Kelland L R, Abel G
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Cancer Chemother Pharmacol. 1992;30(6):444-50. doi: 10.1007/BF00685595.
Using the sulforhodamine B assay, we compared the cytotoxic properties of the novel microtubule agent taxol and the semi-synthetic related compound Taxotere in nine human ovarian-carcinoma cell lines, including three pairs of cell lines rendered resistant to cisplatin or carboplatin. In addition, the cytotoxicity of the commonly used anticancer drugs cisplatin and adriamycin and the topoisomerase II inhibitor etoposide was determined. The results of continuous drug exposure showed that taxol [mean concentration producing 50% growth inhibition (IC50), 1.1 x 10(-9) M; range, 2.8 x 10(-9)-5 x 10(-10) M and Taxotere (mean IC50, 5.1 x 10(-10) M; range, 7.2-3.3 x 10(-10) M) were greater than 1,000 times more cytotoxic than either cisplatin (mean IC50, 3.1 x 10(-6) M; P less than 0.05) or etoposide (mean IC50, 2.3 x 10(-6) M; P less than 0.05) and greater than 100 times more cytotoxic than Adriamycin (mean IC50, 6.9 x 10(-8) M; P less than 0.05). Taxotere was more cytotoxic than taxol; following continuous exposure, the mean difference across the cell lines was 2 orders of magnitude (range, 1.1-3.9 orders of magnitude for individual lines). Although this difference did not reach statistical significance for any individual cell line (P values ranged from 0.17 for HX/62 to 0.9 for OVCAR-3), when all IC50 values for the 96-h experiments were pooled, Taxotere was found to be significantly more potent than taxol (P = 0.05). Following 2 h exposure, the mean cytotoxicity of Taxotere was 3.9-fold greater than that of taxol across the nine lines (range, 0.75- to 10-fold; P less than 0.05 for the CH1 cell line; overall pooled IC50 data, P = 0.05). Although a 71-fold range of sensitivity to cisplatin was observed across the six parent cell lines (IC50 most resistant line/IC50 most sensitive line), this was largely abolished by treatment with taxol (5.6-fold range) and Taxotere (2.2-fold range). Following continuous exposure of the three pairs of lines exhibiting acquired resistance to platinum, no cross-resistance with either Taxotere or taxol was found (resistance factors, less than 1.5). In the 41M and 41McisR pair of lines, in which previous studies have shown resistance to be due to reduced platinum accumulation, taxol and Taxotere exhibited some collateral sensitivity (resistance factors, 0.69 and 0.66, respectively). Taxotere and, particularly, taxol showed a pronounced concentration times exposure duration (C x T) dependence as compared with cisplatin (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
我们使用磺酰罗丹明B检测法，比较了新型微管药物紫杉醇和半合成相关化合物多西他赛在9种人卵巢癌细胞系中的细胞毒性特性，其中包括3对已对顺铂或卡铂产生耐药性的细胞系。此外，还测定了常用抗癌药物顺铂、阿霉素以及拓扑异构酶II抑制剂依托泊苷的细胞毒性。持续药物暴露试验结果显示，紫杉醇[产生50%生长抑制的平均浓度（IC50）为1.1×10⁻⁹M；范围为2.8×10⁻⁹ - 5×10⁻¹⁰M]和多西他赛（平均IC50为5.1×10⁻¹⁰M；范围为7.2 - 3.3×10⁻¹⁰M）的细胞毒性比顺铂（平均IC50为3.1×10⁻⁶M；P < 0.05）或依托泊苷（平均IC50为2.3×10⁻⁶M；P < 0.05）大1000倍以上，比阿霉素（平均IC50为6.9×10⁻⁸M；P < 0.05）大100倍以上。多西他赛的细胞毒性比紫杉醇更强；持续暴露后，各细胞系的平均差异为2个数量级（各细胞系范围为1.1 - 3.9个数量级）。尽管这种差异对任何单个细胞系均未达到统计学显著性（P值范围从HX/62的0.17到OVCAR - 3的0.9），但当汇总96小时实验的所有IC50值时，发现多西他赛的效力显著高于紫杉醇（P = 0.05）。暴露2小时后，多西他赛在9个细胞系中的平均细胞毒性比紫杉醇高3.9倍（范围为0.75 - 10倍；CH1细胞系P < 0.05；总体汇总IC50数据，P = 0.05）。尽管在6个亲本细胞系中观察到对顺铂的敏感性范围为71倍（IC50最耐药细胞系/IC50最敏感细胞系），但在用紫杉醇（5.6倍范围）和多西他赛（2.2倍范围）处理后，这种差异基本消除。在3对已获得铂耐药性的细胞系持续暴露后，未发现对多西他赛或紫杉醇的交叉耐药性（耐药因子小于1.5）。在41M和41McisR这对细胞系中，先前研究表明耐药是由于铂积累减少，紫杉醇和多西他赛表现出一定的协同敏感性（耐药因子分别为0.69和0.66）。与顺铂相比，多西他赛，尤其是紫杉醇表现出明显的浓度乘以暴露持续时间（C×T）依赖性（P < 0.05）。（摘要截于400字）
