Angiogenesis  New Targets for the Development of Anticancer Chemotherapies

Maralea      Gourley; John   S.   Williamson

doi:10.2174/1381612003400867

Abstract

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries (ii) inhibition of endothelial cell migration (iii) inhibition of endothelial cell proliferation (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.

Keywords: Angiogenesis, chemotherapy, endothelial cell proliferation, Disease control and prevention CDC, fibroblast growth factor, proteolitic enzyme, Urokinase plasminogen, matrix metalloproteases, mercaptoacetamides, endothelial cell adhesion, fumagillin and analogs, apoptosis, thalidomide, thrompospondin, CAM assay, tetrandrine, linomide