COMPARATIVE INVITRO CYTOTOXICITY OF TAXOL AND TAXOTERE AGAINST CISPLATIN-SENSITIVE AND CISPLATIN-RESISTANT HUMAN OVARIAN-CARCINOMA CELL-LINES

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 > 1,000 times more cytotoxic than either cisplatin (mean IC50, 3.1 x 10(-6) m; P <0.05) or etoposide (mean IC50, 2.3 x 10(-6) m; P <0.05) and > 100 times more cytotoxic than Adriamycin (mean IC50, 6.9 x 10(-8) M; P <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 > that of taxol across the nine lines (range, 0.75- to 10-fold; P <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, < 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 <0.05). The mean loss in potency across the nine lines for 2 vs 96 h exposure was 97 for taxol, 35 for Taxotere, 30 for Adriamycin and only 9.9 for cisplatin. However, these differences in potency loss observed between taxol and Taxotere did not reach statistical significance (P = 0.18). These data indicate that Taxotere is approximately 2 times more cytotoxic than taxol and shows an encouraging lack of cross-resistance in three cell lines exhibiting acquired resistance to cisplatin and carboplatin.