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Prostate-Restricted Replicative Adenovirus Expressing Human Endostatin-Angiostatin Fusion Gene Exhibiting Dramatic Antitumor Efficacy

Authors' Affiliations: Departments of ¹ Urology, ² Microbiology and Immunology, and ³ Medicine and ⁴ Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana

Requests for reprints: Chinghai Kao, Department of Urology, Indiana University School of Medicine, 1001 West 10th Street, Room OPW #320, Indianapolis, IN 46202. Phone: 317-278-6873; Fax: 317-278-3432; E-mail: chkao{at}iupui.edu.

Purpose: Our previous studies coadministering a replication-deficient adenovirus expressing endostatin and angiostatin fusion gene (EndoAngio) and a prostate-restricted, replication-competent adenovirus (PRRA) showed dramatic antitumor efficacy. This study integrated EndoAngio with an improved PRRA vector to make a single antiangiogenic PRRA, thereby exerting a similarly dramatic antitumor effect with feasibility for future clinical trials.

Experimental Design: We developed an antiangiogenic PRRA with structural improvements. The antitumor efficacy of EndoAngio-PRRA was evaluated in prostate-specific antigen/prostate-specific membrane antigen (PSA/PSMA)-positive, androgen-independent CWR22rv tumor models. The tumor vasculature and cell morphology were observed by dual-photon microscopy. The antiangiogenic effect of EndoAngio delivered by PRRA and the killing activity of EndoAngio-PRRA were evaluated in vitro. Virus-inactivated conditioned media from virus-infected PSA/PSMA-positive cells were tested for apoptosis induction in prostate cancer cells.

Results: Our novel EndoAngio-PRRA is a strong antiangiogenic and antitumor agent. Nine of 10 CWR22rv tumors treated by EndoAngio-PRRA completely regressed, with 1 tumor remaining in a dormant status for 26 weeks after treatment. Dual-photon microscopy revealed that EndoAngio-PRRA not only inhibited the development of tumor vasculature but also induced apoptosis in tumor cells. Subsequent in vitro study indicated that EndoAngio-PRRA exhibited stronger tumor-specific killing activity than enhanced green fluorescent protein-PRRA, which expresses enhanced green fluorescent protein instead of EndoAngio. Virus-inactivated conditioned medium from EndoAngio-PRRA–infected PSA/PSMA-positive cells induced apoptosis in C4-2 and CWR22rv cells.

Conclusions: EndoAngio-PRRA uniquely combines three distinct antitumor effects to eliminate androgen-independent prostate cancer: antiangiogenesis, viral oncolysis, and apoptosis. This novel antiangiogenic PRRA represents a powerful agent feasible for future clinical trials for prostate cancer therapy.