Schedule-dependent interactions between vinorelbine and paclitaxel in human carcinoma cell lines in vitro

Vinorelbine and paclitaxel are new anticancer agents that bind to distinct sites on tubulin and affect microtubules in opposite ways. Clinical studies of combinations of these agents have been in progress against breast cancer and some solid tumors. To clarify the optimal schedule for this combination, we studied the schedule-dependent cytotoxic effects of vinorelbine and paclitaxel against the human lung carcinoma cell line A549, the breast carcinoma cell line MCF7, the ovarian carcinoma cell line PA1, and the colon carcinoma cell line WiDr in vitro. Tumor cells were incubated with vinorelbine and paclitaxel simultaneously for both 24 h and 5 days. Cells were also incubated with vinorelbine for 24 h, followed by a 24-h exposure to paclitaxel and vice versa. Cell growth inhibition after 5 days was determined by MTT assay. The effects of drug combinations at the concentration producing 80% cell growth inhibition (IC80) were analyzed by the isobologram method (Steel and Peckham). The simultaneous exposures to vinorelbine and paclitaxel for both 24 h and 5 days produced additive effects for all four cell lines. The sequential exposure to vinorelbine followed by paclitaxel produced additive effects for the PA1 and WiDr cells, additive and antagonistic effects for the A549 cells, and antagonistic effects for the MCF7 cells. The sequential exposure to paclitaxel followed by vinorelbine produced additive effects for the A549, and PA1 cells, additive and antagonistic effects for the MCF7 cells, and antagonistic effects for the WiDr cells. Our findings suggest that the simultaneous rather than the sequential administration of vinorelbine and paclitaxel may be the optimal schedule for this combination of these two agents. Applications of this schedule dependency may be beneficial for the treatment of breast cancer and other solid tumors.