Goddard P M, Orr R M, Valenti M R, Barnard C F, Murrer B A, Kelland L R, Harrap K R
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Anticancer Res. 1996 Jan-Feb;16(1):33-8.
Two pairs of cis/trans platinum complexes, JM118 (cis-ammine(cyclohexylamine) dichloro platinum(II)) and its trans counterpart, JM334 and JM149 (cis-ammine(cyclohexylamine) dichloro-dihydroxo platinum(IV)) and its trans counterpart JM335 have been evaluated (both in vitro and in vivo) against two murine tumour models of historical importance in the discovery of novel platinum drugs; the ADJ/PC6 plasmacytoma and the L1210 leukaemia and sublines selected for resistance to platinum drugs. In vitro, results showed that the trans complexes induced comparable growth inhibitory properties to those observed for cisplatin and their respective cis isomers. Moreover, retention of activity was observed in a series of 5 acquired platinum drug (cisplatin, carboplatin, iproplatin, tetraplatin and JM149)-resistant L1210 sublines whereas at least partial cross-resistance was observed to the cis isomer JM149 in the acquired carboplatin and iproplatin-resistant lines (in addition to being 11-fold resistant in the line selected for resistance to JM149 itself). In vivo, JM355 showed activity against both the ADJ/PC6 and L1210 models of acquired cisplatin resistance. Furthermore, JM355 was active against an ADJ/PC6 subline possessing resistance to iproplatin and a L1210 subline possessing resistance to its cis isomer JM149. Interestingly, the trans platinum(II) counterpart of JM335(JM334) was inactive in vivo. These data indicate that the trans platinum(IV) complex JM335 possess several in vitro growth inhibitory- and in vivo antitumour properties which are distinct from those observed for cisplatin (or its cis isomer). Thus, JM335 contravenes the original structure-activity rules determined for platinum-containing compounds and, because of its level of activity against cisplatin-resistant tumours, establishes the complex as of interest in the search for new platinum drugs active against cisplatin-resistant disease.
两对顺式/反式铂配合物，JM118（顺式 - 氨（环己胺）二氯铂（II））及其反式对应物，JM334以及JM149（顺式 - 氨（环己胺）二氯二羟基铂（IV））及其反式对应物JM335，已针对在新型铂类药物发现中具有历史重要性的两种小鼠肿瘤模型（ADJ/PC6浆细胞瘤和L1210白血病以及选择对铂类药物耐药的亚系）进行了（体外和体内）评估。在体外，结果表明反式配合物诱导出与顺铂及其各自顺式异构体所观察到的相当的生长抑制特性。此外，在一系列5种获得性铂类药物（顺铂、卡铂、异丙铂、四铂和JM149）耐药的L1210亚系中观察到活性保留，而在获得性卡铂和异丙铂耐药的细胞系中观察到对顺式异构体JM149至少部分交叉耐药（除了在选择对JM149自身耐药的细胞系中耐药11倍）。在体内，JM355对获得性顺铂耐药的ADJ/PC6和L1210模型均显示出活性。此外，JM355对具有异丙铂耐药性的ADJ/PC6亚系和具有其顺式异构体JM149耐药性的L1210亚系也有活性。有趣的是，JM335的反式铂（II）对应物（JM334）在体内无活性。这些数据表明反式铂（IV）配合物JM335具有几种体外生长抑制和体内抗肿瘤特性，这些特性与顺铂（或其顺式异构体）所观察到的不同。因此，JM335违背了为含铂化合物确定的原始构效规则，并且由于其对顺铂耐药肿瘤的活性水平，使该配合物成为寻找对顺铂耐药疾病有活性的新铂类药物的关注对象。
