Recovery of drug sensitivity by MS-209, a new multidrug resistance-reversing agent, on acute myelogenous leukaemic blasts and K562 cells resistant to adriamycin cell line.
The efficacy of MS-209, a quinoline derivative synthesized as a new multidrug resistance (MDR)-reversing agent, was studied on blast cells from 33 acute myelogenous leukaemia (AML) patients and on the human myelogenous leukaemia K562 cell line resistant to adriamycin (K562/ADM). By the addition of MS-209, the intracellular daunorubicin (DNR) contents which had been found to be low in P-gp-positive AML blasts and in K562/ADM were significantly enhanced to the level of P-gp-negative blasts and that of sensitive K562. The intracellular rhodamine (Rh123) contents also increased in P-gp-positive blasts and K562/ADM cells with MS-209. A leukaemic blast colony assay also demonstrated the effect of MS-209, i.e. a high D10 value for DNR of P-gp-positive blasts was reduced to the D10 level similar to that observed in P-gp-negative blasts by the addition of MS-209. The greater DNR sensitivity reversing effect of MS-209 was observed in blasts with higher P-gp positivity. These findings suggest the potential usefulness of MS-209 in overcoming MDR in AML patients, especially those with high P-gp expression. This study clarified the relationship between the clinical outcome of the patients and the P-gp positivity, intracellular DNR content and DNR drug sensitivity of leukaemic progenitors.
Wang
Y H
YH
Department of Hematology, Tokyo Women's Medical College, Japan.
Motoji
T
T
Motomura
S
S
Shiozaki
H
H
Tsuruo
T
T
Mizoguchi
H
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D011804:Quinolines; C087719:dofequidar; D004317:Doxorubicin