Cross-resistance to cytosine arabinoside in a multidrug-resistant human promyelocytic cell line selected for resistance to doxorubicin: implications for combination chemotherapy

The pyrimidine analogue cytosine arabinoside (AraC) is one of the most effe ctive drugs used in the treatment of acute leukaemia. Overexpression of the multidrug resistance (MDR-1) gene and its product, P-glycoprotein (P-gp), is associated with cellular resistance to drugs, such as anthracyclines and vinca alkaloids. This resistance can be reversed by cyclosporine analogues or verapamil (ver). We investigated the in vitro cross-resistance to AraC in a doxorubicin-resistant HL60 cell line, with an elevated expression of t he MDR-1 gene. The resistant clone showed an eightfold increased resistance to AraC and a two- to fourfold resistance to the other analogues, as measu red by cytotoxicity test. There was no significant increase in the activity of 5'-nucleotidase or in the amount of deoxyribonucleotide pools between c ell lines. We could, however, detect a reduction in deoxycytidine kinase (d CK) activity (30%, P = 0.021, using deoxycytidine as substrate) and the lev el of AraC triphosphates was significantly reduced in the resistant cells ( 70%, P = 0.009). When the cells were exposed to cyclosporin A (CsA) or the cyclosporine analogue PSC 833 (PSC) in combination with AraC, there was mor e extensive apoptosis, as measured by formation of oligonucleosomal DNA fra gmentation and caspase-3-like activity; than with exposure to AraC alone. W e also found an increased retention of AraC in the resistant cells when inc ubated with AraC in combination with CsA. Ver in combination with AraC, fai led to increase apoptosis for the resistant cell line. Our data suggests th at the resistance to AraC for the P-gp-expressing cells is a result of a re duction of dCK activity and an increase in efflux, the latter possibly depe nding on P-gp. A combination of CsA or PSC with AraC may improve the effect of AraC in vivo.