Adenoviral vectors expressing human endostatin-angiostatin and soluble Tie2: enhanced suppression of tumor growth and antiangiogenic effects in a prostate tumor model.
Angiogenesis is essential for prostate cancer development and metastasis. Antiangiogenic therapy targeting tumor neovasculature, therefore, represents a promising approach for prostate cancer treatment. We hypothesized that adenoviral-mediated delivery of a combination of antiangiogenic factors might have an enhanced antitumor response. We developed the adenoviral vectors Ad-hEndo-angio, expressing a unique, chimeric human endostatin-angiostatin fusion protein, and Ad-sTie2, expressing a soluble form of endothelium-specific receptor tyrosine kinase Tie2. Matrigel angiogenesis assays using Ad-hEndo-angio revealed significant inhibition of tubular network formation and endothelial sprouting compared to Ad-sTie2. In vivo studies in a bilateral PC-3 tumor xenograft model following either intratumoral or systemic administration of Ad-hEndo-angio led to enhanced tumor growth suppression compared to Ad-sTie2. A novel finding is that an intratumoral, combination therapy employing one-half the dose of Ad-hEndo-angio as well as Ad-sTie2 led to a complete regression of the injected, as well as the contralateral uninjected, tumor and prolonged the tumor-free survival in 80% of the animals. In addition, a novel, real-time, intravital imaging modality was used to monitor antiangiogenic responses following adenoviral-mediated gene transfer. These results suggest that a combinatorial antiangiogenic gene therapy approach involving Ad-hEndo-angio and Ad-sTie2 could become a novel form of treatment for localized human prostate cancer.
Raikwar
Sudhanshu P
SP
Department of Urology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, USA.
Temm
Constance J
CJ
Raikwar
Nandita S
NS
Kao
Chinghai
C
Molitoris
Bruce A
BA
Gardner
Thomas A
TA
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology; D018572:Disease-Free Survival; D004338:Drug Combinations; D043169:Endostatins / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007797:Laminin / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017785:Photons; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D011509:Proteoglycans / Q000737:chemistry / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000096:biosynthesis / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D043169:Endostatins; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D043168:Angiostatins; D003094:Collagen; D042787:Receptor, TIE-2