title: The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer.
abstract: DX-8951f or exatecan mesylate ((1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10-13(9H,15H)-dione methanesulfonate dihydrate), is a new water-soluble derivative of camptothecin. We determined the activity of DX-8951f in experimental human colon cancer and ovarian cancer, being tumor types sensitive to camptothecins. With the use of the MTT assay, DX-8951f was more potent than SN-38 in four out of five human colon cancer cell lines and three out of four human ovarian cancer cell lines (P<0.05). DX-8951f was considerably more potent than topotecan in all cell lines tested (P<0.05). Prolonged exposure to DX-8951f resulted in a greater increase in inhibition of cell proliferation as compared to that obtained with SN-38 or topotecan (P<0.05). Overexpression of Pgp, MRP1, and LRP did not affect the in vitro activity of DX-8951f. DX-8951f administered daily x 5 or weekly x 2 resulted in growth inhibition <50% in two human colon cancer xenografts grown s.c. in nude mice. In three human ovarian cancer xenografts, however, >50% growth inhibition was observed at both schedules. In the OVCAR-3 human ovarian cancer model, DX-8951f showed considerably greater activity than topotecan (P<0.01). DX-8951f combined with cisplatin or paclitaxel did not indicate the presence of a pharmacological interaction. In OVCAR-3 xenografts the combination was clearly more effective than DX-8951f alone, as the number of complete remissions increased substantially. In conclusion, this study shows that DX-8951f is highly potent in vitro and highly effective in experimental human ovarian cancer in vivo. Prolonged exposure to DX-8951f in vitro greatly increased the antiproliferative effects, which may be a rationale for testing a continuous infusion schedule in the clinic. Addition of cisplatin or paclitaxel improved the in vivo antitumor effects of DX-8951f.
authors.affiliation: Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van Hattum
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Hennie M M
authors.initials: HM
authors.lastname: Schlüper
authors.forename: Caroline A M
authors.initials: CA
authors.lastname: Erkelens
authors.forename: Akiko
authors.initials: A
authors.lastname: Tohgo
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000473:pathology; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D060245:Tetraspanin 29; D014407:Tumor Cells, Cultured; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D000970:Antineoplastic Agents; D002166:Camptothecin; D002945:Cisplatin; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D013439:Sulfhydryl Reagents; D060245:Tetraspanin 29; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; C095887:exatecan