Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP) and lung-resistance-protein (LRP) genes.
Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T-cell-leukemia-virus-I (HTLV-I) infection. ATL comprises 4 clinical forms: acute, chronic, smoldering and lymphoma types. ATL is usually resistant to conventional chemotherapy and has a relatively poor prognosis; however, the resistance mechanisms remain undetermined. To explore the multidrug-resistance (MDR) mechanisms of ATL, we examined the expression and functional activity of MDR-related genes in peripheral-blood mononuclear cells (PBMC) from ATL patients by semi-quantitative RT-PCR and FACScan with calcein-AM. PBMC from ATL patients expressed similar or higher levels of MRP, LRP and cMOAT mRNAs, as compared with normal PBMC. In normal controls and ATL patients, MDR1 mRNA expression was undetectable in this study. PBMC from acute and chronic ATL patients expressed significantly higher levels of MRP and LRP mRNA than did normal PBMC (p < 0.01 and p < 0.05 respectively). In chronic ATL, positive correlations were apparent between levels of MRP and LRP mRNA expression (r = 0.759, p = 0.018), and between each mRNA level and the absolute number of abnormal lymphocytes in peripheral blood. Probenecid, an inhibitor of the MRP pump, significantly increased the accumulation of calcein in PBMC from 3 chronic ATL patients. Our findings suggest that the MRP and LRP genes in ATL are often activated by HTLV-I infection and may confer MDR of ATL cells in vivo. Combined chemotherapy with inhibitors of these MDR genes may be promising in the treatment of ATL.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. okamikio@net.nagasaki-u.ac.jp
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Ikeda
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Oka
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Yamada
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Soda
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Fukuda
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A
Kinoshita
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Tsukamoto
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Noguchi
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Isomoto
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Takeshima
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Murase
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Kamihira
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Tomonaga
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Kohno
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005452:Fluoresceins / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D018922:HL-60 Cells; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics*; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D005456:Fluorescent Dyes; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C007740:fluorexon