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) sin ce farnesylation of Pas is required for its biological activity. In this pa per we evaluated the effect of A-170634, a novel and potent: CAAX FTI on an giogenesis. Human umbilical vein endothelial cell (HUVEC) tube formation an d VEGF; secretion were used to assess the effect of A-170634 on angiogenesi s in vitro. In vivo, nude mice were injected with the K-ras mutant colon ca rcinoma cell line HCT116 and treated subcutaneously with A-170634 using osm otic minipump infusion for 10 days. The effect of A-170634 on corneal angio genesis in vivo was assessed using pellets containing hydron, VEGF, A-17063 4 or vehicle. In vitro, A-170634 selectively inhibited farnesyltransferase activity over the closely related geranylgeranyltransferase I, inhibited Pa s processing, blocked anchorage-dependent and -independent growth of HCT116 K-ras mutated cells, decreased HUVEC capillary structure formation, decrea sed 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 tvas reduced by 41% following dr ug-treatment with no apparent toxicity to the animals. VEGF-induced corneal neovascularisation was reduced by 80% following A-170634 treatment for 7 d ays. The data presented here demonstrated that A-170634 was a potent and se lective peptidomimetic CAAX FTI with anti-angiogenic properties. These resu lts implied that A-170634 may affect tumour growth in vivo by one or more a ntitumour pathways. (C) 1999 Elsevier Science Ltd. All rights reserved.