Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One important mechanism of drug resistance in acute leukemia is the overexpression of the multi-drug resistance (MDR1) gene that encodes a 170-kDa membrane protein called P-glycoprotein. To estimate the incidence and role of MDR1 gene expression in patients with acute leukemia, we investigated the expression of MDR1 by using the RT-PCR method in blast cells from 40 cases of de novo acute leukemia. We found a high frequency of MDR1 gene expression: 10 out of 20 with de novo acute myeloid leukemia (AML), 8 out of 17 with de novo acute lymphoblastic leukemia (ALL), and none of the 3 with de novo acute mixed leukemia, were MDR1 mRNA-positive. No correlation between cluster designation (CD) surface markers (CD19, CD7, CD13, CD33, CD34, CD14, HLA-DR) and MDR1 gene expression in AML was found. The complete remission rate was correlated with MDR1 gene expression. Among 40 evaluable patients examined, 17% (3 of 18) with MDR1 mRNA-positive reached complete remission versus 77% (17 of 22) with MDR1 mRNA-negative (p=0.044). These results suggest that MDR1 gene expression can be used as a prognostic factor and may be helpful in determining chemotherapeutic protocol for patients with acute leukemia.
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PMID:Multi-drug resistance (MDR1) gene expression in de novo acute leukemia cells: correlations with CD surface markers and treatment outcome. 988 70

Both the expression of the multidrug transporter, P-glycoprotein (Pgp), and abnormalities of the long arm of chromosome 7 have been shown to be adverse prognostic indicators in acute leukemias. In this study, a clonal duplication, dup(7)(q11.1q31.1), inherited with the classical multidrug resistant phenotype in a drug-resistant derivative of a human T-cell leukemia cell line was characterized. The position of the duplication was of interest as the gene which encodes Pgp, MDR1, is located on the long arm of chromosome 7 at position 7q21.1. Fluorescence in situ hybridization (FISH) analysis with a chromosome 7-specific painting probe confirmed the composition of the abnormal chromosome. A YAC clone hybridizing to the MDR1 locus confirmed that this gene was located within the duplicated region of the derivative chromosome. With a panel of well-characterized YAC clones, the duplicated segment was found to be a direct tandem duplication, somewhat larger than estimated by conventional cytogenetics. The proximal and distal breakpoints of the abnormality were located and a YAC clone spanning the distal breakpoint was identified. This clone is of particular interest, as it harbors the markers D7S523 and D7S471, close to which a putative tumor suppressor gene is thought to lie. Further examination of the breakpoint region may therefore illuminate the mechanism of Pgp upregulation as well as providing information about a tumor suppressor gene.
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PMID:Physical mapping of a tandem duplication on the long arm of chromosome 7 associated with a multidrug resistant phenotype. 1019 19

The best characterized resistance mechanism in adult acute myeloid leukemia (AML) is the one mediated by the MDR1 gene which has been shown to be associated with poor outcome. However, alternative proteins such as the more recently recognized multidrug-associated protein (MRP1), may also contribute to the resistance to anthracyclines and etoposide in AML. Recently, the role of this protein was discussed and was unclear in AML. However, recent data concerning the functionality and the modulation of the activity of MRP1 may elucidate its role in comparison with other mechanisms of resistance. In this paper, we will review these recent data concerning the role of MRP1 in adult AML.
Leukemia 1999 Apr
PMID:Role of MRP1 in multidrug resistance in acute myeloid leukemia. 1021 64

P-glycoprotein (P-gp), a cellular drug-efflux pump, is thought to be one of the major causes of multidrug resistance (MDR) in malignancies. Since therapeutic strategies are being developed to circumvent drug resistance by inhibiting P-gp function, large prospective studies evaluating the clinical relevance of P-gp in childhood acute lymphoblastic leukaemia (ALL) are warranted. P-gp expression was evaluated over a period of 6 years in 102 consecutive patients with de novo childhood ALL and in 35 children with relapse of ALL. Bone marrow and blood smears were studied immunocytochemically with two monoclonal antibodies at initial diagnosis and at relapse. P-gp expression was found in 14 (14%) patients at initial diagnosis. After induction treatment, complete remission was achieved in 100/102 patients (98%), of whom 19 relapsed. Cumulative event-free survival was significantly higher in the P-gp-negative group compared with the P-gp-positive population (Logrank P = 0.02). Multivariate analysis showed the results to be independent of age, WBC count and karyotype, and concomitantly underlined the importance of MDR1 phenotype detection in childhood ALL. P-gp expression was more frequently found at relapse (34%) than at primary diagnosis (P = 0.01). In the relapsed patient group, P-gp-positive patients had a 2-fold greater risk for adverse clinical outcome than the P-gp-negative relapsed patients. P-gp expression was not induced by exposure to previous chemotherapy since the majority of P-gp-negative patients remained negative at relapse. P-glycoprotein expression in newly diagnosed childhood ALL is an independent adverse prognostic parameter with a predictive value for relapse.
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PMID:P-glycoprotein is an independent prognostic factor predicting relapse in childhood acute lymphoblastic leukaemia: results of a 6-year prospective study. 1035 31

One of the underlying mechanisms of multidrug resistance (MDR) is cellular over-production of P-glycoprotein (P-gp), which acts as a drug efflux pump. P-gp is encoded by a small group of related genes termed MDR; only MDR1 is known to confer drug resistance. To overcome P-gp-mediated drug resistance, we have developed two anti-MDR1 hammerhead ribozymes driven by the beta-actin promoter. Upon transduction of the ribozymes into MDR cells, vincristine resistance was decreased. These two ribozymes were constructed, which showed different cleavage activities. In this study, to determine suitable target sites for the anti-MDR1 ribozyme, the exon 1b-intron 1 boundary, the translation-initiation site, the intron 1-exon 2 boundary and the exon 2-intron 2 boundary, codons 179 and 196 of the MDR1 gene were selected as candidates. To improve the ribozyme activity, a retroviral vector containing RNA polymerase III promoter was used. Stable retrovirus producer cells were generated by transfecting the retroviral vector plasmids carrying the ribozyme into the packaging cell line. Retroviral vector transduction of human leukemia cell lines expressing MDR1 was accomplished by co-culturing these with virus producer cells. Stably transduced cells were selected by G418 and pooled to determine the efficacy of each ribozyme. These ribozyme-transduced cells became vincristine-sensitive concomitant with the decreases in MDR1 expression, P-gp amount and drug efflux pump function. Among the ribozymes tested, the anti-MDR1 ribozyme against the translation-initiation site exhibited the strongest efficacy. This retrovirus-mediated transfer of anti-MDR1 ribozyme may be applicable to the treatment of MDR cells as a specific means to reverse resistance.
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PMID:Retrovirus-mediated transfer of anti-MDR1 hammerhead ribozymes into multidrug-resistant human leukemia cells: screening for effective target sites. 1036 43

Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T-cell-leukemia-virus-I (HTLV-I) infection. ATL comprises 4 clinical forms: acute, chronic, smoldering and lymphoma types. ATL is usually resistant to conventional chemotherapy and has a relatively poor prognosis; however, the resistance mechanisms remain undetermined. To explore the multidrug-resistance (MDR) mechanisms of ATL, we examined the expression and functional activity of MDR-related genes in peripheral-blood mononuclear cells (PBMC) from ATL patients by semi-quantitative RT-PCR and FACScan with calcein-AM. PBMC from ATL patients expressed similar or higher levels of MRP, LRP and cMOAT mRNAs, as compared with normal PBMC. In normal controls and ATL patients, MDR1 mRNA expression was undetectable in this study. PBMC from acute and chronic ATL patients expressed significantly higher levels of MRP and LRP mRNA than did normal PBMC (p < 0.01 and p < 0.05 respectively). In chronic ATL, positive correlations were apparent between levels of MRP and LRP mRNA expression (r = 0.759, p = 0.018), and between each mRNA level and the absolute number of abnormal lymphocytes in peripheral blood. Probenecid, an inhibitor of the MRP pump, significantly increased the accumulation of calcein in PBMC from 3 chronic ATL patients. Our findings suggest that the MRP and LRP genes in ATL are often activated by HTLV-I infection and may confer MDR of ATL cells in vivo. Combined chemotherapy with inhibitors of these MDR genes may be promising in the treatment of ATL.
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PMID:Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP) and lung-resistance-protein (LRP) genes. 1040 77

Acute myeloid leukaemia (AML) is a heterogeneous malignant disease in which disease progression at the level of CD34 positive cells has a major impact in drug resistance and relapse. The multi-drug resistance (MDR1) gene product, P-glycoprotein is expressed mainly in CD34 positive AML cells and Bcl-2 is expressed simultaneously with several putative drug resistance parameters in these cells. Bcl-2 over-expression is associated with CD34 positivity, poor response to chemotherapy and reduced overall survival in AML patients. Recently, all-trans retinoic acid (RA) has been reported to enhance cytarabine-induced apoptosis and downregulate Bcl-2 in several human myeloid leukaemia CD34 negative cells. The two CD34 positive human myeloid leukaemia cell lines: KG1 and KGla have the unique feature of expressing significant functional P-glycoprotein. Thus, the efficacy of RA in enhancing cytrabine- and fludarabine-induced apoptosis and overcoming the resistance was examined in both KG1 (CD34+CD7-) and KGla (CD34+CD7+) human myeloid leukaemia cells in the present study. Both cytarabine and fludarabine induced a dose dependent increase in the number of apoptotic cells in both CD34 positive cell types. Interestingly, the cytarabine-induced apoptosis was significantly more than fludarabine-induced apoptosis in both cell types. All-trans RA alone failed to induce apoptosis or inhibit proliferation of either of the two human CD34 positive leukaemia cell types. However, RA enhanced cytarabine- or fludarabine-induced apoptosis and inhibition of proliferation in KG1 CD34+CD7- but not in KGla CD34+CD7+ myeloid leukaemia cells. As single agents, RA, cytarabine and fludarabine reduced Bcl-2 expression in a dose dependent manner in both cell types. Using a quantitative ELISA assay, the Bcl-2 protein concentration was reduced by 86 or 100%, after 72 h of treatment with 10 microM cytarabine or fludarabine, respectively, in both CD34 positive leukaemia cell types. The addition of RA to cytarabine enhanced its induced reduction of Bcl-2 in KG1 CD34+CD7- but not in KGla CD34+CD7+ human myeloid leukaemia cells. Meanwhile, RA failed to augment fludarabine-induced reduction of Bcl-2 in both cell types. In conclusion, the present results suggest a potential role for the combination of RA and cytarabine in the treatment of refractory and/or relapsed AML patients with CD34+CD7- but not CD34+CD7+ blast cells.
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PMID:Effect of all-trans retinoic acid on chemotherapy induced apoptosis and down-regulation of Bcl-2 in human myeloid leukaemia CD34 positive cells. 1045 72

The MDR1 gene encoding the multidrug pump P-glycoprotein is transcriptionally activated in response to diverse extracellular stimuli, including the tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the signal transduction pathway responsible is unknown. Downstream of protein kinase C (PKC), the effects of TPA are often mediated by the Raf-1/MEK/ERK mitogen-activated protein kinase (MAPK) cascade, and Raf-1 has been implicated in MDR1 induction by serum and mitogens. Therefore, we examined the potential role of MAPK activation in TPA-mediated MDR1 induction in human leukemia K562 cells. MDR1 mRNA expression was significantly increased by TPA in the concentration range of 4 - 100 nM, with a maximal response 5 - 10 h after TPA addition. TPA-mediated MDR1 induction was inhibited by several PKC inhibitors including staurosporine, H7 and calphostin C. TPA stimulated the subcellular translocation of PKCalpha from the cytosol to the membrane and nucleus but did not affect other PKC isozymes. TPA also activated the Raf1/MEK/ERK cascade and activated another MAPK member, p38, but not JNK. In order to determine the potential role of MAPKs in MDR1 induction by TPA, specific inhibitors were utilized. The MEK inhibitor PD 098059, as well as the PKC inhibitors, completely blocked TPA-mediated ERK activation. However, under identical conditions, MDR1 induction by TPA was completely unaffected by PD 098059. Furthermore, SB 202190, which effectively inhibited TPA-mediated p38 activation, failed to inhibit TPA-induced MDR1 mRNA expression. These data demonstrate that MDR1 induction by TPA occurs via a PKC-dependent mechanism that operates independently of ERK, p38 or JNK pathways, and thus have important implications for understanding the mechanisms of MDR1 induction by extracellular stimuli.
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PMID:Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways. 1052 56

We analysed the relationship between all-trans retinoic acid (ATRA) resistance and P-glycoprotein (P-gp)-associated multidrug resistance (MDR) in acute promyelocytic leukaemia (APL). There was no difference in the intracellular ATRA accumulation between NB4 cells and an MDR1 cDNA-transduced NB4 subline and between ATRA-resistant NB4 cells (NB4/RA) and an MDR1 cDNA-transduced NB4/RA subline. PSC833, a MDR modifier, did not increase the intracellular accumulation of ATRA or affect the expression of CD11b, the nitroblue tetrazolium (NBT) reduction activity, the proportion of apoptotic cells or the morphology of these four ATRA-treated cell lines. Similar results were obtained in the analysis of APL cells from five patients relapsed after ATRA-induced complete remission.
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PMID:Role of P-glycoprotein in all-trans retinoic acid (ATRA) resistance in acute promyelocytic leukaemia cells: analysis of intracellular concentration of ATRA. 1065 29

We have analyzed MDR1 gene expression in 69 clinical samples obtained from 64 patients with leukemic hematologic malignancies by using a competitive reverse transcription-polymerase chain reaction assay with a heterologous competitor RNA. To exclude a false-positive result caused by concomitant normal lymphocytes that physiologically express MDR1, in samples we determined a cut-off value of 8 amol MDR1 transcript per microgram of RNA by simultaneous measurement of rhodamine 123 dye efflux either in lymphocyte or gated leukemic cell populations. Consequently, 23 of 69 samples were concluded to be MDR1-positive in leukemic cells per se. The MDR1 expression rate was significantly correlated with factors such as a history of preceding chemotherapy, elder age of the patient, and certain disease types (eg, leukemia progressed from myelodysplastic syndrome). Moreover, the complete response rate after chemotherapy was significantly higher in MDR1-negative patients than in MDR1-positive patients (52% vs 17%, respectively; P = .01). The assay established will enable the quantification of MDR1 gene expression in blood samples from patients with leukemic hematologic malignancies and will be applicable to clinical laboratories as a routine test.
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PMID:Competitive reverse transcription-polymerase chain reaction assay for quantification of human multidrug resistance 1 (MDR1) gene expression in fresh leukemic cells. 1069 66


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