Document Detail

Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo.
MedLine Citation:
PMID:  17245119     Owner:  NLM     Status:  MEDLINE    
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.
David J Matthews; F Michael Yakes; Jason Chen; Michele Tadano; Lester Bornheim; Douglas O Clary; Albert Tai; Jill M Wagner; Nicole Miller; Yong D Kim; Scott Robertson; Louis Murray; Larry M Karnitz
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Publication Detail:
Type:  Comparative Study; Journal Article     Date:  2007-01-07
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  6     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-02-01     Completed Date:  2007-04-09     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  104-10     Citation Subset:  IM    
Exelixis Inc., South San Francisco, California 94083, USA.
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MeSH Terms
Antimetabolites, Antineoplastic / pharmacology*
Cells, Cultured
Deoxycytidine / analogs & derivatives*,  pharmacology
Dose-Response Relationship, Drug
Genes, cdc / drug effects*,  physiology
Mice, Nude
Protein Kinases / metabolism
Protein-Serine-Threonine Kinases / metabolism
S Phase / drug effects*,  physiology
Xenograft Model Antitumor Assays / methods
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.-/Protein Kinases; EC kinase 2; EC kinase 1; EC Kinases

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