Zhang Qing-Shuo, Eaton Laura, Snyder Eric R, Houghtaling Scott, Mitchell James B, Finegold Milton, Van Waes Carter, Grompe Markus
Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 97239, USA.
Cancer Res. 2008 Mar 1;68(5):1601-8. doi: 10.1158/0008-5472.CAN-07-5186.
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.
范科尼贫血（FA）是一种遗传性疾病，其特征为先天性异常、骨髓衰竭和显著的癌症易感性。FA患者发生血液系统恶性肿瘤和实体瘤的风险升高。我们使用Fancd2（-/-）基因敲除小鼠作为FA模型，研究了氮氧化物抗氧化剂和超氧化物歧化酶模拟物tempol作为实体瘤肿瘤延迟剂的潜力。饮食中添加tempol可使Fancd2（-/-）Trp53（+/-）小鼠的平均无瘤存活时间延长27%（P < 0.01），从308天延长至390天，且不改变总体肿瘤谱。更引人注目的是，在Fancd2（-/-）Trp53（+/-）小鼠中，tempol延迟了上皮肿瘤的发生，并使平均无上皮肿瘤存活时间延长了38%（P < 0.0001），从312天延长至432天。这些结果表明，tempol可显著延迟Fancd2（-/-）Trp53（+/-）小鼠的肿瘤形成。此外，tempol治疗对FA造血干细胞的再填充能力没有不利影响。tempol处理的FA成纤维细胞和小鼠中氧化性DNA损伤的减少表明，其肿瘤延迟功能可能归因于其抗氧化活性。
