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Anti-angiogenic activity of the purine analog 6-thioguanine

Leukemia volume 16, pages 1490–1499 (2002)Cite this article

Abstract

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.

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Acknowledgements

This work was supported in part by grants from MURST (Centro di Eccellenza ‘IDET’, Cofin 2000, and ex 60%), CNR (Progetto Finalizzato Biotecnologie), and Istituto Superiore di Sanità (AIDS Project) to MP, from Associazione Italiana per la Ricerca sul Cancro to MP and AV, and from Associazione Italiana per la Lotta al Neuroblastoma to DR.

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Authors and Affiliations

  1. Department of Biomedical Sciences and Biotechnology, Unit of General Pathology and Immunology, School of Medicine, University of Brescia, Brescia, Italy

    M Presta & M Belleri

  2. Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy

    A Vacca

  3. Department of Human Anatomy and Histology, University of Bari, Bari, Italy

    D Ribatti

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  1. M Presta
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  2. M Belleri
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  4. D Ribatti
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Presta, M., Belleri, M., Vacca, A. et al. Anti-angiogenic activity of the purine analog 6-thioguanine. Leukemia 16, 1490–1499 (2002). https://doi.org/10.1038/sj.leu.2402646

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