Prostate-restricted replicative adenovirus expressing human endostatin-angiostatin fusion gene exhibiting dramatic antitumor efficacy.
OBJECTIVE
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.


METHODS
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.
Li
Xiong
X
Departments of Urology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Liu
You-Hong
YH
Lee
Sang-Jin
SJ
Gardner
Thomas A
TA
Jeng
Meei-Huey
MH
Kao
Chinghai
C
D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000502:physiology; D043168:Angiostatins / Q000235:genetics*; D000818:Animals; D019677:Artificial Gene Fusion; D015153:Blotting, Western; D043169:Endostatins / Q000235:genetics*; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000628:therapy*; D011993:Recombinant Fusion Proteins
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011993:Recombinant Fusion Proteins; D043168:Angiostatins