Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G 1 checkpoint-defective neuroblastoma Academic Article uri icon

Overview

MeSH Major

  • Antimetabolites, Antineoplastic
  • Neuroblastoma
  • Protein Kinase Inhibitors
  • Protein Kinases
  • Thiophenes
  • Urea

abstract

  • Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G(2) cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14(ARF) genomic status. Four of four p53 mutant lines and three of five MDM2/p14(ARF) abnormal lines were defective in G(1) checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G(1) checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G(1) checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G(2) checkpoint arrest both in vitro and in vivo. In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA-damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G(1) checkpoints.

publication date

  • October 15, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1002/ijc.25842

PubMed ID

  • 21154747

Additional Document Info

start page

  • 1953

end page

  • 62

volume

  • 129

number

  • 8