Davies, Claire Louise; (1998) Multidrug resistance in breast and bladder cancer cell lines. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multidrug resistance (MDR) in cancer cells defines a phenotype of cellular cross-resistance to a broad spectrum of structurally and functionally unrelated cytotoxic drugs. This phenomenon leads to lowered cellular drug uptake and therefore lowered cell death. To try and reverse or circumvent MDR many different types of MDR modulator are being produced and investigated, including essential fatty acids (EFA). This study investigated chemotherapeutic drug uptake and intracellular localisation within drug sensitive and MDR human breast and bladder cancer cell lines. In general a difference in drug uptake, accumulation and intracellular localisation was observed between sensitive and resistant cells. The sensitive cells showed predominantly nuclear localisation of the drugs with little in the cytoplasm. The resistant cells displayed mainly cytoplasmic intracellular drug distribution with reduced overall drug accumulation compared to the sensitive cells. The presence and location of proteins believed to be involved with drug efflux from the cells and hence cellular resistance were investigated in the cell lines and breast and bladder cancer tissue. The drug efflux pumps studied were P- glycoprotein (Pgp), lung resistance protein (LRP) and multidrug resistance associated protein (MRP). From this study Pgp was shown to be present and believed to be the main mechanism of drug efflux functioning in these resistant cells lines. Finally, the thesis was concerned with one method of increasing drug uptake in the resistant cells by using the EFA -linolenic acid (GLA). Modulation of drug uptake and intracellular localisation in resistant cells due to GLA incorporation was drug dependent. The addition of GLA to these cell lines did not affect the profile of the resistance proteins. The field of MDR is changing continually with new mechanisms being discovered. This study gives an insight into cellular MDR and efflux pumps. As the way forward clinically appears to be with adjuvant therapy, the modulation of MDR, such as with GLA, warrants further investigations.

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