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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4143-4155
Antiangiogenesis Is Produced by Nontoxic Doses of Vinblastine
Angelo Vacca,
Monica Iurlaro,
Domenico Ribatti,
Monica Minischetti,
Beatrice Nico,
Roberto Ria,
Antonio Pellegrino, and
Franco Dammacco
From the Department of Biomedical Sciences and Human Oncology (DIMO),
and the Institute of Human Anatomy, Histology and Embryology,
University of Bari Medical School, Bari, Italy.
The effects of vinblastine (VBL) on endothelial cell functions
involved in angiogenesis, namely proliferation, chemotaxis, spreading
on fibronectin (FN), secretion of matrix-metalloproteinase-2 (MMP-2)
and MMP-9, and morphogenesis on Matrigel were tested in vitro, whereas
its effects on angiogenesis were studied in vivo by using the chick
embryo chorioallantoic membrane (CAM) model. In vitro, at noncytotoxic
doses (0.1, 0.25, 0.5, 0.75, and 1 pmol/L), VBL impacted all these
functions, except secretion of MMPs, in a dose-dependent fashion. By
contrast, proliferation of other primary cells such as fibroblasts and
lymphoid tumor cells was not impacted. In vivo, VBL at 0.5, 0.75, and 1 pmol/L again displayed a dose-dependent antiangiogenic activity. Lack
of cytotoxicity in vitro and in vivo was shown both morphologically,
and also because the antiangiogenic effects were rapidly abolished when VBL was removed. Apoptosis was not induced. At the ultrastructural level, impairment of cell functions in vitro was associated with thin
disturbance of the cytoskeleton, in the form of slight depolymerization and accumulation of microfilaments, which was equally reversible. Results suggest that VBL has an antiangiogenic component at very low,
noncytotoxic doses, and that antiangiogenesis by VBL could be used to
treat a wide spectrum of angiogenesis-dependent diseases, including
certain chronic inflammatory diseases, Kaposi's sarcoma, and cancer.
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