SU5416 selectively impairs angiogenesis to induce prostate cancer-specific apoptosis.
We have previously demonstrated the differential expression in tumor-associated blood vessels of two vascular endothelial growth factor receptors (VEGFRs), VEGFR1 and VEGFR2, during initiation and progression of prostate cancer in the genetically engineered transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. In our "progression switch" model, expression of VEGFR1 is associated with early and more differentiated disease, whereas expression of VEGFR2 is associated with advanced and more poorly differentiated disease. To test the hypothesis that stage-specific inhibition of vascular endothelial growth factor signaling could be used as therapy for autochthonous prostate cancer, we initiated a preclinical trial with SU5416, a potent antiangiogenic small molecule inhibitor of VEGFR associated tyrosine kinase activity. In our early intervention trial, administration of SU5416 to TRAMP mice did not appear to influence angiogenesis or tumor progression between 10 and 16 weeks of age, a time corresponding to high levels of VEGFR1 expression. In our late intervention trial, however, we observed a significant decrease in tumor-associated mean vessel density, increased apoptotic index, and pronounced regions of cell death when SU5416 was administered to TRAMP mice between 16 and 22 weeks of age, a time corresponding to high levels of VEGFR2 expression. These results clearly demonstrate that therapy directed specifically against the VEGFR signaling axis can dramatically impair angiogenesis and induce apoptosis of autochthonous spontaneous and progressive prostate cancer.
Huss
Wendy J
WJ
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Barrios
Roberto J
RJ
Greenberg
Norman M
NM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use*; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2