N-(4-hydroxyphenyl)retinamide inhibits vascular tumor growth by angiogenesis inhibition: an example of "angioprevention"

M Morini, DM Noonan, F Campelli, S Minghelli, A Albini, N Ferrari

Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy Centro di Biotecnologie Avanzate, Genove, GE Italy

N-4-Hydroxyphenyl-retinamide (4HPR or fenretinide) is a synthetic retinoid that displays a broad range of biological effects and has also demonstrated clinical efficacy as a chemopreventive agent. Here we have studied 4HPR, successful in chemoprevention, to evaluate whether its potential as antitumoral agent targets neoangiogenesis. We could demonstrate that 4HPR has a wide range of activities aimed at the angiogenic phenotype of both vascular Kaposi's sarcoma cells and endothelial cells. 4HPR was able to inhibit chemotaxis and invasion of Kaposi's sarcoma and HUVE cells. This was accompanied by a decrease in MMP-2, a crucial metalloprotease in invasion. 4HPR decreased HUVEC cell growth and morphogenesis in Matrigel. In a Matrigel plug assay of angiogenesis, 4HPR was able to prevent vessel formation. KS xenografts had a reduced growth in vivo which could be attributed not only to reduced HUVEC invasion but to a decrease of VEGF synthesis in KS cells and KDR expression by HUVE cells. Taken together our data show that 4HPR acts against the proangiogenic program in different ways, influencing growth factors and growth factor receptor expression, and metalloprotease activity leading to impaired invasion in vitro and in vivo growth, candidating the molecule for KS and vascular tumor therapy.

KEY WORDS: Chemoprevention, angiogenesis, retinoid.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Angiogenesis.