Combined Chemo/Anti-Angiogenic Cancer Therapy in Lewis Lung Metastases

Datta, Anjuli. Combined Chemo/Anti-Angiogenic Cancer Therapy in Lewis Lung Metastases. Master of Science (Microbiology and Immunology), May 2002. 41 pp., 17 illustrations, bibliography. The focus of my dissertation studies is an eight amino acid peptide (Å6) derived from the non-receptor binding region of urokinase plasminogen activator (uPA), which partially inhibits the binding of uPA to its receptor (uPAR). Å6 has been synthesized as a potential novel anti-cancer agent and kindly provided by Ångstrom Pharmaceuticals, Inc. (San Diego, CA). We further examined potential therapeutic properties of Å6 in vivo and in vitro. Å6 appeared to directly inhibit the invasion of Lewis lung carcinoma cells through Matrigel by approximately 40-45% compared to control. In addition, Å6 had a morphological effect resulting in thicker tubes on small vessel endothelial tube formation compared to no treatment. Interestingly, doxorubicin had similar effects when added to growing endothelial cells. Moreover, Å6 was administered alone and in combination with a standard clinically used chemotherapeutic agent, doxorubicin, in a Lewis lung carcinoma mouse model to test possible synergy between an anti-angiogenic compound (Å6) and a chemotherapeutic agent. This is the first observation that Å6 has the potential to display a direct anti-metastatic therapeutic effect for established pulmonary metastases in this model. Therefore, we believe that Å6 in combination with doxorubicin has the potential to provide better therapy to cancer patients with tumor metastases than potent chemotherapeutics agents alone, by increasing the dose of non-toxic Å6 and reducing the recommended dose of doxorubicin.