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 chemotherapy of solid tumors has been proposed. To assess the possibility that selected purine analogues may affect tumor neovascularization, 6-methylmercaptopurine riboside (6-MMPR), 6-methylmercaptopurine, 2-aminopurine, and adenosine were evaluated for the capacity to inhibit angiogenesis in vitro and in vivo. 6-MMPR inhibited fibroblast growth factor-2 (FGF2)-induced proliferation and delayed the repair of mechanically wounded monolayer in endothelial GM 7373 cell cultures. 6-MMPR also inhibited the formation of solid sprouts 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 inhibiting the phosphorylation of extracellular signal-regulated kinase-2. The other molecules were ineffective in all of the assays. In vivo, 6-MMPR inhibited vascularization in the chick embryo chorioallantoic membrane and prevented blood vessel formation induced by human endometrial adenocarcinoma specimens grafted onto the chorioallantoic membrane. Also, topical administration of 6-MMPR caused the regression of newly formed blood vessels in the rabbit cornea. Thus, 6-MMPR specifically inhibits both the early and the late phases of the angiogenesis process in vitro and exerts a potent anti-angiogenic activity in vivo. These results provide a new rationale for the use of selected purine analogues in combination therapy of solid cancer.
Presta
M
M
Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Italy.
Rusnati
M
M
Belleri
M
M
Morbidelli
L
L
Ziche
M
M
Ribatti
D
D
D015075:2-Aminopurine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000098:blood supply; D000241:Adenosine / Q000494:pharmacology; D000482:Allantois / Q000098:blood supply / Q000187:drug effects; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D001921:Brain / Q000098:blood supply; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D003864:Depression, Chemical; D016889:Endometrial Neoplasms / Q000098:blood supply; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D015122:Mercaptopurine / Q000031:analogs & derivatives / Q000494:pharmacology; D008778:Methylthioinosine / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D008778:Methylthioinosine; D015075:2-Aminopurine; C010240:6-methylthiopurine; D015122:Mercaptopurine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D000241:Adenosine