AIDS patients who receive protease inhibitors as part of their antiviral therapy not only experience a drop in viral load and an increase in T-cell number, but also a reduced incidence of Kaposi's sarcoma — a cancer that is associated with herpesvirus-8 infection. Although these anticancer effects were originally attributed to the drugs' antiviral activities, researchers have now shown that the protease inhibitors indinavir and saquinavir also have potent anti-angiogenic effects. The discovery that these drugs disrupt proteolytic activity that is not only required for viral replication but also required for tumour growth, reveals a new approach to cancer therapy.

Kaposi's sarcoma is an angio-proliferative cancer that frequently occurs in HIV-infected individuals. The reduced incidence or regression of Kaposi's sarcoma in patients treated with indinavir or saquinavir was first reported several years ago. Epidemiologists were unable, however, to show an association between increased T-cell counts, HIV suppression and Kaposi's sarcoma regression. Furthermore, the rate of Kaposi's sarcoma regression was observed to be significantly lower in patients treated with non-protease-inhibitor-containing combination therapies, despite the ability of these drugs to effectively block HIV replication. So scientists have been searching for secondary effects of these drugs, beyond their antiviral activities.

Because Kaposi's sarcoma is characterized by unregulated angiogenesis and upregulation of the angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), Cecilla Sgadari et al. investigated whether indinavir and saquinavir had direct effects on blood-vessel formation. In the March issue of Nature Medicine, they report that these drugs block bFGF- and VEGF-induced angiogenesis in a chorioallantoic membrane assay. The drugs also inhibit development of angiogenic lesions that are induced by injection of bFGF or VEGF into nude mice, indicating a direct anti-angiogenic effect.

But how do viral protease inhibitors block angiogenesis? Angiogenesis requires invasion of the blood-vessel basement membrane by vascular endothelial cells, and this process is mediated by the matrix metalloproteinase MMP-2. MMP-2 is highly expressed by angiogenic endothelial cells and by Kaposi's sarcoma cells. It is released as a proenzyme that is proteolytically activated by a complex mechanism involving several other proteases. Sgadari et al. showed that although indinavir and saquinavir did not affect MMP-2 expression, they did block conversion of MMP-2 to its active form. These drugs therefore prevent activation of proteases involved in cell invasion and tumour angiogenesis.

So do indinavir and saquinavir have effects on cancers that are not associated with viral infection? Sgadari et al. found that the drugs did indeed inhibit growth of angiogenic lung adenocarcinoma cells implanted in nude mice. Because these drugs have already been shown to be safe and effective for human use, they might be quickly developed for treatment of Kaposi's sarcoma and other types of cancer in HIV-seronegative individuals.