TNP-470 (AGM-1470): mechanisms of action and early clinical development.

Abstract

INTRODUCTION ANGIOGENESIS DEFINES the complex phenomenon that leads to the genesis of new blood vessels from the existing vasculature [ 1, 21. Essential for growth and development, angiogenesis is restricted to some reproductive organs and in wound healing in adults. Folkman, the pioneer of the field, was the first to insist on the importance of angiogenesis in cancer progression and dissemination [3-51. Today, the concept that tumour angiogenesis is an essential phenomenon to sustain tumour growth over a few millimetres is unanimously recognised. The search for angiogenesis inhibitors as potential new anticancer agents has been one of the most challenging objectives of cancer research. One exciting aspect of angiogenesis inhibition therapy is its putative selectivity. The turnover of endothelial cells in adult tissues is very slow (within a year) compared to the turnover of endothelial cells engaged in tumour angiogenesis (4 days) [6]. Therefore, the specific inhibition of endothelial cell proliferation could affect the malignant lesions with no or minor consequences for the host. Among several inhibitors characterised within the last decade, TNP-470, a synthetic analogue of fumagillin, is one of the most promising angioinhibitors.