Combination therapy of androgen-independent prostate cancer using a prostate restricted replicative adenovirus and a replication-defective adenovirus encoding human endostatin-angiostatin fusion gene

Abstract

Although prostate-restricted replicative adenovirus has exhibited significant antitumor efficacy in preclinical studies, it is necessary to develop more potent adenoviruses for prostate cancer gene therapy. We evaluated the synergistic killing effect of prostate-restricted replicative adenovirus and AdEndoAngio, a replication-defective adenovirus expressing the endostatin-angiostatin fusion protein (EndoAngio). When coadministered with AdEndoAngio, prostate-restricted replicative adenovirus significantly elevated EndoAngio expression, suggesting that AdEndoAngio coreplicates with prostate-restricted replicative adenovirus. Conditioned medium from prostate cancer cells infected by prostate-restricted replicative adenovirus plus AdEndoAngio inhibited the growth, tubular network formation, and migration of human umbilical vein endothelial cells better than conditioned medium from prostate cancer cells infected by AdEndoAngio alone. Furthermore, in vivo animal studies showed that the coadministration of prostate-restricted replicative adenovirus plus AdEndoAngio resulted in the complete regression of seven out of eight treated androgenindependent CWR22rv tumors, with a tumor nodule maintaining a small size for 14 weeks. The residual single tumor exhibited extreme pathologic features together with more endostatin-reactive antibody-labeled tumor cells and fewer CD31-reactive antibody-labeled capillaries than the AdEndoAngio-treated tumors. These results show that combination therapy using prostate-restricted replicative adenovirus together with antiangiogenic therapy has more potent antitumor effects and advantages than single prostate-restricted replicative adenovirus and deserves more extensive investigation. [Mol Cancer Ther 2006; 5(3):676 -84]

Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer

“…The efficacy of combination therapy with conventional gene therapy using replication-deficient adenovirus plus virotherapy has been reported previously (27,28). Combined with tumor-specific replication-selective adenovirus, replication-deficient adenoviruses were able to replicate and spread to surrounding tumor cells.…”

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

“…A confluent monolayer of HUVEC cells was scratched, displaced cells were removed, and fresh medium containing CM was added. The gap distances were quantified (12), and data are presented as a comparison value (the gap distance at 12 h/initial distance). ++, P < 0.001.…”

“…In our past studies, we developed a prostate-restricted replicative adenovirus (PRRA; ref. 14) and investigated the synergistic antitumor effect of PRRA combined with a replication-defective adenovirus encoding an endostatin and angiostatin fusion gene (EndoAngio) in androgen-independent prostate cancer (12). We observed that PRRA augmented the transduction effect and expression of antiangiogenic factor, showing a significant antiangiogenic and antitumor effect.…”

Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

“…[4][5][6] The existing therapy for metastasis of PCA is unsatisfactory, with the condition being invariably fatal. [6][7][8] The development of novel therapies, possibly including gene therapy, for management of PCA is thus a clinical priority.…”