Hill B T, Whelan R D, Shellard S A, McClean S, Hosking L K
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, England.
Invest New Drugs. 1994;12(3):169-82. doi: 10.1007/BF00873957.
The in vitro cytotoxic effects of docetaxel (Taxotere; RP56976, NSC688503) proved both time and concentration dependent. Amongst thirteen human cell lines from various tumor types, exposure to increasing concentrations of docetaxel over 24 hrs resulted in a plateau-shaped dose response curve, suggesting that increased cell kill becomes more dependent on increased exposure duration than on concentration. IC50 concentrations (reducing survival by 50%) ranged from 0.13-3.3 ng/ml, with three neuroblastoma lines proving most sensitive and three breast and two colon carcinoma lines showing least sensitivity. There was significant cross-resistance to docetaxel in the classic multidrug resistant (MDR) Chinese hamster ovarian (CHO) CHRC5 line and the human lymphoblastoid CCRF-CEMVLB1000 line, as well as in two vincristine (VCR)-selected MDR MCF-7 sublines. All four of these MDR sublines overexpress P-glycoprotein (Pgp), as did a 6-fold docetaxel-selected resistant CHO subline. As an apparent corollary, in two human teratoma lines selected for etoposide resistance and showing some cross-resistance to VCR and in two CHO sublines expressing low levels of VCR resistance, yet all proving Pgp positive, no docetaxel cross-resistance was identified. Verapamil modulated docetaxel resistance only in sublines expressing resistance to the drug and overexpressing Pgp. Four other human tumor sublines selected for resistance to 5-fluorouracil, cisplatin or teniposide, showed a lack of cross-resistance to docetaxel. Furthermore, cross-resistance to docetaxel was not apparant in four epipodophyllotoxin-selected resistant sublines with alterations in topoisomerase II, indicating its effectiveness against tumor cells expressing the topoisomerase II-related MDR phenotype. Our observation that docetaxel cross-resistance was not automatically expressed by classic MDR tumour cells appears of interest and of potential clinical relevance.
多西他赛（泰索帝；RP56976，NSC688503）的体外细胞毒性作用证明具有时间和浓度依赖性。在来自各种肿瘤类型的13种人类细胞系中，在24小时内暴露于浓度不断增加的多西他赛会导致呈平台状的剂量反应曲线，这表明细胞杀伤的增加更多地取决于暴露持续时间的增加而非浓度。半数抑制浓度（IC50，使存活率降低50%）范围为0.13 - 3.3纳克/毫升，其中三种神经母细胞瘤细胞系最为敏感，而三种乳腺癌细胞系和两种结肠癌细胞系敏感性最低。在经典的多药耐药（MDR）中国仓鼠卵巢（CHO）CHRC5细胞系、人淋巴母细胞CCRF - CEMVLB1000细胞系以及两种长春新碱（VCR）选择的MDR MCF - 7亚系中，对多西他赛存在显著的交叉耐药性。所有这四种MDR亚系均过度表达P - 糖蛋白（Pgp），一个对多西他赛产生6倍耐药性的CHO亚系也是如此。作为一个明显的推论，在两种因对依托泊苷耐药而选择的人类畸胎瘤细胞系中，它们对VCR也表现出一些交叉耐药性，以及在两种表达低水平VCR耐药性但均证明Pgp呈阳性的CHO亚系中，未发现对多西他赛的交叉耐药性。维拉帕米仅在对该药物耐药且过度表达Pgp的亚系中调节多西他赛耐药性。另外四种因对5 - 氟尿嘧啶、顺铂或替尼泊苷耐药而选择的人类肿瘤亚系，对多西他赛未表现出交叉耐药性。此外，在四种因对表鬼臼毒素耐药而选择的、拓扑异构酶II发生改变的耐药亚系中，未出现对多西他赛的交叉耐药性，这表明其对表达拓扑异构酶II相关MDR表型的肿瘤细胞有效。我们观察到经典MDR肿瘤细胞不会自动表现出对多西他赛的交叉耐药性，这一点似乎很有趣且具有潜在的临床相关性。
