Antiangiogenesis agents

Angiogenesis inhibition is a new and exciting target for the development of an anticancer drug, however such drugs pose both conceptual and strategic challenges. As yet, no successful model exists to guide in the development of this drug strategy. The cytotoxic drug development model is likely inappropriate, since angiogenesis inhibitors may act in a cytostatic manner. Permeability of blood vessels are regulated by a family of vascular endothelial growth factors (VEGFs) and receptors. The neovasculari<ation response is primarily mediated by VEGF, a growth factor that is induced by hypoxia, as well as several other pathways. The angiopoietins are other growth factor families specific to vascular endothelial cells and work together with VEGF in vascular biology. In contrast, thrombospondin-1, angiostatin, endostatin, vasostatin and interferon-a, among others, are endogenous inhibitors of angiogenesis and inhibit endothelial proliferation and migration. Thus, the extent of angiogenesis is determined by the local balance between molecules that stimulate or inhibit this process. The inhibitors may be explored to inhibit tumor expansion, and tumor angiogenesis can be targeted in several ways. Interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes that are clearly linked to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration and metastasis. They have more recently been involved in primary and metastatic tumor growth and angiogenesis, and they may even play a role in tumor promotion. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking these enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors is important when discussing the methodological issues associated with determining clinical efficacy of MMP inhibitors and other antiangiogenesis agents. (C) 2002 Prous Science. All rights reserved.