Resistances to therapeutic drugs in human tumor specimens will be comparatively evaluated, focusing on the detection and characterization of pleiotropic multi-drug resistance (PMDR). In preliminary work carried out in collaboration with the laboratory of Dr. Ling, Ontario Cancer Institute, specimens of solid tumor from over 50 unselected patients were tested for the presence of PMDR-associated """"""""P-glycoprotein"""""""" using monoclonal antibody. Specimens from 5 patients showed clear positive results in Western immunoblot analyses. All of these tumors were sarcomas, and 3 of the 5 had received prior chemotherapy. In another investigation, Dr. Ling's laboratory has obtained evidence of P-glycoprotein expression in several ovarian carcinoma specimens. We will confirm and extend these results in analyses of primary and metastatic tumors available to us through clinical collaboration at this Institute. We will analyze the incidence of PMDR in a spectrum of primary and metastatic tumors, including sarcomas, ovarian carcinomas, melanomas, and gastrointestinal and urological tumors, and we will relate our results both to the chemotherapeutic histories of the tumors and to biological characteristics of the tumors elucidated in our own and in collaborating laboratories. Thus, we will determine whether PMDR is more likely to be associated with particular tumor types or metastases, and we will correlate its occurrence with variations in DNA content, karyotype, and other biological properties. These studies will enable development of technology for diagnostic evaluation of PMDR. To facilitate further characterization of the types of PMDR encountered in patients, we will develop cultured cell lines expressing PMDR by cultivation of clonogenic tumor cells and also through fusion and/or transfection of multi-drug resistant tumor cell genomes to established cell lines. We will evaluate these derivatives for genetic and physiological properties associated with clinical PMDR (including stability, karyotype, dominance, cross-resistance, drug-uptake, and membrane composition), in comparison to human cell lines selected in vitro for multi-drug resistance.
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