Schedule-dependent Cytotoxicity of Topotecan Alone and in Combination Chemotherapy Regimens

The schedule-dependent cytotoxic effects of topotecan were evaluated in tissue culture experiments with Chinese hamster V79 cells. One hour exposure to topotecan resulted in a typical phase-specific cell killing curve in which increasing concentrations kill progressively more cells and then reach a plateau when all susceptible cells are killed. In contrast, exposure for 24 h results in a steep concentration-response curve with no plateau. Other S-phase agents such as hydroxyurea or aphidicolin antagonized cytotoxicity when administered by simultaneous exposure with topotecan. Combinations of melphalan, BCNU (1,3 bis(2-chloroethyl)-1-nitrosourea), or cisplatinum with topotecan were most effective when cells were exposed to the alkylating agent or platinating agent during the first hour of a 24-h topotecan exposure. Combinations of topotecan with etoposide or adriamycin produce more cytotoxicity when topotecan is administered by prolonged exposure; however, there is no significant difference depending on whether the topoisomerase II inhibitor is added at the beginning or end of the topotecan exposure. These studies show the importance of appropriate dose scheduling to obtain optimal interaction of chemotherapeutic agents given in combination with topotecan.