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Tempol Protects against Oxidative Damage and Delays Epithelial Tumor Onset in Fanconi Anemia Mice

¹ Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon; ² Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders and ³ Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, Maryland; and ⁴ Department of Pathology, Texas Children's Hospital, Houston, Texas

Requests for reprints: Qing-Shuo Zhang, Oregon Stem Cell Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-6889; Fax: 503-494-5044; E-mail: zhangqi{at}ohsu.edu.

Key Words: Fanconi anemia • tempol • antioxidant • cancer • oxidative stress

Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure, and marked cancer susceptibility. FA patients have an elevated risk of developing hematologic malignancies and solid tumors. Using Fancd2^–/– knockout mice as a model of FA, we examined the potential of tempol, a nitroxide antioxidant and a superoxide dismutase mimetic, as a tumor-delaying agent for solid tumors. Dietary tempol increased the mean tumor-free survival time of Fancd2^–/– Trp53^+/– mice by 27% (P < 0.01), from 308 to 390 days, without changing the overall tumor spectrum. More strikingly, tempol delayed the onset of epithelial tumors and increased the mean epithelial tumor-free survival time by 38% (P < 0.0001), from 312 to 432 days, in Fancd2^–/– Trp53^+/– mice. These results show that tempol can significantly delay tumor formation in Fancd2^–/– Trp53^+/– mice. Furthermore, tempol treatment did not adversely affect the repopulating ability of FA hematopoietic stem cells. The reduction in oxidative DNA damage in tempol-treated FA fibroblasts and mice suggests that its tumor-delaying function may be attributed to its antioxidant activity. [Cancer Res 2008;68(5):1601–8]