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Topotecan Increases Topoisomerase II Levels and Sensitivity to Treatment with Etoposide in Schedule-dependent Process

Departments of Medicine [C. M. W., E. Z., N. A. B.] and Epidemiology and Biostatistics [N. H. G., W. M.] and Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106-4937

To elucidate the effect of topoisomerase (Topo) I inhibitors in the modulation of Topo II levels and sensitivity to Topo II-directed drugs, athymic mice bearing SW480 human colon cancer xenografts were treated with simultaneous, subsequent, or distant doses of topotecan and etoposide. This in vivo study demonstrates that simultaneous administration of topotecan and etoposide results in an antagonistic response. In contrast, inhibition of Topo I by topotecan results in a compensatory increase in Topo II levels associated with increasing sensitivity of tumors to subsequent treatment with the Topo II inhibitor etoposide. Furthermore, we show that Topo II levels decline 5 days after the last dose of topotecan, resulting in restoration of the original response of the xenografts to etoposide. Thus, this study emphasizes the critical role of schedule dependency to optimize the effectiveness of combination chemotherapy with Topo I and Topo II inhibitors.

¹ To whom requests for reprints should be addressed, at Department of Medicine, Case Western Reserve University, School of Medicine BRB 301A, 10900 Euclid Avenue, Cleveland, OH 44106-4937. Phone: (216) 368-2825; Fax: (216) 368-1166.

Received 1/ 6/97. Accepted 3/ 8/97.

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