Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it was estimated that approximately 1.3 million new cases of cancer would have been diagnosed and 555,500 people would have died from cancer in the United States in 2002. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry (see "Cancer Treatment 2002" for a full analysis of current and future pharmaceutical approaches to cancer).

Angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Both stimulators and inhibitors of angiogenesis are being developed, with primary interest being focussed on the use of inhibitors to prevent the growth of tumors. This is based on the concept that cells in the center of the tumor receive inadequate levels of oxygen and nutrients by diffusion alone once they extend past a critical volume of 2 cubic millimeters and instead rely on neovascularization for further growth. One class of drug that has been implicated in the angiogenesis process is that of the matrix metalloproteinases (MMPs) inhibitors. MMPs have a dual function in tumor angiogenesis: MMP-2 is required to break down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In addition to playing a role in angiogenesis, MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix supporting the view that MMP inhibitors may be able to prevent tumor escape as well as growth. This suggests that the therapeutic use of MMP inhibitors may be most beneficial in patients who do not have advanced disease and this is largely borne out by clinical evaluation of class leaders such as Marimastat.

The small GTPase Rho A plays a role in the reorganization of the actin cytoskeleton and regulation of actomyosin contractility. As a result Rho controls cell adhesion and motility and inhibition of this enzyme by Y-27632 limits the invasiveness of prostate cancer cells. It has recently emerged that Rho kinase also activates MMP2 and molecules such as Y-27632 may therefore reduce angiogenesis as well as tumor escape. This has recently been evaluated in prostate cancer PC3 cells and endothelial cells (HUVECs). Of note the Rho kinase inhibitor Wf-536 inhibited vacuolation by endothelial cells and lumen formation, the earliest detectable stages of angiogenesis. Furthermore, combining Wf-536 with Marimastat greatly enhanced in vitro inhibition of angiogenesis. As a result, early treatment of PC3 xenografts with a combination of Wf-536 plus Marimastat, significantly inhibited tumor growth, prevented tumor growth escape, and increased survival.

Together this data suggests that the use of Rho kinase inhibitors in prostate cancer patients who do not have advanced disease may be of clinical benefit especially if used along side an MMP inhibitor.

Entry date March, 2003

Adapted from Somlyo et al, FASEB J 2003 Feb;17(2):223-34 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk