McKeage M J, Abel G, Kelland L R, Harrap K R
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
Br J Cancer. 1994 Jan;69(1):1-7. doi: 10.1038/bjc.1994.1.
Intrinsic resistance to existing clinical platinum drugs is a major cause of treatment failure; moreover, these agents have the drawbacks of cross-resistance and intravenous administration. The mechanism of intrinsic cisplatin resistance and the mechanism of circumvention of intrinsic resistance by a member (JM221) of the ammine/amine platinum (IV) dicarboxylate class of platinum complex was studied in intrinsically resistant (SKOV-3) and sensitive (41M) human ovarian carcinoma cell lines. JM221 reduced the cisplatin resistance factor nine- to 2.7-fold, was more potent than cisplatin and showed marked time-dependent cytotoxicity. Cellular platinum accumulation was 20- to 40-fold greater (P < 0.001), and DNA platination was fourfold greater (P < 0.02), immediately following 2 h equimolar exposure to JM221, compared with cisplatin. DNA platinum levels decreased following cisplatin exposure with a half-life approximating 48 h in both lines, while no net removal of DNA-bound platinum was recorded following JM221 exposure. JM221 caused DNA interstrand cross-linking, but this was 10-20% less frequent with JM221 than with cisplatin when expressed as a proportion of total DNA platinum lesions. Cisplatin DNA interstrand cross-linking was twofold greater in the intrinsically sensitive line (41M) than in the resistant line (SKOV-3) over a range of concentrations and time-points. Neither cellular platinum accumulation, levels of DNA platination nor the rate of removal of DNA-bound platinum in the two cell lines related to their ninefold difference in cisplatin sensitivity. Intrinsic cisplatin resistance appears to be attributable to the inhibition of formation of bifunctional DNA lesions, while the circumvention of intrinsic resistance by JM221 seems to be the result of both improved transport properties and circumvention of DNA repair mechanisms.
对现有临床铂类药物的内在抗性是治疗失败的主要原因；此外，这些药物还存在交叉抗性和静脉给药的缺点。在内在抗性（SKOV-3）和敏感（41M）的人卵巢癌细胞系中研究了顺铂内在抗性的机制以及铂配合物二羧酸氨/胺铂（IV）类成员（JM221）规避内在抗性的机制。JM221将顺铂抗性因子降低了9至2.7倍，比顺铂更有效，并表现出明显的时间依赖性细胞毒性。在等摩尔暴露于JM221 2小时后，与顺铂相比，细胞内铂积累量高出20至40倍（P < 0.001），DNA铂化程度高出四倍（P < 0.02）。顺铂暴露后DNA铂水平下降，两条细胞系中的半衰期约为48小时，而JM221暴露后未记录到与DNA结合的铂的净清除。JM221导致DNA链间交联，但以总DNA铂损伤的比例表示时，JM221引起的交联比顺铂少10 - 20%。在一系列浓度和时间点上，顺铂DNA链间交联在内在敏感细胞系（41M）中比抗性细胞系（SKOV-3）高两倍。两条细胞系中的细胞铂积累、DNA铂化水平以及与DNA结合的铂的去除率均与其顺铂敏感性的九倍差异无关。顺铂的内在抗性似乎归因于对双功能DNA损伤形成的抑制，而JM221对内在抗性的规避似乎是转运特性改善和DNA修复机制规避的共同结果。
