| Autor: |
Motomura, Sayuri, Motoji, Toshiko, Takanashi, Minoko, Wang, Yan-Hua, Shiozaki, Hiroko, Sugawara, Isamu, Aikawa, Eizou, Tomida, Akihiro, Tsuruo, Takashi, Kanda, Naotoshi, Mizoguchi, Hideaki |
| Zdroj: |
Blood; May 1998, Vol. 91 Issue: 9 p3163-3171, 9p |
| Abstrakt: |
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 mdr1mRNA 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. |
| Databáze: |
Supplemental Index |
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