Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: determination of efficacy and possible mechanisms of resistance.
The novel camptothecin derivative BNP1350 (7-[2-trimethylsilyl)ethyl]-20(S)-camptothecin), also known as Karenitecin, has been developed for superior oral bioavailability and increased lactone stability. In our study, we describe the antiproliferative effects of BNP1350, SN-38 and topotecan in 4 human ovarian cancer cell lines. BNP1350 was found to be slightly more potent than SN-38 (p<0.01) and was considerably more potent than topotecan (p<0.01). We extended these studies to well-established human ovarian cancer xenografts in which we compared the growth inhibition induced by BNP1350 with that of topotecan given in equitoxic schedules. The growth inhibition in all 3 xenografts induced by BNP1350 was > or =75%, which was significantly better than that resulting from topotecan (p<0.05). We then selected BNP1350-resistant variants of the A2780 human ovarian cancer cell line, 2780K4 (resistance factor: 41) and 2780K32 (resistance factor: 90), to analyze possible resistance mechanisms. These variants exhibited cross-resistance against all camptothecins tested. In comparison with 2780K4 cells, 2780K32 cells were relatively more resistant against SN-38, topotecan, DX-8951f and BNP1350. In addition, 2780K32 cells were highly cross-resistant against mitoxantrone. In both 2780K4 and 2780K32, the amount of topoisomerase I was not changed but the catalytic activity was reduced. Furthermore, 2780K32 cells clearly overexpressed the breast cancer resistance protein (BCRP), as demonstrated for both the gene and the protein. In contrast to topotecan, BNP1350 proved not to be a good substrate for BCRP. Overall, we conclude that BNP1350 offers advantages over topotecan expressed by high efficacy in experimental human ovarian cancer and poor affinity for BCRP.
Van Hattum
Annemarie H
AH
Department of Medical Oncology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
Schlüper
Hennie M M
HM
Hausheer
Frederick H
FH
Pinedo
Herbert M
HM
Boven
Epie
E
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics / Q000502:physiology; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002166:Camptothecin; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; C116614:ABCG2 protein, human; C406143:cositecan