Modulation of multidrug resistance by BIBW22BS in blasts of de novo or relapsed or persistent acute myeloid leukemia ex vivo

Abstract

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

In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia

“…In an earlier investigation we could demonstrate that patients with de novo AML, treated with IDA and cytosine arabinoside as induction chemotherapy, show an increase in the MDR phenotype at the time of relapse compared with the initial MDR pattern (SchroÈ der et al 1996a). In the present study, we investigate the eect of verapamil (VER) and dexniguldipine (DNIG) on the eux of DNR, IDA and their hydroxylated metabolites DNR-OL and IDA-OL in blast populations of AML and also in the human MDR cell line CEM-VBL and their MDR-negative counterpart.…”

Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia

“…Theoretically, among the most sensitive predictors for treatment response should be those associated with mechanisms of cellular resistance towards anthracyclines and AraC. In fact, although not yet firmly established, there is accumulating recent evidence that the expression of an mdr1 phenotype in leukaemic blasts correlates with anthracycline resistance and is an adverse prognostic factor for reaching a complete remission and long‐term DFS ( Schröder et al , 1996a ; Campos et al , 1992 ; Nuessler et al , 1997 ; Del Poeta et al , 1996 ; van den Heuvel‐Eibrink et al , 1997 ; Kasimir‐Bauer et al , 1998 ). In contrast, although several putative in vitro mechanisms of cellular AraC resistance have been identified during the last two decades, controversy exists as to their potential clinical impact.…”