Concerns Over Antioxidant-Chemotherapy Interactions Overstated

The article by Drs. Dan Labriola and Robert Livingston on possible interactions between dietary antioxidants and chemotherapy, published in the July issue of Oncology (13,1999), is based on a theoretical concern that has proven to be unfounded when actually tested in clinical trials. Contrary to the authors’ assertions, numerous studies, including in vitro experiments, animal trials, and small human trials, have consistently shown an enhancement of tumor kill and patient survival when antioxidants are combined with conventional cancer therapies.

A 1997 article reviewing all of the research on this issue over the past 20 years[1] stated that “there is no evidence that a mixture of vitamins ever stimulates anti-apoptotic events in cancer cells.” A more recent review, published in 1999,[2] also concluded that supplemental antioxidants: (1) potentiate the action of chemotherapy; (2) augment the efficacy of radiation therapy and hyperthermia; (3) induce normal cell growth in cancer cells; and (4) regulate gene expression in cancer cells.

Many of the references cited by Labriola and Livingston are not relevant to the issue of combining chemotherapy and antioxidants, but rather, are review articles on the favorable use of antioxidants in the prevention of cancer or general articles on complementary therapy. The one cited reference that does specifically examine possible interactions showed an enhancement of the in vitro and in vivo antitumor actions of fluorouracil and doxorubicin when combined with antioxidants. This article concludes that “chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.”[3]

In essence, the article by Labriola and Livingston is a pharmacology essay that discusses the proposed mechanisms of action of chemotherapeutic agents, the theories behind the activity of antioxidants, and the “predictable mechanisms of interaction” between the two. Its conclusion, therefore, is basically a biochemical theory based on other biochemical theories. Frankly, we are surprised that the authors seem to believe their own conclusion, despite the large body of actual clinical research that contradicts it.

The authors themselves point out that mesna, an antioxidant, is used to prevent the side effects of the chemotherapeutic agents ifosfamide (Ifex) and cyclophosphamide (Cytoxan, Neosar) without affecting the efficacy of these drugs. Amifostine (Ethyol), another antioxidant, has been used to prevent cisplatin (Platinol)-induced renal damage, again without reducing its efficacy.[4] In addition, amifostine was recently approved for the prevention of xerostomia secondary to irradiation of head and neck tumors.

Findings of Recent Articles

Several recent articles published in the peer-reviewed literature support the contention that antioxidants not only reduce the side effects of cancer treatments but also enhance tumor kill:

A 1994 study published in Nutrition and Cancer showed that a mixture of vitamins enhances the growth-inhibitory effect of the chemotherapy commonly used for melanoma.[5]

A 1991 study demonstrated that vitamin C reduces the toxicity of doxorubicin without reducing its antitumor activity.[6] Another, more recent study, published in 1996, found that vitamin C actually improves the tumor kill of chemotherapeutic agents commonly used for breast cancer.[7]

Green tea, a potent antioxidant, was noted to enhance the effect of doxorubicin by 2.5-fold.[8] Even more interesting, in a 1998 research study, green tea appeared to increase the effectiveness of doxorubicin even in tumors that do not normally respond to this drug.[9]

A large body of work has compared cisplatin alone with cisplatin combined with the antioxidant glutathione in ovarian cancer. The studies repeatedly showed better outcomes with less toxicity when glutathione was used adjunctively. One of the most recent studies found that treatment with glutathione raised the response rate from 62% to 73%.[10]

In 1996, Scientific American published an entire issue devoted to cancer. The matter of antioxidants and chemotherapy was addressed with the following statements: “for many years it was assumed that radiation therapy and many chemotherapeutic drugs killed malignant cells directly by wreaking widespread havoc in their DNA. We now know that the treatments often harm DNA to a relatively minor extent. Nevertheless, the affected cells perceive that the inflicted damage cannot be easily repaired and they actively kill themselves.”[11] An article in Cell states that cancer cells often fail to undergo apoptosis in response to treatment and that agents that stimulate apoptosis would be beneficial.[12] This is precisely how antioxidants work.

Medicine is an evidence-based science. The history of medicine and pharmacology is replete with treatments that were discarded because they did not live up to theoretical predictions. Theory is a starting point for research, but when the evidence contradicts the theory, we must recognize the primacy of the evidence. To date, the evidence on antioxidants strongly favors their use to improve the efficacy of cancer treatments, reduce short-term side effects, and, hopefully, decrease the incidence of secondary cancers caused by these treatments.

The primary rule of medicine is, “first, do no harm.” We must consider the harm caused by ignoring data that do not fit our expectations and, thereby, denying patients access to protective factors. We agree with Labriola and Livingston that the fields of nutrition and oncology are complex, and that patients should consult with those experienced in the integration of the two disciplines as they undergo treatment. This would allow patients who decide to take a holistic approach to their cancer care to optimize that care.

Paul Reilly ND, Lac
Mark Gignac, ND
Ben Chue, MD
Manouchehr Sardo, MD
Cancer Treatment Centers of AmericaSeattle, Washington

The Authors Respond

In their letter, Reilly and colleagues from the Cancer Treatment Centers of America argue in favor of supplementing chemotherapy with antioxidants based on “in vitro experiments, animal trials, and small human trials.” They also suggest that the principles of antioxidant-chemotherapy interactions articulated in our Oncology article are merely theoretical and are refuted by those same references.

Main Points of the Article

Before responding directly to these arguments, we feel that it is important to restate the main points made in our article.

The article addresses human safety and preservation of the benefits of systemic therapy. It does not deal with the efficacy of antioxidants.

The currently known mechanisms of interaction between chemotherapeutic agents and dietary antioxidants predict that, in some cases, positive short-term results may precede negative long-term effects. In vitro and animal studies cannot duplicate these conditions, and short-term human studies may not address the mechanisms in question.

This particular interaction mechanism applies only to chemotherapeutic agents that utilize reactive oxygen species for their cytotoxic effect. (There exist other mechanisms of interaction, which are beyond the scope of the article.) The results of investigations of other drugs cannot reasonably be expected to apply to the vulnerable agents.

 Human studies clearly show that antioxidants can interfere with the actions of certain chemotherapeutic agents. One of many such examples, described and referenced in our article, is the thiol groups, which can reduce the antitumor effects of alkylating agents. Such interaction mechanisms are well known, well studied, and not theoretical.

Of the 12 references cited by Reilly and colleagues, 6 (references 3, 5, 6, 7, 8, and 9) are in vitro or limited animal studies that would not be expected to demonstrate the mechanisms of interaction described in our article.

The only human study cited by Reilly et al (reference 10) measures toxicity and quality of life during treatment with cisplatin. It does not assess long-term survival or any of the specific parameters of the interaction mechanisms described in our paper. In fact, the authors of this human study clearly indicate that “further work is required to define the optimal use of GSH [glutathione] in reducing the toxicity of platinum containing drugs ...”

References 1, 2, and 4 are reviews, while reference 12 is a commentary. None of these references offers any additional evidence to support the writers’ position.

Reilly and colleagues quote a passage from a 1996 issue of the popular magazine Scientific American (not Scientific American Medicine). This quote is extracted from a lay description of apoptosis that, contrary to the letter writers’ assertions, does not address or even mention antioxidants. Although the quote, even out of context, is accurate, it essentially repeats and supports the exemplary description of the actions of alkylators and doxorubicin contained in our article. It does not support the letter writers’ position.

There is a growing body of high-quality knowledge addressing the subject of conventional chemotherapeutic agents and nutrition, including some of the references cited by Reilly et al. As with all good science, however, we must accurately interpret the results of research and not draw overly broad conclusions from them.

Making Clinical Decisions

Our article included an entire section suggesting directions for new research to help enable us to safely and responsibly take advantage of the potential benefits of antioxidant-chemotherapy combinations. As good new data become available, we will be able to safely and effectively incorporate new strategies. In the meantime, we suggest that clinical decisions continue to be made based first on patient safety. The important clinical question is whether the potentia1 benefits of antioxidant-chemotherapy interactions outweigh the potential risks of reduced drug cytotoxicity and recurrence. Our article was meant to be a tool to help answer that question.

In conclusion, Reilly and colleagues do not offer any evidence that actually substantiates their position that the mechanisms of antioxidant-chemotherapy interactions are “unfounded.” In fact, some of their references support the clinical potential for those interactions.

Dan Labriola, ND
Director, Northwest NaturalHealth Specialty Care ClinicSeattle, Washington

 
Robert Livingston, MD
Professor of MedicineDivision of Oncology University of WashingtonMedical CenterSeattle, Washington

References:

1. Cole W, Prasad KN: Contrasting effects of vitamins as modulators of apoptosis in cancer cells and normal cells: A review. Nutr Cancer 29:97-103, 1997.

2. Prasad KN, Kumar A, Kochupillai V, et al: High doses of antioxidant vitamins: Essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr 18:13-25, 1999.

3. Chinery R, Brockman JA, Peller MO, et al Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: A p53-independent action of p21 via C/EBP. Nat Med 3:1233-1241, 1997.

4. Kurbacher CM, Mallman PK: Chemo-protection in anticancer therapy: The emerging role of amifostine (WR-2721). Anticancer Res 18:2203-2210, 1998.

5. Prasad KN, Hernandez C, Edwards-Prasad J, et al: Modification of the effect of tamoxifen, cisplatin, DTIC, and interferon-alpha2b on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer 22:233-245, 1994.

6. Shimpo K, Nagatsu T, Yamada K, et al: Ascorbic acid and Adriamycin toxicity. Am J Clin Nutr 54:1298s-1301s, 1991.

7. Kurbacher C, Wagner U, Kolster B, et al: Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in-vitro. Cancer Lett 103:183-189, 1996.

8. Sadzuka Y, Sugiyama T, Hirota S: Modulation of cancer chemotherapy by green tea. Clin Cancer Res 4:153-156, 1998.

9. Stammier O, Volm M: Green tea catechins (EGCG & ECG) have modulating effects on the activity of doxorubicin in drug-resistant cell lines. Anticancer Drugs 8:265-268, 1997.

10. Smyth JF, Bowman A, Perren T, et al: Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomized trial. Ann Oncol 8:569-573, 1997.

11. Weinberg RA: How cancer arises. Sci Am 275:62, 1996.

12 Hunter T, Pines J: Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 79:573-582, 1994.