title: The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinases.
abstract: Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08540, USA.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Susan
authors.initials: S
authors.lastname: Galbraith
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Steven
authors.initials: S
authors.lastname: Mortillo
authors.forename: Barri S
authors.initials: BS
authors.lastname: Wautlet
authors.forename: Bala
authors.initials: B
authors.lastname: Krishnan
authors.forename: Daniel
authors.initials: D
authors.lastname: Kukral
authors.forename: Harold
authors.initials: H
authors.lastname: Malone
authors.forename: Anne C
authors.initials: AC
authors.lastname: Lewin
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Henley
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000737:chemistry; D011758:Pyrroles / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011758:Pyrroles; D014227:Triazines; C059485:matrigel; D003094:Collagen; C509922:brivanib; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine