Comparative in vitro cytotoxicity of taxol and Taxotere against cisplatin-sensitive and -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 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)
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
L R
LR
Kelland
G
G
Abel
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012235:Rhodamines; D043823:Taxoids; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D012235:Rhodamines; D043823:Taxoids; D000077143:Docetaxel; C022027:lissamine rhodamine B; D005047:Etoposide; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin