Inhibition of P-Glycoprotein and Recovery of Drug Sensitivity of
Human Acute Leukemic Blast Cells by Multidrug Resistance Gene
(mdr1) Antisense Oligonucleotides
Sayuri Motomura,
Toshiko Motoji,
Minoko Takanashi,
Yan-Hua Wang,
Hiroko Shiozaki,
Isamu Sugawara,
Eizou Aikawa,
Akihiro Tomida,
Takashi Tsuruo,
Naotoshi Kanda, and
Hideaki Mizoguchi
From the Department of Hematology and the Department of Anatomy and
Developmental Biology, Tokyo Women's Medical College; the Japanese Red
Cross Center; the Department of Pathology, the Research Institute of
Tuberculosis; the Institute of Molecular and Cellular Bioscience,
University of Tokyo; and the Department of Veterinary Anatomy, Tokyo
University of Agriculture and Technology, Tokyo, Japan.
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 µmol/L MDR1-AS in the K562/ADM cells, and
from 48.1% to 10.2% by 2.5 µmol/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.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3163-3171
© 1998 by The American Society of Hematology.
