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

J Thorac Oncol. 2012 Dec;7(12):1850-1857.

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

Yamanaka M, Tada Y, Kawamura K, Li Q, Okamoto S, Chai K, Yokoi S, Liang M, Fukamachi T, Kobayashi H, Yamaguchi N, Kitamura A, Shimada H, Hiroshima K, Takiguchi Y, Tatsumi K, Tagawa M.

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.