Analysis of exposure times and dose escalation of paclitaxel in ovarian cancer cell lines.

Abstract

Paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NJ) is a promising drug for the treatment of ovarian cancer. Exposure times and dose-response relationships should be explored to optimize future clinical applications of this drug. The cytotoxic effects of paclitaxel on four human ovarian cancer cell lines (Caov-3, SK-OV-3, NIH: OVCAR-3, and A2780) were analyzed using chromium-51 release assays and tetrazolium-based colorimetric assays. Cells were exposed to paclitaxel for 4 and 24 hours at concentrations ranging from 10(-10)-10(-4) M. Two paclitaxel preparations were compared: paclitaxel in DMSO and paclitaxel in cremophor EL, the carrier used in pharmacological preparations. Cell cycle analysis compared cells exposed to 10(-5) M paclitaxel in dimethyl sulfoxide for 4 hours to those exposed for 24 hours. No difference in cell proliferation was demonstrated after 4 hours of treatment when compared with 24 hours of treatment with paclitaxel in dimethyl sulfoxide at 24, 48 and 72 hours after treatment in any of the cell lines tested, over all concentrations tested. When paclitaxel in cremophor was used, there was a significant decrease in cell proliferation only at 10(-4) M of paclitaxel. Similar results were seen with 10(-4) M equivalent concentration of the carrier alone. A cell cycle shift to G2/M was the same after 4 or 24 hours of exposure when assessed at 24 hours. A dose escalation from 10(-10) M to 10(-4) M of paclitaxel in dimethyl sulfoxide did not inhibit cell proliferation significantly in any of these cell lines. Moreover, shorter exposure times did not appear to alter the cellular response to paclitaxel. Consequently, administration of smaller dosages over shorter time periods may not compromise the cytotoxic effect of this agent. Clinical studies must be performed to validate these observations.