Doctor of Philosophy
Faculty of Science
Hang, Minh-Thu Nguyen, Assessment of plasminogen activator inhibitor type 2 (PAI-2) as an imaging and therapeutic agent of human cancer, Doctor of Philosophy thesis, Faculty of Science, University of Wollongong, 2001. http://ro.uow.edu.au/theses/1863
The plasminogen activation cascade is an important proteolytic pathway involved in the growth and spread of cancer. Potentially, an inhibitor of plasminogen activation could make an excellent cancer imaging agent or cancer treatment. The aim of this thesis was to assess whether plasminogen activator inhibitor 2 (PAI-2) can image or treat colorectal cancer. The first part of this thesis examined the ability of PAI-2 to bind specifically to the human colorectal cancer cell line HCT116. These experiments involved confirmation of u-PA expression by HCT116 cells and cell binding studies with 125I-PAI-2. The second part was examining the biodistribution and kinetics of 125I-PAI-2 in nude mice bearing tumour xenografts derived from HCT116 cells. The final part involved examining the effect PAI-2 treatment had on mice bearing HCTl 16 tumour xenografts.
PAI-2 was found to bind specifically to u-PA on HCTl 16 cells. There appeared to be a high turnover rate of bound PAI-2 because it was difficult to detect 125I-PAI-2/u-PA complexes by autoradiography. 125I-PAI-2 had a biphasic distribution in the bloodstream of control mice (distribution phase (T1/2a) 12.5min, elimination phase (T1/2B) 342min) and mice bearing tumour xenografts (T1/2a 1.4min, T1/2B 29min). Approximately 1% of 125I-PAI-2 localised to the tumour xenograft after a single intravenous injection. However, more 125I-PAI-2 could be localised to the tumour by multiple intravenous injections. From three separate therapy experiments with PAI-2, there did not appear to be any effect on relatively large tumours. However, in one experiment PAI-2 injections did cause two 1mm tumours to disappear. In conclusion, PAI-2 does bind to u-PA on HCTl 16 cells in vitro. In vivo, injected PAI-2 appeared unsuitable for the imaging of tumours or metastasis. However preliminary data from this thesis suggest that PAI-2 may have therapeutic potential against smaller tumours.
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