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Clinical Cancer Research Vol. 5, 1189-1196, May 1999
© 1999 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Cellular Pharmacology of the Combination of the DNA Topoisomerase I Inhibitor SN-38 and the Diaminocyclohexane Platinum Derivative Oxaliplatin1

Nadia Zeghari-Squalli, Eric Raymond2, Esteban Cvitkovic and François Goldwasser3

Fédération des Services des Maladies Sanguines, Immunitaires, et Tumorales, Hôpital Paul Brousse, 94804 Villejuif [N. Z-S., E. C., F. G.]; and Unité INSERM U55, Hôpital St. Antoine, 75012 Paris [E. R.], France

CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane platinum derivative, are cytotoxic agents that have demonstrated clinical antitumor activity in colorectal cancer. Given the therapeutic potential of their combination, we studied the cellular pharmacology of SN-38, the active metabolite of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given alone or in combination. The cytotoxicity analysis by the isobolograms method elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount of detectable ISCs 15 h after a 1-h exposure to 10 µM oxaliplatin was 27% of the ISC peak levels and increased to 68% in the presence of 0.1 µM SN-38. The presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38-induced DNA elongation inhibition, as measured by pulse-labeling alkaline elution. Inhibition of DNA and RNA synthesis was longer after exposure to the combination of oxaliplatin and SN-38 than after exposure to each agent alone. Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra-additive cytotoxicity appears related to major modifications in the cellular response to DNA damage rather than to changes in DNA damage formation. The combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This study provides a rationale for the optimal use of CPT-11 and oxaliplatin in combination.




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