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First published on May 28, 2008; DOI: 10.1124/mol.108.047787

0026-895X/08/7403-724-735$20.00
Mol Pharmacol 74:724-735, 2008

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Overcoming S-Phase Checkpoint-Mediated Resistance: Sequence-Dependent Synergy of Gemcitabine and 7-Ethyl-10-hydroxycamptothecin (SN-38) in Human Carcinoma Cell LinesFormula

Marina Gálvez-Peralta, Nga T. Dai, David A. Loegering, Karen S. Flatten, Stephanie L. Safgren, Jill M. Wagner, Matthew M. Ames, Larry M. Karnitz, and Scott H. Kaufmann

Division of Oncology Research and Department of Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, Minnesota

Although agents that inhibit DNA synthesis are widely used in the treatment of cancer, the optimal method for combining such agents and the mechanism of their synergy is poorly understood. The present study examined the effects of combining gemcitabine (2',2'-difluoro 2'-deoxycytidine) and 7-ethyl-10-hydroxycamptothecin (SN-38; the active metabolite of irinotecan), two S-phaseselective agents that individually have broad antitumor activity, in human cancer cells in vitro. Colony-forming assays revealed that simultaneous treatment of Ovcar-5 ovarian cancer cells or BxPC-3 pancreatic cancer cells with gemcitabine and SN-38 resulted in antagonistic effects. In contrast, sequential treatment with these two agents in either order resulted in synergistic anti-proliferative effects, although the mechanism of synergy varied with the sequence. In particular, SN-38 arrested cells in S phase, enhanced the accumulation of gemcitabine metabolites, and diminished checkpoint kinase 1, thereby sensitizing cells in the SN-38 -> gemcitabine sequence. Gemcitabine treatment followed by removal allowed prolonged progression through S phase, contributing to synergy of the gemcitabine -> SN-38 sequence. These results collectively suggest that S-phase-selective agents might exhibit more cytotoxicity when administered sequentially rather than simultaneously.

Received April 7, 2008; accepted May 28, 2008

Address correspondence to: Dr. Scott H. Kaufmann, Division of Oncology Research, Guggenheim 1342C, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905. E-mail: kaufmann.scott{at}mayo.edu






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