Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo

Cell Cycle. 2007 Jan 1;6(1):104-10. doi: 10.4161/cc.6.1.3699. Epub 2007 Jan 7.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Cells, Cultured
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Genes, cdc / drug effects*
  • Genes, cdc / physiology
  • Mice
  • Mice, Nude
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • S Phase / drug effects*
  • S Phase / physiology
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • gemcitabine
  • Protein Kinases
  • Checkpoint Kinase 2
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases