310. Antitumor Effect of Telomerase-Specific Virotherapy in Pleural Dissemination of Human Malignant Mesothelioma
Authors: Yuichi Watanabe, Yuuri Hashimoto, Toru Kojima, Shunsuke Kagawa, Hitoshi Kawamura, Katsuyuki Nagai, Noriaki Tanaka, Yasuo Urata, Toshiyoshi Fujiwara
Journal: Molecular Therapy (2006)

Malignant mesothelioma is an extraordinarily challenging disease to treat; however, locoregional virotherapy may be applicable for this aggressive disease because of the accessibility by intrapleural and/or intratumoral virus delivery. We previously reported that an attenuated adenovirus OBP-301 (Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, could replicate in and causes selective lysis of human cancer cells. In the present study, we examined the antitumor effect of Telomelysin on human malignant mesothelioma cell lines in vitro and in vivo. The XTT assay demonstrated that Telomelysin could efficiently kill four human mesothelioma cell lines H2052, H2452, H28, and 211H, all of which expressed the coxsackievirus and adenovirus receptor (CAR), in a dose-dependent manner. In vivo antitumor effect was also evaluated in an orthotopic pleural dissemination model. Intrathoracic administration of 2 × 108 plaque forming units (PFU) of Telomelysin markedly reduced the size (1 ± 1.8 mg vs. 190 ± 75 mg, p < 0.01) of H2452 tumors intrathoracically implanted into BALB/c- nu/nu mice compared to mock-treated mice. These results suggest that locoregional administration of Telomelysin into the thoracic cavity may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma. Malignant mesothelioma is an extraordinarily challenging disease to treat; however, locoregional virotherapy may be applicable for this aggressive disease because of the accessibility by intrapleural and/or intratumoral virus delivery. We previously reported that an attenuated adenovirus OBP-301 (Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, could replicate in and causes selective lysis of human cancer cells. In the present study, we examined the antitumor effect of Telomelysin on human malignant mesothelioma cell lines in vitro and in vivo. The XTT assay demonstrated that Telomelysin could efficiently kill four human mesothelioma cell lines H2052, H2452, H28, and 211H, all of which expressed the coxsackievirus and adenovirus receptor (CAR), in a dose-dependent manner. In vivo antitumor effect was also evaluated in an orthotopic pleural dissemination model. Intrathoracic administration of 2 × 108 plaque forming units (PFU) of Telomelysin markedly reduced the size (1 ± 1.8 mg vs. 190 ± 75 mg, p < 0.01) of H2452 tumors intrathoracically implanted into BALB/c- nu/nu mice compared to mock-treated mice. These results suggest that locoregional administration of Telomelysin into the thoracic cavity may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.