Fischer Joshua L, Mihelc Elaine M, Pollok Karen E, Smith Martin L
Indiana University Cancer Center, Indiana University School of Medicine, Room 155, 1044 West Walnut Street, Indianapolis, IN 46202, USA.
Mol Cancer Ther. 2007 Jan;6(1):355-61. doi: 10.1158/1535-7163.MCT-06-0472.
Selenium in various chemical forms has been the subject of cancer chemoprevention trials, but, more recently, selenium has been used in combination with DNA-damaging chemotherapeutics. Specifically, selenium protected tissues from dose-limiting toxicity and, in fact, allowed delivery of higher chemotherapeutic doses. At the same time, selenium did not protect cancer cells. Therefore, we seek to define the genetic basis for the observed selectivity of selenium in combination chemotherapeutics. The tumor suppressor p53 is mutated in the vast majority of cancers, but is by definition wild-type in nontarget tissues such as bone marrow and gut epithelium, tissues that are often dose-limiting due to DNA damage. We used primary, low-passage mouse embryonic fibroblasts that are wild-type or null for p53 genes to test differential effects of selenium. Seleno-l-methionine, nontoxic by itself, was used to pretreat cell cultures before exposure to UV radiation or UV-mimetic cancer chemotherapy drugs. Seleno-l-methionine pretreatment caused a DNA repair response, which protected from subsequent challenge with DNA-damaging agents. The observed DNA repair response and subsequent DNA damage protection were p53 dependent as neither was observed in p53-null cells. The data suggest that (a) p53 may be an important genetic determinant that distinguishes normal cells from cancer cells, and (b) combinatorial chemotherapeutics that act by p53-dependent mechanisms may enhance chemotherapeutic efficacy by increasing the chemotherapeutic window distinguishing cancer cells from normal cells.
各种化学形式的硒一直是癌症化学预防试验的研究对象，但最近，硒已被用于与具有DNA损伤作用的化疗药物联合使用。具体而言，硒可保护组织免受剂量限制性毒性的影响，事实上，还能使更高剂量的化疗药物得以应用。与此同时，硒并不保护癌细胞。因此，我们试图确定在联合化疗中观察到的硒选择性的遗传基础。肿瘤抑制因子p53在绝大多数癌症中发生突变，但根据定义，在非靶组织如骨髓和肠道上皮中为野生型，这些组织常因DNA损伤而成为剂量限制性组织。我们使用p53基因野生型或缺失的原代、低传代小鼠胚胎成纤维细胞来测试硒的不同作用。本身无毒的硒代-L-蛋氨酸在细胞培养物暴露于紫外线辐射或模拟紫外线的癌症化疗药物之前用于预处理。硒代-L-蛋氨酸预处理引发了DNA修复反应，从而保护细胞免受随后DNA损伤剂的攻击。观察到的DNA修复反应及随后的DNA损伤保护均依赖于p53，因为在p53缺失的细胞中均未观察到这些现象。数据表明：（a）p53可能是区分正常细胞与癌细胞的重要遗传决定因素；（b）通过p53依赖机制起作用的联合化疗可能通过扩大区分癌细胞与正常细胞的化疗窗口来提高化疗疗效。
