Topotecan increases topoisomerase IIalpha levels and sensitivity to treatment with etoposide in schedule-dependent process
Whitacre, C.M.; Zborowska, E.; Gordon, N.H.; Mackay, W.; Berger, N.A.
Cancer Research 57(8): 1425-1428
1997
ISSN/ISBN: 0008-5472 PMID: 9108439 Document Number: 475929
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-alpha levels associated with increasing sensitivity of tumors to subsequent treatment with the Topo II inhibitor etoposide. Furthermore, we show that Topo III-alpha 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.