MODULATION OF MULTIDRUG-RESISTANCE BY BIBW22BS IN BLASTS OF DE-NOVO OR RELAPSED OR PERSISTENT ACUTE MYELOID-LEUKEMIA EX-VIVO

The phenylpteridine derivative BIBW22BS (BIBW22) is a potent modulator of multidrug resistance (MDR). We investigated BIBW22 in comparison t o dexniguldipine and verapamil as modifier of MDR in blasts of de novo , relapsed or persistent acute myeloid leukemia (AML) in vitro. All pa tients with relapsed or persistent AML had been pretreated with idarub icin and cytosine arabinoside. The degree of MDR was determined by eff lux kinetics of rhodamine 123 (R123), daunorubicin, and idarubicin mea sured by flow cytometry (FACS). A total of 51 patients with AML, 25 de novo and 26 relapsed or persistent, were investigated. While only 6 o ut of 25 de novo AML blast populations showed moderate efflux of R123 and daunorubicin, 17 out of 26 blast populations of relapsed or persis tent AML had an efflux between 20% and 44% within 15 min ex vivo. This efflux could be significantly inhibited by 1 mu M BIBW22, 1 mu M dexn iguldipine, or 10 mu M verapamil. For idarubicin we found an effusion of 40+/-9% within 15 min in all blast populations that could not be in hibited by the modulators. Clinically achievable drug concentrations c ausing only moderate side-effects are in the range of 0.5 mu M dexnigu ldipine and 3 mu M verapamil. Up to now, BIBW22 has not been investiga ted clinically. Thus, the potential toxicity of concentrations of 0.5- 1 mu M BIBW22, sufficient for an optimal efflux inhibition ex vivo, is not known yet. We conclude from our ex vivo investigations in blast p opulations of de novo, relapsed or persistent AML that BIBW22 is a pot ent modulator of MDR.