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

Abstract

Purpose: Our previous studies coadministering a replication-deficient adenovirus expressing endostatin and angiostatin fusion gene (EndoAngio) and a prostate-restricted, replicationcompetent 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 virusinfected 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 1tumor 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.

Baculovirus vectors for antiangiogenesis-based cancer gene therapy

“…35 Although the antitumor effects are temporary and subpar to completely lead to tumor regression, this is not uncommon as antiangiogenesis monotherapy fails to block tumor progression in the clinical studies. 36 Nevertheless, antiangiogenic agents can make the tumor more susceptible to eradication, enhancing the effectiveness of radiotherapy or chemotherapy, even at lower cumulative doses.…”

“…Alternatively, Bac-ITR-hEA may be administered intramuscularly because muscle provides a microenvironment more suitable for sustained expression and hEA can exert the antitumor effects via systemic administration. 4 Finally, although hEA gene delivery can be achieved by either adenovirus 35 or vaccinia virus, 8 the pre-existing immunity against these vectors in humans can attenuate the antitumor efficacies. In contrast, baculovirus is an insect virus in nature, and humans do not appear to possess preexisting antibody and T cells specifically against baculovirus.…”

Adenovirus-Based Gene Therapy for Cancer

“…Endostatin, a 20-kDa C-terminal fragment of collagen XVIII, is the most potent angiogenesis inhibitor and specifically inhibits endothelial cell proliferation and migration, induces apoptosis of vascular endothelial cells (Lai et al, 2007;Li et al, 2008;Ning et al, 2008), and has been demonstrated to be with antitumor effect in many solid tumors, and without toxicity, immunogenesis or resistance. The adenovirus vector carrying a secretable form of mouse endostatin, Av3mEndo, mediated the secreted expression of endostatin from Av3mEndo-transduced mammalian cells and showed a potential inhibition of endothelial cell migration in vitro.…”

Angiogenesis as a strategic target for prostate cancer therapy

“…351 Li et al's recent study indicated that a replication-deficient adenovirus expressing endostatin and angiostatin fusion gene (EndoAngio) and a prostate-restricted, replication competent adenovirus (PRRA) showed dramatic antitumor efficacy. 352 EndoAngio-PRRA uniquely combines three distinct antitumor effects to eliminate AI CaP: anti-angiogenesis, viral oncolysis, and apoptosis. 352 This novel anti-angiogenic PRRA represents a powerful agent feasible for future clinical trials for CaP therapy.…”