title: Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene (mdr1) antisense oligonucleotides.
abstract: To overcome the problem of multidrug resistance, we investigated the effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells. Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS-treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed with sense or random control oligonucleotides. The expression of mdr1 mRNA in K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the random control. Intracellular rhodamine retention and [3H]daunorubicin also increased after antisense treatment. Chemosensitivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucleotides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia.
authors.affiliation: Department of Hematology and the Department of Anatomy and Developmental Biology, Tokyo Women's Medical College, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Motomura
authors.forename: T
authors.initials: T
authors.lastname: Motoji
authors.forename: M
authors.initials: M
authors.lastname: Takanashi
authors.forename: Y H
authors.initials: YH
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Shiozaki
authors.forename: I
authors.initials: I
authors.lastname: Sugawara
authors.forename: E
authors.initials: E
authors.lastname: Aikawa
authors.forename: A
authors.initials: A
authors.lastname: Tomida
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
authors.forename: N
authors.initials: N
authors.lastname: Kanda
authors.forename: H
authors.initials: H
authors.lastname: Mizoguchi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D001692:Biological Transport; D001854:Bone Marrow Cells / Q000166:cytology; D002455:Cell Division; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000627:therapeutic use; D013873:Thionucleotides; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides