ANNAMYCIN CIRCUMVENTS RESISTANCE MEDIATED BY THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) IN BREAST MCF-7 AND SMALL-CELL LUNG UMCC-1 CANCER CELL-LINES SELECTED FOR RESISTANCE TO ETOPOSIDE

Annamycin (Ann) is a highly lipophilic anthracycline antibiotic that h as been shown to circumvent MDR-1 both in vitro and in vivo. A liposom al formulation of Ann is currently in phase I clinical trials. The mul tidrug resistance associated protein (MRP) has been found to be over-e xpressed in some human leukemias at relapse and to be a poor prognosti c factor in neuroblastoma. We studied the in vitro cytotoxicity and th e cellular uptake and efflux of Ann and doxorubicin (Dox) in 2 pairs o f human cell lines, breast carcinoma MCF7 and small-cell lung cancer U MCC-1, and their MRP expressing counterparts, MCF-7/VP and UMCC-1/VP. Resistance indexes were 1.1 and 1.4 for Ann vs. 6.9 and 11.6 for Dox. Ann cellular accumulation was 3- to 5-fold higher than that of Dox in both sensitive and resistant cells. No changes in drug efflux between sensitive and resistant cells were observed in the case of Ann, while Dox efflux at 1 hr was 20-25% higher in resistant than in sensitive ce lls. By confocal microscopy, the subcellular distribution of Ann was i dentical in sensitive and resistant cells, localizing mostly in the pe rinuclear structures, while that of Dox was exclusively nuclear in sen sitive cells and nuclear and in the cell membrane in resistant cells. There was a good correlation between the extent of DNA breaks induced by each drug in the different cell lines and cytotoxic effect. Our res ults indicate that Ann may be effective in the treatment of malignanci es in which MRP is a relevant mechanism of clinical resistance. (C) 19 97 Wiley-Liss, Inc.