Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line.
The clinical development of combinations of cisplatin or carboplatin with DNA topoisomerase I (Topo I) inhibitors is based on their overlapping spectrum of antitumor activity and their in vitro synergy, but is limited by significant hematotoxicity. We studied the cellular interactions between oxaliplatin and topotecan in the IGROV-1 human ovarian cancer cell line prior to evaluating the combination in the clinic. Growth inhibition was studied after a 96 h exposure to oxaliplatin and topotecan. The analysis of the cytotoxicity by the isobolograms method revealed supra-additivity with maximal cytotoxicity obtained by giving oxaliplatin prior to topotecan. In the presence of topotecan, the formation of oxaliplatin-induced DNA interstrand crosslinks was not modified in cells, but their reversion was slower, as measured by alkaline elution. Successive topotecan exposures did not affect the level of Topo I-mediated DNA single-strand breaks (SSBs). Pre-exposure to oxaliplatin transiently increased Topo I-mediated SSBs, suggesting that DNA platination might stimulate Topo I DNA cleavage activity. Hence, the cellular pharmacology of oxaliplatin combined with topotecan appeared highly dependent on the schedule. Therefore, this study suggests that the combination of topotecan with oxaliplatin might exhibit sequence-dependent pharmacodynamic interactions in the clinic.
Goldwasser
F
F
Experimental Therapeutics and Translational Research Section, FSMSIT, Hôpital Paul Brousse, Villejuif, France. f.goldwasser@wanadoo.fr
Bozec
L
L
Zeghari-Squalli
N
N
Misset
J L
JL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006207:Half-Life; D006801:Humans; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077150:Oxaliplatin; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D059004:Topoisomerase I Inhibitors; D000077150:Oxaliplatin; D019772:Topotecan