Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity.
Resistance to multiple chemotherapeutic agents has been related to the production of P-glycoprotein, a trans-membrane drug efflux pump that is encoded by the multidrug resistance (MDR) gene mdr1. To investigate whether mdr1 could be involved in clinical resistance to chemotherapy in acute leukemias, we have analyzed retrospectively the RNA from adult acute leukemia cells by slot-blot hybridization with a human mdr1 probe. Units of mdr1 expression were defined by reference to drug-sensitive human sarcoma and K562 leukemia cell lines (1 U) and the highly resistant doxorubicin selected leukemia cells K562/R7 (50 U). We studied 41 adult patients with acute leukemias: 5 acute lymphoblastic leukemias, 23 acute myeloid leukemias, and 13 secondary leukemias or blast crisis of chronic myelogenous leukemia. Expression of 10 U or more of mdr1 was found in 6 of 31 (19%) leukemias at diagnosis, versus 5 of 10 (50%) after relapse from therapy, P = .06. The complete remission rate and in vitro sensitivity to daunorubicin were both correlated with low expression (1 U, v 2 U or more) of mdr1. Among 36 evaluable attempts to induce remission, the complete remission rate was 67% (8 of 12) for patients with undetectable or minimal mdr1 expression (1 U), versus 29% (7 of 24) in patients with 2 U or more of expression, P = .03. In vitro resistance to daunorubicin or other MDR-related drugs was associated with expression of 2 U or more of mdr1 in 11 of 11 cases, while specimens that were sensitive to these agents were negative for mdr1 expression in 5 of 11 cases, P = .03. These data suggest that mdr1 expression contributes to chemoresistance in acute leukemia. Determination of mdr1 gene expression may be useful in designing therapy for patients with leukemia.
Marie
J P
JP
Department of Medicine, Stanford University School of Medicine, CA.
Zittoun
R
R
Sikic
B I
BI
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012189:Retrospective Studies; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D012333:RNA, Messenger