TY - JOUR
T1 - Overcoming S-phase checkpoint-mediated resistance
T2 - Sequence-dependent synergy of gemcitabine and 7-ethyl-10-hydroxycamptothecin (SN-38) in human carcinoma cell lines
AU - Gálvez-Peralta, Marina
AU - Dai, Nga T.
AU - Loegering, David A.
AU - Flatten, Karen S.
AU - Safgren, Stephanie L.
AU - Wagner, Jill M.
AU - Ames, Matthew M.
AU - Karnitz, Larry M.
AU - Kaufmann, Scott H.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
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U2 - 10.1124/mol.108.047787
DO - 10.1124/mol.108.047787
M3 - Article
C2 - 18509065
AN - SCOPUS:50449109440
SN - 0026-895X
VL - 74
SP - 724
EP - 735
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 3
ER -