Properties of a Human Metastatic Variant Lung Cancer Model




Poirot, Julie E.


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Poirot, 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.