Rischin D, Ling V
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Br J Cancer. 1996 Aug;74(4):590-6. doi: 10.1038/bjc.1996.406.
Ormaplatin (also known as tetraplatin) is a platinum-containing analogue which has recently undergone clinical trials. Ormaplatin may undergo conversion to dichloro(D,L-trans)-1,2-diaminocyclohexaneplatinum(II) [P1Cl2(trans-dach)]. The cisplatin-resistant murine lymphoma cell lines E8 and E5, were found to be cross-resistant to ormaplatin and PtCl2(trans-dach). We found an inverse rank correlation between drug resistance and drug accumulation for PtCl2(trans-dach) similar to our previous findings with cisplatin; however, accumulation of ormaplatin in the resistant cells was increased. Ormaplatin cytotoxicity appears to result primarily from extracellular conversion to PtCl2(trans-dach), since ormaplatin cytotoxicity was decreased under conditions where extracellular conversion to PtCl2(trans-dach) was minimised. Co-incubation with different inhibitors of energy metabolism resulted in a 65-70% increase in PtCl2(trans-dach) accumulation in the parental cell line R1.1 and a 113-307% increase in the resistant cell line E5 which suggests that the decrease in accumulation in E5 may be at least partly energy dependent. We conclude from these findings that cross-resistance to ormaplatin is associated with an energy-dependent decreased accumulation of PtCl2(trans-dach) in these cisplatin-resistant cell lines.
奥马铂（也称为四铂）是一种含铂类似物，最近已进行临床试验。奥马铂可能会转化为二氯（D，L -反式）-1,2 -二氨基环己烷铂（II）[P1Cl2（反式-达卡）]。发现顺铂耐药的小鼠淋巴瘤细胞系E8和E5对奥马铂和PtCl2（反式-达卡）具有交叉耐药性。我们发现PtCl2（反式-达卡）的耐药性与药物积累之间存在反向等级相关性，这与我们之前关于顺铂的研究结果相似；然而，耐药细胞中奥马铂的积累增加了。奥马铂的细胞毒性似乎主要源于细胞外转化为PtCl2（反式-达卡），因为在细胞外转化为PtCl2（反式-达卡）最小化的条件下，奥马铂的细胞毒性降低了。与不同的能量代谢抑制剂共同孵育导致亲代细胞系R1.1中PtCl2（反式-达卡）的积累增加65 - 70%，耐药细胞系E5中增加113 - 307%，这表明E5中积累的减少可能至少部分依赖于能量。我们从这些发现中得出结论，在这些顺铂耐药细胞系中，对奥马铂的交叉耐药性与PtCl2（反式-达卡）的能量依赖性积累减少有关。
