RESISTANCE MECHANISMS DETERMINING THE IN-VITRO SENSITIVITY TO PACLITAXEL OF TUMOR-CELLS CULTURED FROM PATIENTS WITH OVARIAN-CANCER

Paclitaxel, a drug which stabilises microtubules, demonstrates marked activity against ovarian cancer. We investigated the sensitivity to paclitaxel of tumour cells from disaggregated solid tumours or tumour-bearing ascites from 7 ovarian cancer patients, and 21 established tumour cell lines (ovarian, melanoma and lung). Response was quantitated by [H-3]-thymidine incorporation in 96-well plates or by colony growth. Dose-response curves to paclitaxel were biphasic with a dose-dependent phase providing an IC50 value (50% reduction in incorporation) and dose-independent ''plateau'' phase where the effect was independent of paclitaxel concentration. Ic,, values ranged from 2.5 to 110 nM with evidence of multidrug resistance in the two most resistant cell lines. The ''plateau'' killing values varied from 0.1 log(10) to >3.4 log,, units reduction, and were found to be significantly correlated (r = 0.86; P < 0.0001) with logarithmic culture doubling times of the cell lines. Cellular glutathione levels were measured and found not to be significantly associated with response to paclitaxel. The results suggest that the ratio of paclitaxel exposure time to the culture doubling time is a major factor in paclitaxel cytotoxicity. The relationship between tumour cell cytokinetics and paclitaxel pharmacokinetics in vivo may therefore be crucial in determining clinical paclitaxel response.