Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis in vitro and in vivo.
Ras oncogenes can contribute to tumour development by stimulating vascular endothelial growth factor (VEGF)-dependent angiogenesis. The effect of Ras on angiogenesis may be affected by farnesyltransferase inhibitors (FTI) since farnesylation of Ras is required for its biological activity. In this paper we evaluated the effect of A-170634, a novel and potent CAAX FTI on angiogenesis. Human umbilical vein endothelial cell (HUVEC) tube formation and VEGF secretion were used to assess the effect of A-170634 on angiogenesis in vitro. In vivo, nude mice were injected with the K-ras mutant colon carcinoma cell line HCT116 and treated subcutaneously with A-170634 using osmotic minipump infusion for 10 days. The effect of A-170634 on corneal angiogenesis in vivo was assessed using pellets containing hydron, VEGF, A-170634 or vehicle. In vitro, A-170634 selectively inhibited farnesyltransferase activity over the closely related geranylgeranyltransferase I, inhibited Ras processing, blocked anchorage-dependent and -independent growth of HCT116 K-ras mutated cells, decreased HUVEC capillary structure formation, decreased VEGF secretion from tumour cells and HUVEC growth stimulating activity in a dose-dependent manner. In vivo, tumour growth was decreased by 30% and vascularisation in and around the tumours was reduced by 41% following drug-treatment with no apparent toxicity to the animals. VEGF-induced corneal neovascularisation was reduced by 80% following A-170634 treatment for 7 days. The data presented here demonstrated that A-170634 was a potent and selective peptidomimetic CAAX FTI with anti-angiogenic properties. These results implied that A-170634 may affect tumour growth in vivo by one or more antitumour pathways.
Gu
W Z
WZ
Abbott Laboratories, Department 4N6 AP9/2, Abbott Park, Illinois, USA.
Tahir
S K
SK
Wang
Y C
YC
Zhang
H C
HC
Cherian
S P
SP
O'Connor
S
S
Leal
J A
JA
Rosenberg
S H
SH
Ng
S C
SC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular; D051231:Farnesyltranstransferase; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C403907:A 170634; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase