Modulation of multidrug resistance in de novo adult acute myeloid leukemia: variable efficacy of reverting agents in vitro. Eastern Cooperative Oncology Group.
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 MDR1 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Paietta
E
E
Department of Oncology, Montefiore Medical Center, Bronx, N.Y. 10467, USA.
Andersen
J
J
Racevskis
J
J
Ashigbi
M
M
Cassileth
P
P
Wiernik
P H
PH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000208:Acute Disease; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34; D016572:Cyclosporine / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism; D018432:Drug Resistance, Multiple; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D012235:Rhodamines; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D018952:Antigens, CD34; D012235:Rhodamines; D003907:Dexamethasone; D016572:Cyclosporine; D014700:Verapamil