title: Inhibition of VEGF receptors significantly impairs mammary cancer growth in C3(1)/Tag transgenic mice through antiangiogenic and non-antiangiogenic mechanisms.
abstract: Cancer growth and progression is often critically influenced by the production of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. VEGF produced by tumor cells stimulates endothelial cell growth through the binding and activation of the KDR/Flk-1 receptor (VEGFR-2) on endothelial cells. Recently, some human breast cancer epithelial cells have been shown to express VEGF receptors, suggesting a potential autocrine-mediated growth stimulation of a subset of cancers by VEGF. We demonstrate that mammary tumors in the C3(1)/Tag transgenic model express VEGF and VEGF receptors and tumor growth is stimulated by this autocrine mechanism. GW654652, an indazolylpyrimidine, is a VEGFRs tyrosine kinase inhibitor that dramatically reduces both angiogenesis and tumor cell growth in this model, as demonstrated using both in vitro and in vivo assays. GW654652 significantly decreased cell proliferation and induced apoptosis in human umbilical vein endothelial cells and M6 mammary tumor cells derived from C3(1)/Tag (Tag: simian virus 40 T-antigen) transgenic mice. A 75% reduction in VEGF-induced angiogenesis was observed with GW654652 using the chick chorioallantoic membrane assay, whereas GW654652 produced an approximately 85% reduction in angiogenesis as assessed by the Matrigel plug assay. A profound inhibitory effect on tumor growth in the C3(1)/Tag transgenic model of human breast cancer was observed with oral administration of GW654652 as measured by delayed tumor onset, decreased multiplicity, reduced tumor volume, and extended animal survival. The antitumor effects of GW654652 were associated with reduced tumor vascularization and no apparent toxicity. Tumor growth, however, rapidly advanced following cessation of treatment. This is the first demonstration that a VEGF receptor inhibitor, GW654652, has a strong inhibitory effect on angiogenesis and tumor progression in a transgenic model of mammary cancer, suggesting that this is a useful approach for preclinical testing of such agents.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jung-Im
authors.initials: JI
authors.lastname: Huh
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Stafford
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Deborah
authors.initials: D
authors.lastname: Philp
authors.forename: Hynda K
authors.initials: HK
authors.lastname: Kleinman
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
mesh_terms: D000482:Allantois / Q000166:cytology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002823:Chorion / Q000166:cytology; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014471:Umbilical Veins; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D017931:DNA Primers; C486980:GW 654652; D007093:Imidazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2