Modulation of multidrug resistance in de novo adult acute myeloid leukemia

Variable efficacy of reverting agents in vitro

Elisabeth M. Paietta, Janis Racevskis, J. Ashigbi, P. H. Wiernik, J. Andersen, P. Cassileth

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The efficacy of verapamil and cyclosporine A as modulators of P-glycoprotein, the multidrug resistance (MDR1) gene product, was studied in leukemic blast cells from 56 patients with de novo acute myeloid leukemia (AML) in vitro. Rhodamine123 dye-efflux was measured flow cytometrically as a cellular parameter reflecting P-glycoprotein activity. While dye-efflux was measurable in 3 4 of the cases, the capacity of the P-glycoprotein inhibitors varied substantially among patients. In 23 patients, P-glycoprotein function was completely inhibited by the resistance modulators, whereas in 17 patients neither verapamil nor cyclosporine had any reverting effect on dye-efflux at concentrations even 10-times higher than achievable in vivo. Cells with a drug-sensitive rhodamine123-pump effluxed more efficiently (p=0.0016) and contained significantly higher levels of MDR1 specific RNA transcripts (p=0.0002), as determined by quantitative PCR, than cells exhibiting an efflux process that could not be inhibited. However, flow cytometric evaluation of the staining of gated blast cells with the anti-P-glycoprotein antibody, 4E3.16, revealed no difference in P-glycoprotein expression between modulator-sensitive and -insensitive cases (p=0.86), indicating disproportionate translation of MDRI mRNA. In leukemic cell populations with increased P-glycoprotein function that could be inhibited, significantly more blasts expressed the progenitor cell antigen, CD34 (median 83%), than was the case in leukemias with P-glycoprotein activity that could not be inhibited (median 7%) (p=0.0001). The present study demonstrates that a substantial fraction of AML patients constitutively display a drug-efflux mechanism suggestive of P-glycoprotein activity. However, in many of those patients rhodamine123-efflux from blast cells in vitro was not sensitive to classical P-glycoprotein inhibitors.

Original languageEnglish (US)
Pages (from-to)47-52
Number of pages6
JournalBlood Reviews
Volume9
Issue number1
DOIs
StatePublished - 1995

Fingerprint

Multiple Drug Resistance
P-Glycoprotein
Acute Myeloid Leukemia
Coloring Agents
Verapamil
Cyclosporine
CD34 Antigens
In Vitro Techniques
MDR Genes
Protein Biosynthesis
Pharmaceutical Preparations
Leukemia
Stem Cells
RNA
Staining and Labeling
Polymerase Chain Reaction
Antibodies

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Modulation of multidrug resistance in de novo adult acute myeloid leukemia : Variable efficacy of reverting agents in vitro. / Paietta, Elisabeth M.; Racevskis, Janis; Ashigbi, J.; Wiernik, P. H.; Andersen, J.; Cassileth, P.

In: Blood Reviews, Vol. 9, No. 1, 1995, p. 47-52.

Research output: Contribution to journalArticle

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abstract = "The efficacy of verapamil and cyclosporine A as modulators of P-glycoprotein, the multidrug resistance (MDR1) gene product, was studied in leukemic blast cells from 56 patients with de novo acute myeloid leukemia (AML) in vitro. Rhodamine123 dye-efflux was measured flow cytometrically as a cellular parameter reflecting P-glycoprotein activity. While dye-efflux was measurable in 3 4 of the cases, the capacity of the P-glycoprotein inhibitors varied substantially among patients. In 23 patients, P-glycoprotein function was completely inhibited by the resistance modulators, whereas in 17 patients neither verapamil nor cyclosporine had any reverting effect on dye-efflux at concentrations even 10-times higher than achievable in vivo. Cells with a drug-sensitive rhodamine123-pump effluxed more efficiently (p=0.0016) and contained significantly higher levels of MDR1 specific RNA transcripts (p=0.0002), as determined by quantitative PCR, than cells exhibiting an efflux process that could not be inhibited. However, flow cytometric evaluation of the staining of gated blast cells with the anti-P-glycoprotein antibody, 4E3.16, revealed no difference in P-glycoprotein expression between modulator-sensitive and -insensitive cases (p=0.86), indicating disproportionate translation of MDRI mRNA. In leukemic cell populations with increased P-glycoprotein function that could be inhibited, significantly more blasts expressed the progenitor cell antigen, CD34 (median 83{\%}), than was the case in leukemias with P-glycoprotein activity that could not be inhibited (median 7{\%}) (p=0.0001). The present study demonstrates that a substantial fraction of AML patients constitutively display a drug-efflux mechanism suggestive of P-glycoprotein activity. However, in many of those patients rhodamine123-efflux from blast cells in vitro was not sensitive to classical P-glycoprotein inhibitors.",
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