Pharmacological Abrogation of S-phase Checkpoint Enhances the Anti-tumor Activity of Gemcitabine in Vivo.
From: Exelixis Inc., South San Francisco, California 94083, USA. matthews@exelixis.com
Cell cycle (Georgetown, Tex.)
- Publish Date: Jan 2007
- ISSN: 1551-4005
- Volume: 6
- Issue: 1
- Pages: 104-10
- Medium: Internet
- Language: English
- Citation (JAMA): Matthews David J, Yakes F Michael, Chen Jason, et al. Pharmacological Abrogation of S-phase Checkpoint Enhances the Anti-tumor Activity of Gemcitabine in Vivo.. Cell Cycle Jan 2007;6:104-10
Abstract
Chk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase DNA damage response, may be involved in resistance to genotoxic therapies that target DNA synthesis. We studied the in vitro and in vivo effects of EXEL-9844 (XL844), a potent, orally available, and specific inhibitor of Chk1 and Chk2, in combination with gemcitabine. In clonogenic assays using multiple cell lines in vitro, EXEL-9844 had only minor effects as a single agent but substantially enhanced gemcitabine-induced cell killing. Correspondingly, in PANC-1 cells, EXEL-9844 increased gemcitabine-induced H2AX phosphorylation, blocked Cdc25A phosphorylation, and induced premature mitotic entry. In a PANC-1 xenograft model, EXEL-9844 significantly enhanced gemcitabine antitumor activity but had limited effect as a single agent. Together, these data show that cell cycle checkpoint inhibitors may have significant clinical utility in potentiating the activity of gemcitabine.
Mesh Headings (Keywords): Animals, Antimetabolites, Antineoplastic, Cells, Cultured, Deoxycytidine, Dose-Response Relationship, Drug, Female, Genes, cdc, Mice, Mice, Nude, Protein Kinases, Protein-Serine-Threonine Kinases, S Phase, Xenograft Model Antitumor Assays
Check for Full Text / PubMed Unique Identifier (PMID): 17245119
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