Aspects of doxorubicin resistance in breast cancer
Less than half of all breast cancer patients respond to the anthracycline agents Epirubicin and Doxorubicin, the most effective agents available. Of those that do respond initially many eventually fail to do so. In this thesis some of the possible reasons for this failure are explored and ways of improving responses are also discussed. Doxorubicin uptake to breast cancers is examined in patients undergoing mastectomy who are given a dose pre-operatively. A range of uptakes is seen, but all tumours contained measurable levels of Doxorubicin. Intra-tumoural distribution is assessed using the auto fluorescent properties of Doxorubicin. There was variability of distribution but no gross penetration barriers were observed. To assess the range of 'inherent' variation in the sensitivity of breast cancers individual tumour cells and cells from distant normal breast were cultured in vitro from fresh specimens. Successful cultures were achieved in thirty four out of seventy three tumour samples (46%). Sixteen out of fifty for normal breast samples grew in vitro (29.6%). Chemosensitivity to Doxorubicin was measured using a short term clonogenic assay. There was a wide range in tumour sensitivities (1 x 10-7M to 6 x 10-9M) and also a marked interpatient variation in cells from normal breast (4 x 10-8M - 7 x 10-9M). In vitro sensitivities are correlated with the expression of the MDR-1 gene and gst π gene and long term clinical follow up was carried out to assess eventual responses to chemotherapy drugs and survival. The ability of a range of resistance modifying agents to overcome resistance to Doxorubicin was measured using the cell line MCF-AdrRes , and Quinidine was found to be the most effective resistance modifier.