Gene therapy for antiangiogenesis.

Angiogenesis inhibitors have evolved as a new diverse class of compounds that can be used to block tumor growth (1,2). The inhibitors, which may be natural or synthetic, include protease inhibitors (i.e., tissue inhibitors of matrix metalloproteinases), tyrosine kinase inhibitors, chemokines, interleukins, and proteolytic fragments of diverse molecules (i.e., endostatin, vasostatin, canstatin, arrestin, etc.). These antiangiogenic molecules function in multiple ways, including the inhibition of endothelial cell proliferation, migration, protease activity, and tubule formation, as well as the induction of apoptosis. The antiangiogenic function of many of these molecules is well documented in vitro and in vivo, and some are currently being tested in clinical trials (http://cancertrials.nci.nih.gov). Less is known about the exact mechanism(s) of angiogenic regulation of some of the inhibitors. More than 40 endogenous inhibitors have been identified, and others may likely exist. Exactly why so many “stop signals” are present in mammals to inhibit angiogenesis is unclear, but their abundance indicates that angiogenesis must be tightly regulated in the adult. Because of the abundance of angiogenic inhibitors, whether each works independently or in concert with other inhibitors remains to be determined. Furthermore, angiogenesis may be regulated on multiple levels because simple withdrawal of an angiogenic stimulator in vivo can reduce blood vessel formation, suggesting that angiogenic inhibitors have cell-type, as well as functional, specificity. For example, it is possible that the inhibitor(s) that function to stop new blood vessel development in maturing organs are different from those that stop new blood vessel formation in repaired wounds. Some inhibitors may function to inhibit the formation of new blood vessels, whereas others may disrupt or modify existing vessels. Angiogenesis inhibitors may also be specific for a particular tissue bed because endothelia with functional and genetic lineage differences have been identified (3). The tumor vasculature is distinct from that in normal tissues, with altered endothelial cell morphology and a decreased number of perivascular cells that help to maintain the blood vessel integrity (2). A hallmark of many tumors is the increased production of vascular endothelial growth factor (VEGF), which appears to serve as a stabilization factor for the tumor endothelium in place of perivascular cells (4). In addition, some tumors have been found to have “channels” formed by tumor cells (5), as well as “mosaic vessels” formed by both tumor cells and endothelial cells (6). A recent study (7) has identified that the expression of a number of genes is increased in the tumor endothelium when compared with the nontumor endothelial cells. Thus, because the tumor endothelium appears to have a number of altered features, the best candidate antiangiogenic molecules for cancer therapy should be directed at differences between the tumor vasculature and normal vasculature to increase specificity and efficacy. However, many of the current antiangiogenic candidates also regulate similar activities, not only in tumor endothelium but also in normal endothelium and even in nontransformed cell types. The effectiveness of angiogenesis inhibitors in the treatment of various cancers remains to be determined. Despite the possibility of tumor endothelium being heterogeneous and tumor type specific, antiangiogenesis inhibitors have