Naredi P, Heath D D, Enns R E, Howell S B
Department of Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
Cancer Res. 1994 Dec 15;54(24):6464-8.
The metal compound cisplatin (DDP) is a widely used anticancer agent but naturally occurring and acquired resistance to DDP limits its effectiveness. Resistance is associated with a decreased accumulation of DDP and increased levels of glutathione and metallothioneins. Such changes also serve as protective and detoxification mechanisms for other metal salts in prokaryotes and lower eukaryotes. The aim of this study was to find metal salts for which the cross-resistance profile was the same as for DDP in sublines of the parental 2008 human ovarian carcinoma cells selected with either DDP (2008/C13*5.25) or CdCl2 and ZnCl2 (2008/MT). Among the metal salts tested the resistance profile of trivalent antimony most closely resembled that of DDP. DDP-selected cells were 15-fold resistant to DDP and 4.4-fold cross-resistant to antimony potassium tartrate, whereas of the cations tested (Cd2+, Zn2+, Ni2+ and Co2+) cross-resistance was observed only for Cd2+ (2.4-fold). When 2008 cells were selected for resistance to antimony (6.6-fold) they were found to be 16-fold cross-resistant to DDP. Accumulation of the DDP analogue cis-[3H]dichloro(ethylenediamine)platinum(II) was 59% lower in the DDP-selected subline and 48% lower in the antimony-selected variant than in the parental cell line. We conclude from the mutual cross-resistance to DDP and antimony potassium tartrate and from the impaired uptake of [3H]DEP in both the DDP and antimony-selected variants that DDP and antimony share a common mechanism of resistance. The significance of this observation lies in the fact that several evolutionarily conserved mechanisms for antimony detoxification are already known in lower organisms which may point the way to identification of additional DDP resistance mechanisms in mammalian cells.
金属化合物顺铂（DDP）是一种广泛使用的抗癌药物，但天然存在的以及后天获得的对DDP的耐药性限制了其疗效。耐药性与DDP积累减少以及谷胱甘肽和金属硫蛋白水平升高有关。这些变化在原核生物和低等真核生物中也是针对其他金属盐的保护和解毒机制。本研究的目的是在分别用DDP（2008/C13*5.25）或CdCl2和ZnCl2（2008/MT）选择的亲本2008人卵巢癌细胞亚系中寻找与DDP具有相同交叉耐药谱的金属盐。在所测试的金属盐中，三价锑的耐药谱与DDP最为相似。DDP选择的细胞对DDP有15倍的耐药性，对酒石酸锑钾有4.4倍的交叉耐药性，而在所测试的阳离子（Cd2+、Zn2+、Ni2+和Co2+）中，仅观察到Cd2+有交叉耐药性（2.4倍）。当2008细胞被选择对锑产生耐药性（6.6倍）时，发现它们对DDP有16倍的交叉耐药性。DDP类似物顺式-[3H]二氯（乙二胺）铂（II）在DDP选择的亚系中的积累比亲本细胞系低59%，在锑选择的变体中低48%。从对DDP和酒石酸锑钾的相互交叉耐药性以及在DDP和锑选择的变体中[3H]DEP摄取受损，我们得出结论，DDP和锑共享一种共同的耐药机制。这一观察结果的意义在于，在低等生物中已经知道几种进化上保守的锑解毒机制，这可能为在哺乳动物细胞中鉴定其他DDP耐药机制指明方向。
