Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process

Angiogenesis has been identified as an important target for antineoplastic therapy. The use of purine analogue antimetabolites in combination chemothe rapy of solid tumors has been proposed. To assess the possibility that sele cted purine analogues may affect tumor neovascularization, 6-methylmercapto purine riboside (6-MMPR), 6-methylmercaptopurine, 2-aminopurine, and adenos ine were evaluated for the capacity to inhibit angiogenesis in vitro and in vivo, 6-MMPR inhibited fibroblast growth factor-2 (FGF2)-induced prolifera tion and delayed the repair of mechanically wounded monolayer in endothelia l GM 7373 cell cultures. 6-MMPR also inhibited the formation of solid sprou ts within fibrin gel by FGF2-treated murine brain microvascular endothelial cells and the formation of capillary-like structures on Matrigel by murine aortic endothelial cells transfected with FGF2 cDNA, 6-MMPR affected FGF2- induced intracellular signaling in murine aortic endothelial cells by inhib iting the phosphorylation of extracellular signal-regulated kinase-2, The o ther molecules were ineffective in all of the assays. In vivo, 6-MMPR inhib ited vascularization in the chick embryo chorioallantoic membrane and preve nted blood vessel formation induced by human endometrial adenocarcinoma spe cimens grafted onto the chorioallantoic membrane. Also, topical administrat ion of 6-MMPR caused the regression of newly formed blood vessels in the ra bbit cornea, Thus, 6-MMPR specifically inhibits both the early and the late phases of the angiogenesis process ill vitro and exerts a potent anti-angi ogenic activity in vivo. These results provide a new rationale for the use of selected purine analogues in combination therapy of solid cancer.