Mistry P, Kelland L R, Loh S Y, Abel G, Murrer B A, Harrap K R
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Cancer Res. 1992 Nov 15;52(22):6188-93.
We have compared the cellular accumulation and cytotoxicity of three platinum compounds in a panel of five human ovarian carcinoma cell lines. The cell lines, which were established from both untreated and pretreated patients, showed a wide range in sensitivity to cisplatin and other platinum drugs. The panel consisted of two sensitive (41M, CH1), one in vivo acquired resistant (PXN/94) with moderate sensitivity, and two intrinsically resistant (SKOV-3, HX/62) cell lines. The cisplatin 2-h concentration of drug required to inhibit cell growth by 50% compared with vehicle treated control cells (IC50 values) for these cell lines were in the following order: CH1 < 41M < PXN/94 < SKOV-3 < HX/62. None of the cell lines showed saturation of platinum accumulation (per mg protein) at 2 h after exposure to cisplatin concentrations of up to 500 microM. The highest cellular platinum accumulation was observed in the sensitive 41M cell line which was established from an untreated patient. The lowest accumulation was found in the intrinsically resistant HX/62 cell line. The rate of platinum accumulation at an equimolar concentration of cisplatin was 41M > SKOV-3 > CH1 > PXN/94 > HX/62. The relationship between drug accumulation and cytotoxicity was evaluated by comparing 2-h IC50 values with platinum accumulation following exposure to both equimolar and equitoxic doses of the agent. The results suggest that reduced drug accumulation may play a partial role in the mechanism of intrinsic resistance to cisplatin in one cell line (SKOV-3) and a major role in another (HX/62), where reduced accumulation is attributable to reduced uptake rather than enhanced efflux. Decreased drug accumulation may also contribute significantly to the lower sensitivity of the PXN/94 cell line to cisplatin. Interestingly, both the PXN/94 and the sensitive CH1 cell lines, which were established from patients pretreated with platinum drugs, showed reduced drug accumulation relative to the 41M cell line. Cellular accumulation of tetraplatin and JM221 [(ammine)dibutyratodichloro(cyclohexylamine)platinum(IV)], a novel platinum(IV) dicarboxylate complex exhibiting enhanced cytotoxicity compared to cisplatin, was also examined. Comparison with platinum accumulation from cisplatin suggests that the increased cytotoxicity of tetraplatin and JM221 may be related to their increased accumulation. Significantly both agents are more lipophilic than cisplatin, which may account partially for their improved uptake in cisplatin resistant cells.
我们比较了三种铂化合物在一组五种人卵巢癌细胞系中的细胞蓄积和细胞毒性。这些细胞系取自未经治疗和经过预处理的患者，对顺铂和其他铂类药物的敏感性差异很大。该细胞系组包括两个敏感细胞系（41M、CH1）、一个体内获得性耐药且具有中等敏感性的细胞系（PXN/94）以及两个固有耐药细胞系（SKOV-3、HX/62）。与溶媒处理的对照细胞相比，这些细胞系抑制细胞生长50%所需的顺铂2小时药物浓度（IC50值）顺序如下：CH1 < 41M < PXN/94 < SKOV-3 < HX/62。在暴露于高达500微摩尔的顺铂浓度2小时后，没有一个细胞系显示出铂蓄积（每毫克蛋白质）达到饱和。在从未经治疗的患者中建立的敏感41M细胞系中观察到最高的细胞铂蓄积。最低的蓄积量出现在固有耐药的HX/62细胞系中。在等摩尔浓度的顺铂下，铂的蓄积速率为41M > SKOV-3 > CH1 > PXN/94 > HX/62。通过比较等摩尔和等毒性剂量的药物暴露后2小时的IC50值与铂蓄积量，评估了药物蓄积与细胞毒性之间的关系。结果表明，药物蓄积减少可能在一个细胞系（SKOV-3）对顺铂的固有耐药机制中起部分作用，而在另一个细胞系（HX/62）中起主要作用，在HX/62中蓄积减少归因于摄取减少而非外排增强。药物蓄积减少也可能是PXN/94细胞系对顺铂敏感性较低的重要原因。有趣的是，从接受过铂类药物预处理的患者中建立的PXN/94和敏感CH1细胞系，相对于41M细胞系，均显示出药物蓄积减少。还检测了四铂和JM221[（氨）二丁酸二氯（环己胺）铂（IV）]的细胞蓄积情况，JM221是一种新型的铂（IV）二羧酸配合物，与顺铂相比具有增强的细胞毒性。与顺铂的铂蓄积情况比较表明，四铂和JM221细胞毒性增加可能与其蓄积增加有关。值得注意的是，这两种药物均比顺铂更具亲脂性，这可能部分解释了它们在顺铂耐药细胞中摄取的改善。
