In vitro schedule dependency in the treatment of topoisomerase I and II inhibitor.

Topoisomerase targeting chemotherapy is an excellent strategy for lung cancer treatment. We studied the cytotoxic effects of exposure to topoisomerase I inhibitor SN-38 and topoisomerase II inhibitor etoposide (VP-16) in lung cancer cell line Ma-1 using WST-1 assay and isobologram analysis. Cells were concurrently or sequentially exposed to drugs for 30 minutes, 2 hours and 24 hours. Simultaneous exposure for 30 minutes showed antagonistic. However, 2 hours or 24 hours exposure resulted in additive or supra-additive interaction, respectively. Sequential exposures to SN-38 followed by VP-16 resulted in synergistic interaction for all schedules. Whereas, VP-16 followed by SN-38 resulted in sub-additive interaction for 30 minutes and 2 hours exposures, however, 24 hours exposure resulted in additive interaction. These findings suggest that maximum cytotoxic effects can be obtained when SN-38 precedes VP-16, and that prolonged simultaneous administration may circumvent antagonistic interaction between them. These findings may be useful in clinical trials.