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- Title
Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G<sub>1</sub> checkpoint-defective neuroblastoma.
- Authors
Xu, Hong; Cheung, Irene Y.; Wei, Xiao X.; Tran, Hoa; Gao, Xiaoni; Cheung, Nai-Kong V.
- Abstract
Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G2 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 G1 checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G1 checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G1 checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G2 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 G1 checkpoints.
- Publication
International Journal of Cancer, 2011, Vol 129, Issue 8, p1953
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.25842