Overcoming S-phase checkpoint-mediated resistance: Sequence-dependent synergy of gemcitabine and 7-ethyl-10-hydroxycamptothecin (SN-38) in human carcinoma cell lines

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

Research output: Contribution to journalArticle

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Abstract

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-phase-selective 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 antiproliferative 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-383 → 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.

Original languageEnglish (US)
Pages (from-to)724-735
Number of pages12
JournalMolecular Pharmacology
Volume74
Issue number3
DOIs
StatePublished - Sep 2008

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irinotecan
gemcitabine
S Phase Cell Cycle Checkpoints
Carcinoma
S Phase
Cell Line
Deoxycytidine
Pancreatic Neoplasms
Human Activities
Ovarian Neoplasms
Neoplasms

ASJC Scopus subject areas

  • Pharmacology

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

In: Molecular Pharmacology, Vol. 74, No. 3, 09.2008, p. 724-735.

Research output: Contribution to journalArticle

Gálvez-Peralta, Marina ; Dai, Nga T. ; Loegering, David A. ; Flatten, Karen S. ; Safgren, Stephanie L. ; Wagner, Jill M. ; Ames, Matthew M. ; Karnitz, Larry M ; Kaufmann, Scott H. / Overcoming S-phase checkpoint-mediated resistance : Sequence-dependent synergy of gemcitabine and 7-ethyl-10-hydroxycamptothecin (SN-38) in human carcinoma cell lines. In: Molecular Pharmacology. 2008 ; Vol. 74, No. 3. pp. 724-735.
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