TY - JOUR
T1 - Modulation of multidrug resistance in de novo adult acute myeloid leukemia
T2 - Variable efficacy of reverting agents in vitro
AU - Paietta, E.
AU - Racevskis, J.
AU - Ashigbi, J.
AU - Wiernik, P. H.
AU - Andersen, J.
AU - Cassileth, P.
N1 - Funding Information:
This publication was supported by grants CA21 115 (ECOG Operations Office), CA14958 (Einstein Cancer Center), CA23318 (Dana Farber Cancer Institute), P30CA13330 (Einstein Cancer Center) from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Support was also received from the Phi Beta Psi Sorority and the Chemotherapy Foundation.
PY - 1995/3
Y1 - 1995/3
N2 - 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.
AB - 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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U2 - 10.1016/0268-960X(95)90039-X
DO - 10.1016/0268-960X(95)90039-X
M3 - Article
C2 - 7540903
AN - SCOPUS:0028925191
SN - 0268-960X
VL - 9
SP - 47
EP - 52
JO - Blood Reviews
JF - Blood Reviews
IS - 1
ER -