Mirzayans R, Sabour M, Rauth A M, Paterson M C
Department of Medicine, Cross Cancer Institute, Edmonton, Alberta, Canada.
Br J Cancer. 1993 Nov;68(5):838-44. doi: 10.1038/bjc.1993.442.
Dermal fibroblasts cultured from members of a family presenting multiple polyps and sarcomas were compared with fibroblast strains from unrelated healthy donors for sensitivity to killing by four genotoxic agents. Cells from the sister of the male proband (strain 3437T), mother (strain 3703T), two of his paternal aunts (3701T and 3704T) and one paternal uncle (3702T) displayed marked resistance (1.8 to 4.3 times greater than the normal mean) to 4-nitroquinoline 1-oxide (4NQO), a procarcinogen whose DNA-damaging properties encompass those of both far (254 nm) ultraviolet (UV) light and ionising radiation. These same 4NQO-resistant cells, however, responded normally to reproductive inactivation by UV light, 60Co gamma radiation or the alkylating agent methylnitrosourea, signifying that the abnormal resistance of these cells to 4NQO is not associated with aberrant DNA metabolism. In keeping with this conclusion, exposure to a given dose of 4NQO produced decreased amounts of DNA damage and stimulated lower levels of repair DNA synthesis in all five 4NQO-resistant strains than in normal controls. Moreover, exogenous radiolabelled 4NQO accumulated to a lesser extent in the 4NQO-resistant than in the normal fibroblasts. Cell sonicates of strains 3437T, 3701T and 3702T exhibited reduced capacities (40-60% of normal) to catalise the conversion of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide. However, the 4NQO-resistant strains 3703T and 3704T carried out 4NQO bioreduction at normal rates. Our data therefore indicate that enhanced resistance to 4NQO cytotoxicity in 3437T, 3701T and 3702T is a consequence of anomalies in both intracellular accumulation and enzymatic reduction of 4NQO, whereas 4NQO resistance in 3703T and 3704T appears to result solely from reduced intracellular drug accumulation.
从一个患有多发性息肉和肉瘤的家族成员中培养出的皮肤成纤维细胞，与来自无亲缘关系的健康供体的成纤维细胞系进行比较，以研究它们对四种基因毒性剂杀伤作用的敏感性。男性先证者的姐姐（3437T细胞系）、母亲（3703T细胞系）、两位父系姑姑（3701T和3704T细胞系）和一位父系叔叔（3702T细胞系）的细胞，对4-硝基喹啉-1-氧化物（4NQO）表现出显著抗性（比正常平均值高1.8至4.3倍）。4NQO是一种前致癌物，其DNA损伤特性兼具远紫外线（254nm）和电离辐射的特性。然而，这些对4NQO具有抗性的细胞，对紫外线、60Coγ射线或烷化剂甲基亚硝基脲导致的生殖失活反应正常，这表明这些细胞对4NQO的异常抗性与异常的DNA代谢无关。与此结论一致的是，与正常对照相比，在所有五个对4NQO具有抗性的细胞系中，暴露于给定剂量的4NQO后，DNA损伤量减少，修复DNA合成水平降低。此外，外源性放射性标记的4NQO在对4NQO具有抗性的细胞中积累程度低于正常成纤维细胞。3437T、3701T和3702T细胞系的细胞超声裂解物催化4NQO转化为近致癌物4-羟基氨基喹啉-1-氧化物的能力降低（为正常水平的40-60%）。然而，对4NQO具有抗性的3703T和3704T细胞系以正常速率进行4NQO生物还原。因此，我们的数据表明，3437T、3701T和3702T细胞系对4NQO细胞毒性的抗性增强是4NQO细胞内积累和酶促还原异常的结果，而3703T和3704T细胞系对4NQO的抗性似乎仅源于细胞内药物积累减少。
