207. Enhanced Antitumor Efficacy by Combination of Oncolytic Adenovirus with Taxol Via Active Induction of Apoptosis and Augment of Viral Production

Cancer - Targeted Gene Therapy: Virotherapy leading to an increased anti-tumor effect and survival advantage. Upon histological analysis, Ad-∆E1B-DCNG also elicited greater percentage of apoptotic cells and extensive necrosis compared to those from untreated or control virus-treated tumors. Furthermore, Ad-∆E1B-DCNG substantially decreased extracellular matrix components within the tumor tissue, while normal tissue adjacent to the tumor was not affected. Finally, intratumoral administration of Ad-∆E1B-DCNG did not enhance but inhibited the formation of pulmonary metastases of B16BL6 melanoma cells in mice. Taken together, these data demonstrate the utility of decorin as a dispersion agent and suggest its utility and potential in improving the efficacy of replicating adenovirus-mediated cancer gene therapy.

207. Enhanced Antitumor Efficacy by Combination of Oncolytic Adenovirus with Taxol Via Active Induction of Apoptosis and Augment of Viral Production

A-Rum Yoon,1,2 Chae-Ok Yun,1,2 Joo-Hang Kim.1,2 1 Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.

Retroviral (LCMV-GP) vectors displayed a very low, albeit specific transduction of xenografts (figure2E). In conclusion both, LCMV-GP and VSV-G lentiviral vectors show specific and efficient transduction of human glioblastoma cells in vitro and in vivo and therfore are attractive candidates for glioma gene therapy in patients. Further, the glioma model system used in this study is highly suitable for preclinical evaluation of new therapeutic strategies as it is the first animal model that confirms the low transduction efficacy of retroviral vectors for human glioblastoma in clinical studies.

206. Markedly Enhanced Intratumoral Spread and Antitumor Effect of Oncolytic Adenovirus Expressing Decorin

Oncolytic adenoviruses (Ads) are currently being developed as novel anti-tumor therapeutics. Chemotherapy has been shown to enhance the tumor-eradicating activity of replication-competent adenoviruses. For the aim to enhance therapeutic potential, E1Bmodified oncolytic Ads (Ad-DE1B55, Ad-DE1B19/55) have been administered in combination with taxol. Marked increase in cytotoxicity was observed when oncolytic Ads were combined with taxol. Propidium iodide staining and TUNEL assay also revealed that combination of taxol with oncolytic Ads caused greater induction of apoptosis. Similarly in vivo, combination of oncolytic Ads with taxol also induced greater antitumor effect in human cervical xenograft models. A more profound induction of apoptosis was observed in tumor tissue treated with oncolytic Ads plus taxol than any other treatment. Additionally, viral presence was confirmed by the immunohistological staining, where increased numbers of adenoviral particle were detected in wider areas of tumors treated with oncolytic Ads plus taxol. Furthermore, taxol increased the adenoviral gene expression (E1A13S, ADP and hexon genes), which is correlated with an increase in viral production. Taken together, these findings show that oncolytic adenoviruses in combination with taxol may enhance the therapeutic efficacy via active induction of apoptosis and augment of viral production.

Il-Kyu Choi,1,2 Young-Sook Lee,2 Ji Young Yoo,2 A-Rum Yoon,2 Hoguen Kim,3 Daniela G. Seidler,4 Joo-Hang Kim,1,2 Chae-Ok Yun.1,2 1 KOSEF through National Core Research Center for Nanomedical Technology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Department of Physiological Chemistry and Pathobiochemistry, University Hospital of Münster, Münster, Germany. With the aim of improving viral distribution and tumor penetration, we have engineered decorin expressing replication-incompetent (dl-LacZ-DCNG) and -competent (Ad-∆E1B-DCNG) adenoviruses. In both tumor spheroids and established solid tumors in vivo, administration of dl-LacZ-DCNG resulted in greater transduction efficiency and viral spread throughout the tumor mass. Ad∆E1B-DCNG also enhanced viral distribution and tumor spread, S78

Molecular Therapy Volume 16, Supplement 1, May 2008 Copyright © The American Society of Gene Therapy