Summary. Breast cancer resistance protein (BCRP) is a recently described member of the ATP binding cassette transporter superfamily. It has been shown to confer resistance to mitoxantrone, topotecan, doxorubicin and daunorubicin in human tumour cell lines. We describe a study of BCRP expression in blast cells derived from 20 patients with acute myeloid leukaemia (AML). Twelve samples were from patients who had received previous cytotoxic therapy. BCRP expression was measured by immunocytochemistry using the BXP-34 monoclonal antibody. In vitro drug sensitivity was assessed using the methyl thiazol tetrazoliumbromide assay. BCRP expression varied between patients, and six out of 22 (27%) samples had . 10% cells staining positively (median 37%, range 13± 95%). BCRP positivity was seen in both de novo samples and those from previously treated patients. There was a marked variation in the effect of all drugs tested between patients. Although there was no correlation between BCRP positivity and the effect of mitoxantrone, topotecan or doxorubicin, the median daunorubicin LC 50 value of BCRP 1 cells was fourfold higher than that of BCRP 2 cells (0´89 mmol/l compared with 0´21 mmol/l, P , 0´05). These results suggest that BCRP may be involved in resistance to the agents commonly used in AML and may explain some of the anomalous results found when studying other membrane transporters, such as P-gp or MRP.
Summary Enhanced DNA repair has been observed in cisplatin-resistant ovarian cancer cell lines. This resistance can be modulated, on co-incubation with aphidicolin in established cell lines and animal tumour models, by inhibiting DNA polymerases. We describe a study of the in vitro modulation effect of aphidicolin on cisplatin and carboplatin using fresh cells harvested from biopsy samples or ascitic fluids from 25 patients with ovarian adenocarcinoma. The MTT assay was used to measure cell survival after drug exposure. Aphidicolin (up to 30 pM) showed no cytotoxicity when tested alone. Forty-seven comparisons were made between drug with and without aphidicolin, and 37 (79%) cases demonstrated a significant increase in sensitivity to the platinum agents on co-incubation. Overall, there was a median 10-fold (range 1.64-to 58.5-fold) increase in sensitivity. When patients were grouped according to in vitro sensitivity to platinum, aphidicolin had a significantly greater effect in the 'resistant' group, causing a median 13.5-fold increase in sensitivity compared with 2.4-fold in the 'sensitive' group. Furthermore, a positive correlation between the LC50 for platinum and the corresponding fold increase in sensitivity suggests that aphidicolin overcomes platinum resistance in fresh cells from primary tumours. These results encourage the further development of this interesting compound.
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