IN-VITRO SCHEDULE-DEPENDENT INTERACTION BETWEEN PACLITAXEL AND SN-38 (THE ACTIVE METABOLITE OF IRINOTECAN) IN HUMAN CARCINOMA CELL-LINES

Paclitaxel and irinotecan are important new anticancer agents. The com bination of these two agents has been considered for use against a var iety of advanced solid tumors. Since the schedule-dependent effects of this combination may be crucial to its use, we studied the interactio n of paclitaxel and SN-38 (the active metabolite of irinotecan) in var ious schedules in four human cancer cell lines in culture. Cell growth in hibition after 5 days was determined using an MTT assay. The effec ts of drug combinations at the IC80 level were analyzed by the isobolo gram method. Simultaneous exposure to paclitaxel and SN-38 for 24 h pr oduced antagonistic (subadditive and protective) effects in the human lung cancer cell line A549, the breast cancer cell line MCF7, and the colon cancer cell line WiDr, and produced additive effects in the ovar ian cancer cell line PA1. Sequential exposure to paclitaxel for 24 h f ollowed by SN-38 for 24 h, and the reverse sequence, produced additive effects in all four cell lines. These findings suggest that sequentia l administration, not simultaneous administration, may be the appropri ate schedule for the therapeutic combination of paclitaxel and irinote can. Continued preclinical and clinical studies should provide further insights and assist in determining the optimal schedule for this comb ination in clinical use.