In the US and much of the developed world, the age-adjusted HIV death rate has dropped by about 4-fold since the early 1990's and is now the lowest rate since 1987. This dramatic reduction in AIDS related deaths has largely been due to the advent of anti-retroviral agents which prolong AIDS-free HIV infection as well as life-expectancy once AIDS has developed. A reduction in the incidence of Kaposi's sarcoma has long been known to parallel the drop in HIV death rates. However it has now been shown that this reduction is not simply an indirect consequence of improved immunosurveillance resulting from the use of anti-retroviral agents. In a breakthrough study, Italian researchers have made the important observation that the anti-retroviral agents indinavir and saquinavir reduce the progression and cause the regression of Kaposi's sarcoma in nude mice. Anti-cancer activity was not specific to Kaposi's sarcoma and was reflected by the antiangiogenic properties of these anti-virals. Both indinavir and saquinavir were shown to block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). Anti-angiogenic activity resulted from the inhibition of endothelial- and tumor-cell invasion and of matrix metalloproteinase-2 proteolytic activation at concentrations present in plasma of treated individuals. The potential market for anti-angiogenic molecules is predicted to be as high as $1.75 billion, however current revenues are estimated as only $70 million due to the lack of molecules on the market. Indeed the current market is shared between thalidomide and Glivec which are both used off-label. Indinavir and saquinavir may represent further off-label treatments of angiogenesis and controlled clinical trials are eagerly awaited to determine whether their indication can be expanded to include diseases associated with increased angiogenesis. Furthermore it is hoped that SAR or HTS studies may allow further optimization of protease inhibitors with improved angiogenic activity.

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