indinavir-sulfate and Neoplasms

The use of anti-HIV drugs as cancer treatments is not new. Azidothymidine was studied as an antineoplastic in the 1990s, but despite promising in vitro data, clinical trials showed little antitumour activity. HIV protease inhibitors were developed in the early 1990s, and their subsequent incorporation into highly active antiretroviral therapy (HAART) has profoundly changed the natural history of HIV infection. The potential antitumour properties of these drugs have been investigated because of their success in treating HIV-related Kaposi's sarcoma. HAART's effects on Kaposi's sarcoma did not always correlate with immune reconstitution, and activity against other solid and haematological malignancies has been established. Inhibition of tumour-cell invasion and angiogenesis were properties first ascribed to inhibition of HIV protease; however, they have pleiotropic antitumour effects, including inhibition of inflammatory cytokine production, proteasome activity, cell proliferation and survival, and induction of apoptosis. HIV protease inhibitors are thus a new class of anticancer drugs with multiple effects, and other anti-HIV drugs might hold similar promise.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cidofovir; Cytosine; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Neoplasms; Organophosphonates; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

Topics: Anti-HIV Agents; Cell Transformation, Neoplastic; HIV Protease Inhibitors; Humans; Indinavir; Neoplasms; Rheumatic Diseases; Ritonavir; Saquinavir

Human immunodeficiency virus protease inhibitors (HIV-PIs), such as indinavir and saquinavir, have been shown to block angiogenesis and tumor cell invasion and to induce tumor cell apoptosis and growth arrest, respectively, both in vitro and in vivo. These findings have suggested that HIV-PIs or their analogues can be used as antitumor drugs. To this regard, indinavir and saquinavir were assessed for their ability to inhibit in vivo the growth of highly prevalent human tumors, such as lung, breast, colon and hepatic adenocarcinomas. We show here that both HIV-PIs significantly inhibited the growth of all adenocarcinomas tested in the mice model. This was not mediated by effects on proteasome-dependent cell growth arrest or on apoptosis but by the block of angiogenesis and matrix metalloproteinase activity. Accordingly, therapeutic steadystate concentrations of indinavir or saquinavir were highly effective in inhibiting invasion of tumor cells in vitro. In contrast, growth arrest was induced only by high concentrations of saquinavir that are not reached or are only transiently present in plasma of treated patients, likely through a proteasome-mediated mechanism. These data suggest that HIV-PIs or their analogues, characterized by a better biodistribution and lower toxicity, may represent a new class of antitumor drugs capable of targeting both matrix metalloproteinases and the proteasome for a most effective antitumor therapy.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Female; HIV Protease Inhibitors; Humans; Immunohistochemistry; Indinavir; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Proteasome Endopeptidase Complex; Saquinavir; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; HIV Protease Inhibitors; Humans; Immunohistochemistry; Indinavir; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mice; Neoplasms; Neovascularization, Pathologic; Saquinavir; Xenograft Model Antitumor Assays