Combination therapy of androgen-independent prostate cancer using a prostate restricted replicative adenovirus and a replication-defective adenovirus encoding human endostatin-angiostatin fusion gene.
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 androgen-independent 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.
Department of Urology, Indiana University School of Medicine. 1001 West 10th Street, Room OPW 320, Indianapolis, IN 46202, USA.
Xiong
X
Li
Sudhanshu P
SP
Raikwar
You-Hong
YH
Liu
Sang-Jin
SJ
Lee
Yan-Ping
YP
Zhang
Shaobo
S
Zhang
Liang
L
Cheng
Sang-Don
SD
Lee
Beth Elisa
BE
Juliar
Thomas A
TA
Gardner
Meei-Huey
MH
Jeng
Chinghai
C
Kao
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000728:Androgens / Q000378:metabolism; D043168:Angiostatins / Q000235:genetics*; D000818:Animals; D019677:Artificial Gene Fusion; D043169:Endostatins / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D014158:Transcription, Genetic; D014779:Virus Replication
D000728:Androgens; D043169:Endostatins; D043168:Angiostatins