CROSS-RESISTANCE RELEVANCE OF THE CHEMICAL-STRUCTURE OF DIFFERENT ANTHRACYCLINES IN MULTIDRUG-RESISTANT CELLS

Positively charged doxorubicin (DOX) and non-positively charged anthra cyclines, aclarubicin (ACR) and morpholino-carminomycin (KRN 8602), ha ve been investigated with respect to pharmacological parameters, cytot oxicity, DNA damage and repair in DOX-sensitive and -resistant murine and human cells. Friend leukemia cells (FLC) resistant to high concent rations of doxorubicin (DOX-RFLC3) or daunorubicin (DNR-RFLC3) (1771 a nd 1543 fold resistance respectively) express less than 10 fold resist ance to aclarubicin (ACR). In these cells, the intracellular accumulat ion of ACR is similar in sensitive and resistant cells. Resistance to ACR was not observed in either DOX-RFLC1 or DNR1 with a lower level of resistance (27 fold). Increased expression of a 170,000-dalton surfac e antigen (gp-170) was found to be correlated with the level of resist ance. However, when the selective agent is ACR, despite the low level of resistance (2.8 fold) both high expression of gp 170 and resistance to DOX (77 fold) or DNR (62 fold) are observed. It is assumed therefo re that induction of multidrug resistance phenotype can be achieved by compounds which do not display cross resistance with DOX or DNR. Redu ced levels or absence of cross-resistance can be related to the electr ical charge of the compound. This assumption is supported by further s tudies on DOX-sensitive or -resistant human K562 cells exposed to anot her non-positively charged anthracycline, KRN 8602. In the continuous presence of drug, K562/DOX were less resistant to KRN 8602 (2.9 fold) than to DOX (31 fold). After short time exposure followed by growth in drug-free medium, absence of cross-resistance to KRN 8602 has been ob served in K562/DOX. Furthermore, accumulation experiments showed that high intracellular drug concentrations were rapidly achieved (within 1 5 min) in both DOX-sensitive and -resistant cells. In cells exposed to DOX, DNA single-strand break (DNA-SSBs) frequencies were related to t ime and drug concentration while those produced by KRN 8602 or ACR wer e maximal after short time incubation. DNA-SSBs produced by these anth aracyclines are not repaired when cells are incubated in drug free med ium. In DOX resistant cells, DNA-SSBs produced by DOX were repaired wh ereas those produced by ACR or KRN 8602 were not. It is suggested, the refore, that absence of cross resistance to various anthracyclines is related to differences in the chemicalelectrical charge, which may inf luence drug accumulation and DNA repair in resistant cells.