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Concerns Over Antioxidant-Chemotherapy Interactions Overstated

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 America
Seattle, Washington

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