Additive and supra-additive cytotoxicity of cisplatin-taxane combinations in ovarian carcinoma cell lines

Abstract

SummaryThe purpose of this study was to compare the growth-inhibitory effect of cisplatin-paclitaxel with that obtained with a cisplatin-docetaxel combination and to assess the type of interaction. Concomitant use of taxanes and cisplatin was studied in seven human ovarian carcinoma cell lines, using the 96-well plate clonogenic assay. Chemosensitivity was expressed in terms of IC 50 values, the drug concentration causing 50% inhibition of clonogenic survival. The type of interaction was studied using the area under the survival curve ratios (AUC ratios) obtained by numerical integration. Comparison of the AUC ratio and the surviving fraction (SF) value after taxane alone was made using Student's t-test. The influence of the drug concentration was tested by one-way analysis of variance (Anova). A supra-additive or additive effect was seen when seven ovarian carcinoma cell lines were exposed to paclitaxel or docetaxel concomitantly with cisplatin. A supra-additive effect was found in four cell lines (UT-OC-3, UT-OC-4, UT-OC-5 and SK-OV-3) after simultaneous use of cisplatin with all docetaxel concentrations tested, and in two cell lines (UT-OC-4 and SK-OV-3) when cisplatin was used concomitantly with paclitaxel. A more pronounced supra-additive effect was seen with the combination of cisplatin and docetaxel. The degree of supra-additivity was dose dependent, with increasing synergy after a higher taxane dose. The data obtained in this study suggest that a supra-additive or additive effect can be achieved in ovarian carcinoma with the concomitant use of cisplatin and a taxane. for cervical cancer 30 and 5 years before the diagnosis of ovarian carcinoma. The donors of the UT-OC-1 and UT-OC-3 cell lines had not received any cytotoxic therapy before the establishment of the cell lines. Keywords Cell cultureBefore the experiments, the cells were kept in logarithmic growth in T25 culture flasks by passing weekly in Dulbecco's modified Eagle's minimal essential medium (DMEM) containing 2 mM L-glutamine, 1% non-essential amino acids, 100 U ml -1 streptomycin, 100 U ml -1 penicillin and 10% fetal bovine serum (FBS). Cells in mid-logarithmic growth (40-60% confluence) were used for the experiments and fed with fresh medium on the day before plating. Drug preparationCisplatin (Platinol) 0.5 mg ml -1 was diluted with growth medium to get a stock solution of 100 µg ml -1 . Final cisplatin dilutions of 0.05-0.6 µg ml -1 were used, and new stock solutions were made for each experiment. Paclitaxel (Taxol, kindly provided by BristolMyers Squibb) was initially dissolved in 0.9% sodium chloride to get a solution of 0.1 mM. Stock solutions were prepared in Ham's F-12 medium containing 10% FBS to obtain a solution of 100 nM, and stored at -40°C. Final dilutions of 0.4-5 nM paclitaxel were used for the experiments. Docetaxel (Taxotere, 807.9 mg, kindly provided by Rhone-Poulenc Rorer) was diluted in 1 ml of ethanol to obtain a stock solution of 0.1 mM and stored at -40°C. These solutions were further diluted in sterile water to obtain...

Carboplatin-paclitaxel- and carboplatin-docetaxel-induced cytotoxic effect in epithelial ovarian carcinoma in vitro

“…Data obtained from our recent 15 and current experiments suggest that the taxane concentrations required for a synergistic effect to emerge with platinum analogues are different. The taxanes have a completely distinct mechanism of action compared with the platinum analogues and there also are a number of differences between paclitaxel and docetaxel.…”

“…Data obtained from the current study do not indicate that there is a positive association between the sensitivities of the taxanes and carboplatin, which is in agreement with previous results regarding nine ovarian carcinoma cell lines. 28 In a recent study from our laboratory 15 the combination of docetaxel and cisplatin was more cytotoxic on a molar basis than the combination of paclitaxel and cisplatin. A supra-additive effect was found in four of seven cell lines after simultaneous exposure to cisplatin at all docetaxel concentrations tested and in two cell lines when cisplatin was used concomitantly with paclitaxel.…”

“…15 On a molar basis, the combination of cisplatin and docetaxel was more cytotoxic than the combination of cisplatin and paclitaxel. In the current study we compare the combination of carboplatin and paclitaxel with that of carboplatin and docetaxel and assess the type of interaction between these agents.…”

Differential alteration of cisplatin cytotoxicity and myelotoxicity by the paclitaxel vehicle cremophor EL

“…Combination chemotherapy with CDDP and paclitaxel resulted in a significant antitumor synergy (Eltabbakh et al 1998;Hsu et al 1998;Kennedy et al 1998) and less hematological toxicities than anticipated (Pronk et al 1997;Engblom et al 1999). The present study demonstrates that CR, the paclitaxel vehicle, seems to be responsible for the pharmacological interaction between CDDP and paclitaxel observed in clinical therapy.…”

Regulation of UT-OC-3 ovarian carcinoma cells by cytokines: inhibitory effects on cell proliferation and activation of transcription factors AP-1 and NF-kappaB

“…The UT-OC-3 cell line has been established at the University of Turku from a primary tumour of a 60-year-old patient with well differentiated stage III ovarian serous cystadenocarcinoma (12,13). Lowpassage cells were used throughout all experiments.…”