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首页> 外文期刊>Journal of experimental & clinical cancer research : >Induction of a multifactorial resistance phenotype by high paclitaxel selective pressure in a human ovarian carcinoma cell line.
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Induction of a multifactorial resistance phenotype by high paclitaxel selective pressure in a human ovarian carcinoma cell line.

机译：高紫杉醇选择性压力在人卵巢癌细胞系中诱导多因素耐药表型。

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Paclitaxel (PTX) is a potent anti-neoplastic agent that is highly effective in treating ovarian cancer. Nevertheless, the emergence of PTX resistance has limited the control of this disease. To gain insight into the molecular alterations accompanying drug resistance in ovarian cancer, we generated a new stable PTX-resistant ovarian carcinoma cell line. CABA I cells, which display an intrinsic PTX resistance (IC50 = 800 ng/ml), were subjected to continuous exposure to PTX. From the residual surviving cells, the highly PTX-resistant line CABA-PTX (IC50 = 256000 ng/ml) was generated and stably maintained in vitro. Analysis of beta-tubulin expression indicated that only the HM40 and Hbeta9 isotypes were expressed in both parental and resistant cells. No specific point mutations in the HM40 were detected in either cell line, but expression levels of this isotype were significantly reduced (40%) in CABA-PTX cells. Hbeta9 levels were unchanged. In those cells, PTX resistance was associated with cross-resistance to vinblastine but not to methotrexate or 5-fluorouracil. Verapamil treatment did not reverse the intrinsic drug resistance of parental cells, but partially modulated the sensitivity of CABA-PTX cells to PTX and induced total sensitivity to vinblastine. No changes in the cell surface expression of the drug efflux pumps MRP1, MRP2 and P-glycoprotein were observed. PTX influx, monitored using a fluorescent drug derivative, was significantly reduced and delayed in CABA-PTX cells as compared to the parental cells. Together, these findings suggest that more than one mechanism is involved in PTX resistance, making CABA-PTX cell line a potentially valuable in vitro tool to study multifactorial acquired drug resistance in ovarian cancer.
机译：紫杉醇（PTX）是一种有效的抗肿瘤药物，在治疗卵巢癌方面非常有效。但是，PTX耐药性的出现限制了对这种疾病的控制。为了深入了解伴随卵巢癌耐药性的分子变化，我们生成了一种新的稳定的对PTX耐药的卵巢癌细胞系。表现出固有的PTX抗性（IC50 = 800 ng / ml）的CABA I细胞连续暴露于PTX。从残留的存活细胞中产生高度PTX抗性的系CABA-PTX（IC50 = 256000 ng / ml），并在体外稳定维持。对β-微管蛋白表达的分析表明，仅HM40和Hbeta9同种型在亲代和耐药细胞中均表达。在任一细胞系中均未检测到HM40中的特定点突变，但在CABA-PTX细胞中该同种型的表达水平显着降低（40％）。 Hbeta9水平保持不变。在这些细胞中，PTX耐药与对长春碱的交叉耐药有关，而与对甲氨蝶呤或5-氟尿嘧啶的交叉耐药无关。维拉帕米治疗并未逆转亲代细胞的内在耐药性，而是部分调节了CABA-PTX细胞对PTX的敏感性，并诱导了对长春碱的总敏感性。没有观察到药物外排泵MRP1，MRP2和P-糖蛋白在细胞表面表达的变化。与亲代细胞相比，使用荧光药物衍生物监测的PTX流入在CABA-PTX细胞中显着减少和延迟。总之，这些发现表明PTX耐药性涉及多种机制，这使CABA-PTX细胞系成为研究卵巢癌多因素获得性耐药性的潜在有价值的体外工具。

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