Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line.

Abstract:

: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.

journal_name

Anticancer Drugs

journal_title

Anti-cancer drugs

authors

Goldwasser F,Bozec L,Zeghari-Squalli N,Misset JL

doi

10.1097/00001813-199902000-00008

subject

Has Abstract

pub_date

1999-02-01 00:00:00

pages

195-201

issue

2

eissn

0959-4973

issn

1473-5741

journal_volume

10

pub_type

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