Many anticancer drugs work by increasing the levels of tumor cell hydrogen peroxide. Tumor cells are particularly sensitive to hydrogen peroxide and die as a result. However, certain enzymes in the body can work to protect cells from this kind of damage, rendering certain cancer drugs less effective. In addition, the drugs are toxic to normal cells. The drug mangafodipir, a contrast agent given to patients before they have an MRI, helps promote the production of hydrogen peroxide while at the same time, through different biologic mechanisms, protects healthy cells from the negative effects of oxidative damage.
Jérôme Alexandre, M.D., of the Groupe hospitalier Cochin-Saint Vincent de Paul in Paris, and colleagues exposed tumor cells and white blood cells from 10 cancer patients and white blood cells from six control subjects to three chemotherapy drugs--paclitaxel, oxaliplatin, and 5-fluorouracil--in the presence or absence of mangafodipir. They also studied the effects of mangafodipir on colon cancer cells in mice treated with paclitaxel.
The authors found that mangafodipir protected the white blood cells taken from healthy volunteers and from cancer patients. The drug also protected paclitaxel-treated mice from infection that would cause a lowered white blood cell count and helped increase the cancer cell-killing ability of the chemotherapy drug paclitaxel against the cancer cells in mice.
"Our results support investigation of the use of mangafodipir in cancer patients, because mangafodipir may enhance the therapeutic index of anticancer agents by both protecting normal cells and increasing antitumoral activity of these agents," the authors write. "The safety of mangafodipir administered as a contrast agent in magnetic resonance imaging has already been demonstrated."
In an accompanying editorial, James H. Doroshow, M.D., of the National Cancer Institute, suggests that clinical trials may be the next approach for studies of drugs such as mangafodipir that affect oxidative stress in tumor cells. He writes, "Overall, this study contributes to our rapidly developing understanding of tumor cell [oxidation-reduction] balance and to the possibility that therapeutic approaches to the modulation of oxidant-mediated growth control may be possible in the near future, perhaps with mangafodipir or with other [oxidation-reduction] modulators in development."
Contact:
Article: Bernard Weill, M.D., Ph.D., 33-1-58-41-20-07, bernard.weill@cch.aphp.fr
Editorial: NIH Press Officers, 301-496-6641, NIHPressOfficers@mail.nih.gov
Citations:
Article: Alexandre J, Nicco C, Chéreau C, Laurent A, Weill B, Goldwasser F, et al. Improvement of the Therapeutic Index of Anticancer Drugs by the Superoxide Dismutase Mimic Mangafodipir. J Natl Cancer Inst. 2006; 98:236-244.
Editorial: Doroshow JH, Redox Modulation of Chemotherapy-Induced Tumor Cell Killing and Normal Tissue Toxicity. J Natl Cancer Inst 2006; 98: 223-225.
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Journal
JNCI Journal of the National Cancer Institute