Ma J, Maliepaard M, Kolker H J, Verweij J, Schellens J H
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/University Hospital Rotterdam, The Netherlands.
Cancer Chemother Pharmacol. 1998;41(3):186-92. doi: 10.1007/s002800050727.
The parental IGROV-1 human ovarian adenocarcinoma cell line was intermittently exposed to increasing concentrations of cisplatin to obtain resistant sublines. A stable resistant subline with a resistance factor of 8.4 had been developed after 9 months and 28 passages, which was denoted IGROV(CDDP). A high correlation coefficient of 0.97 was found between the log cell survival and the DNA-adduct peak level during the process of resistance development. IGROV(CDDP) was strongly cross-resistant to carboplatin and doxorubicin and moderately cross-resistant to etoposide, docetaxel, and topotecan. Only minor resistance against 5-fluorouracil was observed, whereas IGROV(CDDP) was not cross-resistant to methotrexate. Intracellular accumulation of cisplatin was 65% lower in IGROV(CDDP) as compared with parental IGROV-1 at 37 degrees C under normal conditions. Coincubation of cisplatin with the Na+/K+-ATPase inhibitor ouabain resulted in a more pronounced decrease in platinum accumulation in IGROV-1 (44% decrease) than in IGROV(CDDP) (26% decrease). Under energy-depleting conditions the accumulation of cisplatin in the parental cell line was approximately 60% lower than that observed under normal (energy [i.e., ATP] rich) culture conditions. In contrast, the accumulation in IGROV(CDDP) was not affected by ATP-depletion. There appeared to be no significant difference between the intracellular accumulation of platinum in the resistant and sensitive cells under conditions of energy deprivation or when the uptake was studied at 0 degrees C. In conclusion, abrogation of energy-dependent accumulation in IGROV(CDDP) seems to be a major mechanism of resistance to cisplatin in this cell line.
亲代IGROV - 1人卵巢腺癌细胞系间歇性暴露于浓度不断增加的顺铂中，以获得耐药亚系。9个月和28次传代后，已培养出一个耐药因子为8.4的稳定耐药亚系，命名为IGROV(CDDP)。在耐药形成过程中，对数细胞存活率与DNA加合物峰值水平之间发现了0.97的高相关系数。IGROV(CDDP)对卡铂和多柔比星有强烈的交叉耐药性，对依托泊苷、多西他赛和拓扑替康有中度交叉耐药性。仅观察到对5 - 氟尿嘧啶有轻微耐药性，而IGROV(CDDP)对甲氨蝶呤无交叉耐药性。在正常条件下，37℃时IGROV(CDDP)中顺铂的细胞内积累量比亲代IGROV - 1低65%。顺铂与Na+/K+-ATP酶抑制剂哇巴因共同孵育导致IGROV - 1中铂积累的下降更为明显（下降44%），而在IGROV(CDDP)中下降26%。在能量耗竭条件下，亲代细胞系中顺铂的积累量比正常（能量即ATP丰富）培养条件下观察到的低约60%。相比之下，IGROV(CDDP)中的积累不受ATP耗竭的影响。在能量剥夺条件下或在0℃研究摄取时，耐药细胞和敏感细胞中铂的细胞内积累似乎没有显著差异。总之，IGROV(CDDP)中能量依赖性积累的消除似乎是该细胞系对顺铂耐药的主要机制。
