Chresta C M, Arriola E L, Hickman J A
Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
Behring Inst Mitt. 1996 Oct(97):232-40.
Cytotoxic drugs currently remain as the basis for the chemotherapy of metastatic cancer. Why they fail to kill sufficient tumour cells in the major human solid cancers, such as the carcinomas, is suggested in this review to be due to the inherent inability of these cells to engage apoptosis after drug-induced damage. As a paradigm for drug resistant cancers, the resistance of bladder carcinoma cell lines to DNA damaging drugs is described here in terms of their response to the topoisomerase II poison etoposide. 60%-70% of bladder carcinomas have mutant p53; this can prevent the detection of and response to DNA damage. In vitro studies with a bladder carcinoma cell line containing a wild type p53 showed that it underwent a G1 checkpoint after etoposide, potentially allowing DNA damage repair, as well as apoptosis. In lines with mutant or non-functional p53 there is no checkpoint and no apoptosis. All lines showed constitutive expression of bcl-2 and bcl-XL (the suppressors of apoptosis) with low and non-inducible levels of bax (a promoter of apoptosis). Taken together, this menu of gene expression is more favourable to survival than apoptosis after the imposition of drug-induced DNA damage and may contribute to their inherent drug resistance.
细胞毒性药物目前仍然是转移性癌症化疗的基础。在这篇综述中指出，在诸如 carcinomas 等主要人类实体癌中，它们未能杀死足够数量肿瘤细胞的原因，是这些细胞在药物诱导损伤后内在无法启动凋亡。作为耐药性癌症的一个范例，本文根据膀胱癌细胞系对拓扑异构酶 II 毒药依托泊苷的反应，描述了它们对 DNA 损伤药物的耐药性。60%-70%的膀胱癌有 p53 突变；这会阻止对 DNA 损伤的检测和反应。对含有野生型 p53 的膀胱癌细胞系进行的体外研究表明，依托泊苷处理后它经历了 G1 期检查点，这可能允许 DNA 损伤修复以及凋亡。在具有突变型或无功能 p53 的细胞系中，不存在检查点且不会发生凋亡。所有细胞系均显示 bcl-2 和 bcl-XL（凋亡抑制因子）的组成型表达，而 bax（凋亡促进因子）的水平较低且不可诱导。综上所述，这种基因表达情况在药物诱导 DNA 损伤后更有利于存活而非凋亡，可能导致它们固有的耐药性。
