Thursday, November 22, 2012

E1B-55 kDa-Defective Adenoviruses Activate p53 in Mesothelioma and Enhance Cytotoxicity of Anticancer Agents

http://www.ncbi.nlm.nih.gov/pubmed/23154556


 2012 Dec;7(12):1850-1857.

E1B-55 kDa-Defective Adenoviruses Activate p53 in Mesothelioma and Enhance Cytotoxicity of Anticancer Agents.

Source

Divisions of *Pathology and Cell Therapy and †Translational Genomics, Chiba Cancer Center Research Institute, Chiba, Japan; Departments of ‡Respirology, §Molecular Biology and Oncology, and ‖Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan; Departments of ¶Biochemistry and #Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan; **TOT Shanghai RD Center, Shanghai, China; ††Department of Surgery, School of Medicine, Toho University, Tokyo, Japan; and ‡‡Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan.

Abstract

INTRODUCTION:: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways. METHODS:: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents. RESULTS:: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model. CONCLUSIONS:: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic formesothelioma.

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