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Int J Cancer. 2011 Oct 15;129(8):1953-62. doi: 10.1002/ijc.25842. Epub 2011 Mar 8.

Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G1 checkpoint-defective neuroblastoma.

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  • 1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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.

Copyright © 2010 UICC.

PMID:
21154747
[PubMed - indexed for MEDLINE]
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