Tempol protects against oxidative damage and delays epithelial tumor onset in Fanconi anemia mice
Tempol protects against oxidative damage and delays epithelial tumor onset in Fanconi anemia mice
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DOI：
10.1158/0008-5472.can-07-5186
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Grompe, Markus
中科院分区：
文献类型：
--
作者：
Zhang, Qing-Shuo;Eaton, Laura;Grompe, Markus
范可尼贫血（FA）是一种遗传性疾病，其特征是先天性异常、骨髓衰竭和明显的癌症易感性。 FA 患者患血液系统恶性肿瘤和实体瘤的风险较高。我们使用 Faned2(-/-) 基因敲除小鼠作为 FA 模型，研究了 tempol（一种硝基氧抗氧化剂和超氧化物歧化酶模拟物）作为实体瘤肿瘤延迟剂的潜力。饮食tempol使Fancd2(-/-) Trp53(+/-)小鼠的平均无肿瘤生存时间从308天增加了27% (P < 0.01)至390天，并且没有改变总体肿瘤谱。更引人注目的是，在 Fancd2(-/-) Trp53(+/-) 小鼠中，tempol 延迟了上皮肿瘤的发生，并将平均上皮肿瘤无瘤生存时间从 312 天增加了 38% (P < 0.0001)，从 312 天增加到 432 天。这些结果表明tempol可以显着延缓Fancd2(-/-) Trp53(+/-)小鼠的肿瘤形成。此外，tempol治疗不会对FA造血干细胞的再生能力产生不利影响。 tempol 处理的 FA 成纤维细胞和小鼠中氧化 DNA 损伤的减少表明其延缓肿瘤的功能可能归因于其抗氧化活性。
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 Faned2(-/-) 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.