Anti-angiogenic activity of the purine analog 6-thioguanine.
The antimetabolite 6-thioguanine (6-TG) is utilized in the management of acute myelogenous leukemia (AML). Angiogenesis is a possible therapeutic target in hematologic tumors. Thus, we addressed the possibility that 6-TG may also act as an anti-angiogenic molecule. 6-TG inhibited endothelial cell proliferation triggered by fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF) and delayed the repair of a mechanically wounded endothelial cell monolayer. Also, 6-TG inhibited sprouting within fibrin gel, morphogenesis on Matrigel, and collagen gel invasion by endothelial cells. 2-Aminopurine was ineffective. In vivo, 6-TG inhibited basal, VEGF-induced, and FGF2-induced vascularization in the chick embryo chorioallantoic membrane and prevented neovascularization triggered by leukemia LIK cells or their conditioned medium. Finally, bone marrow vascularization in AML patients was decreased to control values in the early remission phase and persisted unvaried after 8-12 months of maintenance therapy with 6-TG. Thus, 6-TG inhibits different steps of the angiogenesis process in vitro and exerts a potent anti-angiogenic activity in vivo. Its anti-angiogenic activity, together with its antimetabolite activity towards tumor cells, may contribute to its action during maintenance therapy in AML. These results suggest a new rationale for the use of purine analogs in the management of AML.
Presta
M
M
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.
Belleri
M
M
Vacca
A
A
Ribatti
D
D
D015075:2-Aminopurine / Q000494:pharmacology; D000208:Acute Disease; D000368:Aged; D000482:Allantois / Q000098:blood supply / Q000187:drug effects; D000740:Anemia / Q000188:drug therapy / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000098:blood supply; D002417:Cattle; D002461:Cell Line, Transformed; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D004341:Drug Evaluation; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005500:Follow-Up Studies; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012074:Remission Induction; D013314:Stress, Mechanical; D013866:Thioguanine / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003561:Cytarabine; D016222:Fibroblast Growth Factor 2; D015075:2-Aminopurine; D005047:Etoposide; D013866:Thioguanine; D003630:Daunorubicin