Current Pharmaceutical Design, 2004, 10, 1-9 1 1381-6128/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. Angiogenesis Inhibitors: Current & Future Directions Shaker A. Mousa * and Ahmed S. Mousa 1 Albany College of Pharmacy & Pharmaceutical Research Institute (PRI) at Albany, Albany, NY and 1 Cornell University, Ithaca, NY, USA Abstract: The field of angiogenesis modulation is at a major crossroad. A tremendous advancement in basic science in this field is providing an excellent support for the concept, which is in contrast to a lack of strong clinical support to date. With regard to the large gap between experimental data and clinical data, the best model of human malignancy is in human cancer patients and the best model of human ocular angiogenesis-mediated disorders such as diabetic retinopathy (DR) and age related macular degeneration (AMD) is in human RD and AMD patients. Additionally, clinical outcomes should include benefit/risk ratios, hard end points (mortality and quality of life as opposed to increased microvascular density with pro-angiogenic agents or tumor size reduction with anti-angiogenesis agents) as well as cost effectiveness. Experimental models should be used to provide guidance, placebo effect, comparative data, and mechanistic understanding as opposed to being used for expected clinical efficacy. We also have to understand existing strategies and how angiogenesis modulation can add further value (i.e. not to replace existing strategy but rather improve efficacy/safety). Recent investigation defined numerous strategies in the modulation of angiogenesis. Those strategies are driven from haemostatic, fibrinolytic, cell adhesion molecules, extracellular matrix, growth factors, and other endogenous systems involved in the modulation of angiogenesis. INTRODUCTION In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth [1]. The process can be divided into two main phases [2]; an activation phase and a resolution phase. Each of these phases will comprise a variety of processes. The activation phase requires increased vascular permeability and extra-vascular fibrin deposition, vessel wall disassembly, degradation of the basement membrane, cell migration leading to ECM invasion, cell proliferation and tube formation. The resolution phase of angiogenesis requires that each of these processes be halted (cell migration and proliferation), reversed (basement membrane reconstitution), or brought to completion (recruitment of pericytes and smooth muscle cells facilitating vessel maturation). Extra-cellular proteolysis is a vital biochemical activity in all of these processes, which is a highly regulated, coordinated series of events [3]. Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), *Address correspondence to this author at the Albany College of Pharmacy & PRI, 106 New Scotland Avenue, Albany, NY 12208-3492, USA; Tel: (518)-445-7397; Fax: (518) 445-7392; E-mail: mousas@acp.edu invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible [1, 4, 5]. Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit the same [1, 4]. About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (FGF, acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-a, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1, interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinases [1, 4]. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor, are expressed by many tumors and seem to be important in sustaining tumor growth [1, 3]. Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that