Browsing by Subject "urokinase plasminogen activator"
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Item Combined Chemo/Anti-Angiogenic Cancer Therapy in Lewis Lung Metastases(2002-05-01) Sinha-Datta, Anjuli; Goldfarb, Ronald H.; Agarwal, Neeraj; Mathew, Porunelloor A.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.Item Properties of a Human Metastatic Variant Lung Cancer Model(2003-05-01) Poirot, Julie E.; Mart Hart; Robert Wordinger; Rick KitsonPoirot, J. Properties of a Human Metastatic Variant Lung Cancer Model. Master of Science (Molecular Biology and Immunology). May 2003. 44 pp., 11 illustrations, 1 table, 39 bibliography titles. A model of non-small cell lung cancer (NSCLC) has been developed for screening and preclinical drug evaluation by implanting the A549 lung cancer cell line orthotopically into immunocompromised (SCID) mice. Aggressive metastatic sublines were then derived from metastases from the primary implant. The purpose of this project is to elucidate some of the cellular properties involved in the tumor aggressiveness of the metastatic variant cell lines. In vitro migration and invasion assays produced data showing no significant differences between the rates of migration or invasion of parental and metastatic sublines. In vivo tumor burden experiments, however, produced data showing significant differences in the numbers and sizes of metastatic tumors formed when the three cell lines were compared in SCID mice. RT-PCR analysis has indicated that there are differences in the mRNA levels of certain matrix metalloproteinases. The A549 parental cells have matrix metalloproteinase-2 (MMP-2) but not MMP-9, while both metastatic variants show MMP-9 mRNA but no MMP-2. Western blots and gelatin zymographies also confirm these findings. RT-PCR analysis and casein zymography experiments have also shown no differences in the message or activity of urokinase plasminogen activator *uPA0 among the cell lines. Multidrug resistance studies were done on the tumor cell lines in order to compare their resistance to various classes of antineoplastic drugs. These studies indicate that there is no significant difference in the resistance to doxorubicin or paclitaxel, but the parental cell line is substantially more resistant to cisplatin than either of the metastatic sublines.