A Novel, Non-Cytotoxic, Anti-Invasive Therapeutic Agent for Ovarian Cancer

摘要

The 5-year survival is only about 30% when ovarian cancer (OC) is first detected at an advanced stage, which is the case for ～70% of women with OC. The combination of debulking surgery and cytotoxic chemotherapy is the primary treatment modality for OC. There has been much interest in the use of intraperitoneal (IP) chemotherapy for OC and the National Cancer Institute of the USA has endorsed this form of therapy. Disintegrins represent a class of disulfide-rich polypeptides, originally isolated from snake venom, many of which contain a cyclic-Arg-Gly-Asp (c-RGD) motif Due to their ability to bind to integrins that are important to cancer progression and dissemination, disintegrins hold a significant translational potential as anti-cancer therapeutic agents. Integrins are heterodimeric adhesion receptors on the surface of cells that relay signals bi-directionally across the plasma membrane between the extracellular matrix and cytoskeletal proteins and signaling molecules inside the cell. They are closely associated with OC progression and dissemination. Multiple studies have demonstrated that adding IP therapy to intravenous therapy produces survival benefits in patients with advanced OC. We report the use of IP delivery of a recombinant disintegrin, vicrostatin (VCN), in mouse models of OC, which leads to highly effective inhibition of progression and dissemination of OC. When impregnated in a gel formulation VCN has extended time-release activity and retains therapeutic levels for 7-10 days; with weekly VCN injections activity is retained for prolonged times. This IP delivered formulation is effective against several human ovarian cancer cell lines, and warrants further translational studies.