A NOVEL ENERGY-DEPENDENT MECHANISM REDUCING DAUNORUBICIN ACCUMULATIONIN ACUTE MYELOID-LEUKEMIA

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) function we showed previously that there was a discordance between the ability of acute myeloid leukemic (AML) blast cells to accumulate daunorubicin a nd P-gp antigen expression (Xie et al, Leukemia 1995; 9: 1882-1887). T his discordance suggests that a CsA-sensitive drug efflux mechanism di stinct from P-gp is expressed in many clinical samples. In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, we observed even lar ger increases in daunorubicin accumulation than were seen with CsA. Si milar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with t he expression of mRNA for multidrug resistance-associated protein (MRP ), the only other member of the ABC family of membrane transporters th at is known to be capable of effluxing daunorubicin. Thse results sugg est that daunorubicin accumulation in many cases of AML is modulated b y one or more novel energy-dependent processes that are distinct from P-gp or MRP. We speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other t herapeutic agents.