MDR1 gene expression and drug resistance of AML cells.
We investigated the cellular drug resistance to aclarubicin (Acla), cytosine arabinoside (Ara-C), daunorubicin (Dau), doxorubicin (Dox), etoposide (Etop) and mitoxantrone (Mitox) using the MTT assay at time of disease presentation in 93 cases of acute myeloid leukaemia (AML). In 31 cases we concomitantly investigated MDR1 (multiple drug resistance 1 gene) expression (semi-quantitative competitive RT-PCR) of the leukaemic cells. Drug resistance towards Dau, Dox and Etop was correlated to the MDR1 expression of the AML cells (P<0.05) with high MDR1 expression being associated with high drug resistance towards these drugs. Although the data did not allow firm conclusions to be drawn on the correlation between MDR1 expression and drug resistance towards Ara-C and Mitox, the drug resistance towards Acla clearly was not correlated to, or dependent on, the MDR1 expression level of the AML blast cells. In addition, when examining the cross-activities among the six drugs distinct patterns emerged. Thus, high to very high degrees of cross-activity were found to exist between Dau, Dox, Etop and Mitox, whereas Ara-C had moderate cross-activity with the other drugs except Acla, which showed absent to moderate cross-activity with the other drugs. We conclude that MDR1 gene expression is of significance for cellular drug resistance towards specific (MDR1-related) drugs in AML, whereas it is not of significance regarding drug resistance towards other drugs, which is the case with the anthracycline Acla. We suggest that in the place of other more or less complicated ways to circumvent MDR1-mediated drug resistance, Acla may be used to replace Dau, Dox and other MDR1-related drugs if proven as potent as the drug it is to substitute.
Nørgaard
J M
JM
Department of Medicine and Haematology, Aarhus University Hospital, Denmark.
Bukh
A
A
Langkjer
S T
ST
Clausen
N
N
Palshof
T
T
Hokland
P
P
D015250:Aclarubicin / Q000627:therapeutic use; D000208:Acute Disease; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003561:Cytarabine / Q000627:therapeutic use; D003630:Daunorubicin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000627:therapeutic use; D015870:Gene Expression; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007928:Lethal Dose 50; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics*; D008942:Mitoxantrone / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003561:Cytarabine; D005047:Etoposide; D015250:Aclarubicin; D004317:Doxorubicin; D008942:Mitoxantrone; D003630:Daunorubicin