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An investigation of the role of the ErbB receptor family in chemotherapeutic drug resistance and invasion in human breast cancer

Sharon A. Glynn-2002-01-01-Arrow@dit (Dublin Institute of Technology)
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The purpose of the work described in this thesis was to investigate the effects of upregulation of c-erbB-2 by cDNA transfection and the downregulation by ribozyme transfection on chemotherapeutic drug sensitivity, in vitro invasion, and expression of a range of mRNA and proteins.\n\nFour novel multidrug resistant variants of the human breast carcinoma cell line, MDAMB- 435S-F, were established by pulse selection with taxol or adriamycin. In vitro toxicity tests revealed that the taxol resistant variants, MDA-MB-435S-F/Taxol-10p and MDA-MB-435S-F/Taxol-10p4p were significantly more resistant to taxol, with crossresistance to vincristine and taxotere, but not to adriamycin, carboplatin, etoposide or 5-fluorouracil. Adriamycin accumulation studies revealed that both variants displayed increased adriamycin efflux. P-glycoprotein and possibly topoisomerases, but not mrpl, mrp2, mrp4, mrp5, DHFR, thymidylate synthase or GST n, were found to play a role in taxol resistance.\n\nMDA-MB-435S-F

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The purpose of the work described in this thesis was to investigate the effects of upregulation of c-erbB-2 by cDNA transfection and the downregulation by ribozyme transfection on chemotherapeutic drug sensitivity, in vitro invasion, and expression of a range of mRNA and proteins.\n\nFour novel multidrug resistant variants of the human breast carcinoma cell line, MDAMB- 435S-F, were established by pulse selection with taxol or adriamycin. In vitro toxicity tests revealed that the taxol resistant variants, MDA-MB-435S-F/Taxol-10p and MDA-MB-435S-F/Taxol-10p4p were significantly more resistant to taxol, with crossresistance to vincristine and taxotere, but not to adriamycin, carboplatin, etoposide or 5-fluorouracil. Adriamycin accumulation studies revealed that both variants displayed increased adriamycin efflux. P-glycoprotein and possibly topoisomerases, but not mrpl, mrp2, mrp4, mrp5, DHFR, thymidylate synthase or GST n, were found to play a role in taxol resistance.\n\nMDA-MB-435S-F

Keywords

DoxorubicinP-glycoproteinVincristineCarboplatinMultiple drug resistanceEtoposideDownregulation and upregulationPharmacology

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