Topotecan increases topoisomerase IIalpha levels and sensitivity to treatment with etoposide in schedule-dependent process.
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 II 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.
Whitacre
C M
CM
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4937, USA.
Zborowska
E
E
Gordon
N H
NH
Mackay
W
W
Berger
N A
NA
D000818:Animals; D000951:Antigens, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D019772:Topotecan; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D019772:Topotecan; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin