Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines.
Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines.
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发表时间：
1993-11
期刊：
影响因子：
11.2
通讯作者：
K. Hamaguchi;A. Godwin;M. Yakushiji;P. O'dwyer;R. Ozols;T. C. Hamilton
中科院分区：
文献类型：
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作者：
K. Hamaguchi;A. Godwin;M. Yakushiji;P. O'dwyer;R. Ozols;T. C. Hamilton
我们先前通过暴露于接近连续增加浓度的顺铂，获得了一组对药物表现出广泛的原发性耐药（9至> 400倍）的人卵巢癌细胞系。这些细胞的谷胱甘肽（GSH）水平与来源的药物敏感细胞相比显著增加（4- 50倍）（A. K. Godwin等人，Proc. Natl. Acad. Sci. USA，89：3070-3074，1992）。利用这组耐药细胞系，我们评估了对经典烷化剂、天然产物药物和辐射的交叉耐药性。我们观察到对卡铂的交叉耐药性超过顺铂，最终耐药性约为250倍。类似地，美法仑交叉耐药性继续增加至> 400倍，并再次超过原发性顺铂耐药性。对顺铂具有低至非常高水平抗性的细胞系对表鬼臼毒素衍生物依托泊苷具有8至850倍的抗性。其他天然产物药物也观察到交叉耐药性，包括阿霉素（约80倍）、米托蒽醌（约440倍）和紫杉醇（约40倍）。然而，对辐射的交叉抗性是适度的（< 2倍）。对顺铂具有最大原发性耐药的细胞通常对所检查的其他药物具有最高的交叉耐药。通过北方和南方印迹分析评估，基于这些基因缺乏协调增加的表达或扩增，发现对天然产物类药物的交叉耐药性不是由多药耐药1（MDR 1）或多药耐药相关蛋白（MRP）基因的产物介导的。此外，维拉帕米未能显着增加药物敏感性。虽然没有迹象表明这些天然产物药物外排泵是有效的，但我们观察到这些细胞系中对天然产物交叉耐药的多柔比星积累减少。此外，DNA拓扑异构酶II mRNA水平的改变，这已被观察到在体外选择的多种人类肿瘤细胞系的依托泊苷或替尼泊苷的耐药性，没有检测到。只有细胞内的谷胱甘肽水平与这些不同的抗癌药物的交叉耐药性和部分损失的阻力与谷胱甘肽水平显着下降。在缺乏替代机制的情况下，我们推测在该模型系统中观察到的非常广泛的临床相关交叉耐药可能至少部分是GSH介导的药物失活的直接结果，或者可能是由于GSH与药物结合以及由推定的ATP依赖性谷胱甘肽S-结合物输出泵介导的结合物外排的组合。
We have previously obtained, by exposure to near continuous increasing concentrations of cisplatin, a panel of human ovarian cancer cell lines that exhibit a wide range of primary resistance to the drug (9- to > 400-fold). These cells had strikingly increased (4- to 50-fold) levels of glutathione (GSH) as compared with the drug-sensitive cells of origin (A. K. Godwin et al., Proc. Natl. Acad. Sci. USA, 89: 3070-3074, 1992). Utilizing this panel of resistant cell lines, we evaluated cross-resistance to classical alkylating agents, natural product drugs, and irradiation. We observed that cross-resistance to carboplatin paralleled that of cisplatin, culminating in approximately 250-fold resistance. Similarly, melphalan cross-resistance continued to increase to > 400-fold and again paralleled the primary cisplatin resistance. Cell lines with low to very high levels of resistance to cisplatin are 8- to 850-fold resistant to the epipodophyllotoxin derivative etoposide. Cross-resistance is also observed for other natural product drugs, including Adriamycin (approximately 80-fold), mitoxantrone (approximately 440-fold), and taxol (approximately 40-fold). Cross-resistance to irradiation is, however, modest (< 2-fold). The cells with the greatest primary resistance to cisplatin most commonly had the highest cross-resistance to the other drugs examined. The cross-resistance to the natural product category drugs was found not to be mediated by the products of either the multidrug resistance 1 (MDR1) or multidrug resistance-associated protein (MRP) genes based on lack of coordinate increased expression or amplification of these genes as assessed by Northern and Southern blot analyses. Furthermore, verapamil failed to markedly increase drug sensitivity. Although there was no indication that these natural product drug efflux pumps were operative, we observed decreased doxorubicin accumulation in these cell lines cross-resistant to natural products. In addition, alternations in DNA topoisomerase II mRNA levels, which have been observed in a variety of human tumor cell lines selected in vitro for resistance to etoposide or teniposide, were not detected. Only intracellular levels of GSH correlated with cross-resistance to these diverse anticancer agents and partial loss of resistance was associated with a marked decrease in glutathione levels. In the absence of alternative mechanisms, we speculate that the very broad clinically relevant cross-resistance seen in this model system may, at least in part, be the direct result of GSH-mediated drug inactivation or may be due to a combination of GSH conjugation to drug and conjugate efflux mediated by the putative ATP-dependent glutathione S-conjugate export pump.