Mellish K J, Barnard C F, Kelland L R, Harrap K R
Drug Development Section, Institute of Cancer Research, Belmont, Sutton, UK.
Int J Cancer. 1994 Oct 1;59(1):65-70. doi: 10.1002/ijc.2910590114.
Acquired resistance to tetraplatin [d,1-trans-1,2-diaminocy-clohexane tetrachloroplatinum (IV)] has been generated in vitro in the human ovarian carcinoma cell line PXN94; the derived line, PXN94tetR, was 24-fold resistant to tetraplatin. Intracellular tetraplatin accumulation was reduced in PXN94tetR compared with PXN94 by an average of 1.3-fold across the concentration range 1-100 microM (2 hr exposure). There was no significant difference in glutathione levels between the 2 cell lines. PXN94tetR was 1.6-fold more resistant to cadmium chloride than PXN94, suggesting that metallothionein levels may be elevated. However, no significant difference was observed between PXN94 and PXN94tetR in the levels of total platinum bound to DNA or DNA interstrand cross-links immediately after tetraplatin exposure (10-100 microM x 2 hr). There was also no significant difference between the 2 cell lines in the rate of removal of total platinum or interstrand cross-links from DNA following 2 hr exposure to 25 microM tetraplatin. Hence the major mechanism of acquired tetraplatin resistance in PXN94tetR appears to be increased tolerance of platinum-DNA adducts. PXN94tetR was partially cross-resistant to the bifunctional alkylating agents melphalan, chlorambucil and mitomycin C. Partial cross-resistance was also observed to Adriamycin, bleomycin, etoposide, 5-fluorouracil and vinblastine; however, no elevation in P-glycoprotein levels was apparent in PXN94tetR. No cross-resistance was observed to taxotere. PXN94tetR was partially cross-resistant to cisplatin, carboplatin and several novel cis platinum complexes. In contrast, resistance was completely circumvented by the novel trans platinum complex JM335 [trans ammine (cyclohexylamine) dichloro dihydroxo platinum (IV)].
已在人卵巢癌细胞系PXN94中体外诱导出对四铂[顺式，反式-1,2-二氨基环己烷四氯铂(IV)]的获得性耐药；衍生细胞系PXN94tetR对四铂的耐药性为24倍。在1-100微摩尔浓度范围内(暴露2小时)，与PXN94相比，PXN94tetR细胞内四铂的蓄积平均减少了1.3倍。两细胞系间谷胱甘肽水平无显著差异。PXN94tetR对氯化镉的耐药性比PXN94高1.6倍，提示金属硫蛋白水平可能升高。然而，在四铂暴露后即刻(10-100微摩尔×2小时)，PXN94和PXN94tetR在与DNA结合的总铂水平或DNA链间交联水平上未观察到显著差异。在暴露于25微摩尔四铂2小时后，两细胞系在从DNA中清除总铂或链间交联的速率上也无显著差异。因此，PXN94tetR中获得性四铂耐药的主要机制似乎是对铂-DNA加合物的耐受性增加。PXN94tetR对双功能烷化剂美法仑、苯丁酸氮芥和丝裂霉素C有部分交叉耐药性。对阿霉素、博来霉素、依托泊苷、5-氟尿嘧啶和长春花碱也观察到部分交叉耐药性；然而，PXN94tetR中P-糖蛋白水平未明显升高。对多西他赛未观察到交叉耐药性。PXN94tetR对顺铂、卡铂和几种新型顺铂复合物有部分交叉耐药性。相比之下，新型反式铂复合物JM335[反式氨(环己胺)二氯二氢氧铂(IV)]可完全克服耐药性。
