewer side effects, and the survival was better than expected.19
o In a study of 17 patients with squamous cell carcinoma of the upper digestive tract, patients were treated with radiotherapy, antioxidants, and beta-alanine (an amino acid). After observing the patients for 63 months, they were found to have decreased side effects from radiotherapy, improved physical comfort, and increased survival compared to a reference population of patients with squamous cell carcinoma of the upper digestive tract.20
o In a study of 32 patients with breast cancer that spread to axillary lymph nodes, patients were given conventional surgical and therapeutic treatments, as well as daily supplements of vitamin C (2,850 mg), vitamin E (2,500 IU), beta-carotene (32.5 IU), selenium (387 μg),essential fatty acids (1.2 g gamma linolenic acid and 3.5 g omega-3 fatty acids), and coenzyme Q10 (90 mg). Compared to patients who received conventional treatment only, this group had decreased rates of recurrence and increased quality of life, survival rates, and partial remission rates.21
o In a randomized trial, patients with metastatic breast carcinoma treated by chemotherapy were administered vitamin A. The daily doses (given indefinitely) ranged from 350,000 to 500,000 IU according to bodyweight. A significant increase in the complete response rate was observed.22
· Men who took vitamin E supplements for 10 years or more had a 30% lower risk of bladder cancer.23
· People who took multivitamin supplements daily for 10 years had one-half the risk of colon cancer, compared to those who did not take multivitamins.24
· In an observational study of 50 consecutive patients with untreated stage III or stage IV ovarian cancer, patients were treated with 2 cycles of cisplatin (40 mg/m2), carboplatin (60 mg/m2),and glutathione (2,500 mg before chemotherapy). Fifty-four percent of patients had a complete response, fewer side effects were noted, and survival was better than expected (median survival >48 months).25
· People with diets high in vitamin C have about half the risk for many types of cancer compared to people with low vitamin C diets.26,27
· People with the highest dietary intakes of vitamin C, beta-carotene, and vitamin E had a 68% lower risk of lung cancer.28
· A systematic literature review and meta-analysis suggest a modest reduction in endometrial cancer risk with higher consumption of beta-carotene, vitamin C, and vitamin E from food sources, based on data from case-control studies. The authors estimated a 12% reduction in endometrial cancer risk per 1,000 mcg/1,000 kcal for beta-carotene, a 15% decreased risk per 50 mg/1,000 kcal vitamin C, and a 9% reduction in risk per 5 mg/1,000 kcal vitamin E.29
Also,antioxidant nutrients provide other mechanisms of action that have proven benefits in cancer:
· Laboratory and animal data have revealed that antioxidants increase cancer cell differentiation and/or apoptosis and growth inhibition by several additional complex mechanisms not related to antioxidant action.30,31 As outlined by Simone et al:12
· “Antioxidants inhibit gene expression and/or activity of p53 mutant, c-myc, H-ras, Bcl2, c-neu, c-erbB2, vascular endothelial growth factor (VEGF), phosphotyrosine kinase, and protein kinase C.”
· “Vitamin E reduces the expression of VEGF and thus acts as an anti-angiogenic factor.”
· “Antioxidants selectively inhibit repair of radiation damage of cancer cells but protect normal cells when antioxidants are used before, during, and after radiation—there are no published studies that show antioxidants protect cancer cells against radiation.”32
Oncologists prescribe antioxidant medications to their cancer patients.
If antioxidants negatively affected cancer patients, the following two strong antioxidant medications would not be so widely prescribed by oncologists:
- Amifostine is an antioxidant prescription drug that reduces several forms of radiation and chemotherapy toxicity without reducing effectiveness. In fact, preliminary trials have demonstrated enhanced response rates to radiation therapy in oncology patients taking the drug.33
- Dexrazoxane protects against chemotherapy induced free radical damage to the heart. Overall, clinical trials have not shown a significant difference in response rates, time to disease progression or survival times in patients receiving chemotherapy with dexrazoxane compared tochemotherapy alone.34
Ill-informed media reporters have incited great concern among the public by improperly contextualizing Sayin’s findings. This preclinical work simply provides evidence about the effects of synthetic vitamin E and N-acetylcysteine in mutant mice under specific laboratory conditions. Findings from this experimental study cannot be extrapolated to humans.
Although the media machine prefers fear mongering to accurately reporting scientific developments, Life Extension members can rest assured that any news stories based upon this research cannot be directly translated to humans. We continue to recommend that aging individuals consume antioxidants to obtain meaningful health benefits that has been elucidated byresearch conducted in human subjects.
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