Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

WEHI-3B/NOVO is a cloned murine leukemia cell line selected for resistance to novobiocin that is cross-resistant to the cytotoxic action of etoposide (VP-16) and to a lesser extent to a variety of other topoisomerase II (topo II)-reactive drugs. We have reported previously (Cancer Res. 52: 2782-2790, 1992) that WEHI-3B/NOVO cells exhibit a pronounced decrease in VP-16 induced DNA-topo II cross-link formation compared to the parental WEHI-3B/S cell line in intact cells, in the absence of a significant difference in the P4 unknotting activity of topo II assayed in nuclear extracts. Because the pattern of cross-resistance was suggestive of a topo II-mediated mechanism, we have ascertained whether a change in topo II can account for the multidrug-resistant phenotype of WEHI-3B/NOVO cells. No differences existed between WEHI-3B/S and WEHI-3B/NOVO cells in topo II mRNA and protein levels, as well as in the amount of topo II associated with the nuclear matrix. Neither sensitive nor resistant cells expressed detectable levels of the MDR1 gene; however, VP-16 accumulation in WEHI-3B/NOVO cells was 3-4-fold less than that present in WEHI-3B/S cells, whereas doxorubicin accumulation was the same in both cell lines. Over the first 60 s, no difference existed in the rate of uptake of VP-16 between parental and resistant cells; however, beyond the first 60 s of incubation, [3H]VP-16 accumulated to a greater extent in parental sensitive cells. Thus, an increased rate of efflux of VP-16 was responsible for the lower steady-state concentration of the drug in resistant cells. The efflux Km for VP-16 in WEHI-3B/NOVO cells was 254.7 microM and the Vmax was 10.4 pmol/s/10(7) cells. In the presence of the inhibitors of energy metabolism, sodium azide and deoxyglucose, the efflux of VP-16 was markedly inhibited; readdition of glucose restored the original efflux rate. Northern blot analyses using the human 10.1 probe for the 3'-terminal region of the multidrug-resistance protein (MRP) cDNA revealed a mRNA species of approximately 6 kb in WEHI-3B/NOVO cells but not in WEHI-3B/S cells. Overexpression was associated with amplification of the cognate gene. To ascertain whether the overexpressed gene in WEHI-3B/NOVO cells was the murine MRP or a different member of the same superfamily of ATP-binding ABC cassette transporters, a 341-bp MRP cDNA probe was generated from a murine genomic library.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Increased rate of adenosine triphosphate-dependent etoposide (VP-16) efflux in a murine leukemia cell line overexpressing the multidrug resistance-associated protein (MRP) gene. 767 Dec 47

MDR1 gene expression was examined in acute leukemia cells from 75 Japanese patients at diagnosis (50 with acute myeloblastic leukemia [AML]: 10 M1, 18 M2, 5 M3, 8 M4, 9 M5; 25 with acute lymphoblastic leukemia [ALL]: 13 B-precursor, 12 T-lineage). The results of MDR1 mRNA expression by reverse transcriptase polymerase chain reaction were confirmed by immunostaining using the anti-P-glycoprotein monoclonal antibody UIC2 and by a functional study using the rhodamine efflux test. Morphologically, AML M1 cases had the highest incidence of MDR1 gene expression (6 of 10 patients). Phenotypically, CD7 and CD34 were the only surface markers that were significantly associated with MDR1 gene expression (P < .01). In CD7+CD4-CD8- ALL, which is thought to originate from the lymphohematopoietic stem cell, expressed the MDR1 gene with a high incidence (six of eight patients), whereas three surface CD3+ and one CD4+CD8+ T-cell ALL (T-ALL) did not have detectable MDR1 transcripts. Only two cases of 13 B-precursor ALL had MDR1 mRNA, one of which had the Philadelphia (Ph1) chromosome. No association was observed between MDR1 gene expression and CD34 positivity in ALL. Our results that MDR1 mRNA was frequently expressed in CD7+ AML and CD7+CD4-CD8- ALL, together with the previous reports indicating clinical similarities between these leukemias, provides a clue to clarify a relationship between CD7+ AML and CD7+CD4-CD8- ALL. In addition, MDR1 expression in CD7+ AML/ALL might be responsible for the poor response to conventional chemotherapies of these types of leukemia.
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PMID:Expression of MDR1 gene in acute leukemia cells: association with CD7+ acute myeloblastic leukemia/acute lymphoblastic leukemia. 769 87

The MDR1 gene product, P-glycoprotein, functions as a transmembrane efflux pump for certain cytotoxic agents including anthracyclines. Based upon the clinical observation that patients with acute promyelocytic leukaemia (APL) respond favourably to anthracyclines, we hypothesized that APL cells may have low levels of MDR1 expression. We therefore investigated MDR1 expression in 10 patients with APL and compared results with those obtained in 18 patients with other subtypes of acute myelogenous leukaemia (AML). Prior to reverse transcriptase polymerase chain reaction with MDR1 specific primers, leukaemic cells were purified by fluorescence activated cell sorting to exclude normal haemopoietic cells, in particular lymphocytes, from the MDR1 analysis. In sorted APL cells, MDR1 expression was detected in only two of 10 patients, which was significantly different from findings in other AML subtypes (MDR1 expression in 14/18 patients; P < 0.01). When unsorted specimens from APL patients were studied, five of six cases were MDR1 positive, whereas sorted APL cells were shown to express MDR1 mRNA in only one of these cases. MDR1 mRNA levels expressed as MDR1/beta-2 microglobulin ratios were significantly lower in APL (0.24 +/- 0.2, mean +/- SD) than in AML (0.75 +/- 0.48; P < 0.01). We conclude that low or absent expression of MDR1 in APL cells may contribute to the efficacy of anthracyclines in the treatment of APL.
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PMID:Low incidence of MDR1 expression in acute promyelocytic leukaemia. 779 59

A semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to investigate and compare transcription levels of the human multidrug resistance gene (MDR1) and the recently described multidrug resistance-associated protein (MRP) in 105 samples from patients with acute leukaemia at presentation and relapse. MRP gene expression was significantly greater in samples from patients with acute lymphoblastic leukaemia (ALL) compared with samples from normal peripheral mononuclear cells (PBMC) and patients with de novo acute myeloid leukaemia (AML). MRP gene expression was found to be higher in patients with relapsed de novo AML compared to those at presentation but prior therapy did not affect MRP gene expression in ALL. MDR1 gene expression was significantly lower in ALL patients compared to normal PBMC and AML samples. Samples from patients with secondary AML had higher levels of MDR1 expression than those of de novo AML. No changes of MDR1 expression were observed in AML or ALL at relapse. No correlation was observed between MDR1 and MRP gene expression in this group of patients. Our results suggest that MRP expression may be of prognostic importance in AML but the significance of the increased levels we have detected remain unclear.
Leukemia 1994 Dec
PMID:Expression of the multidrug resistance-associated protein (MRP) in acute leukaemia. 780 5

Drug resistant variant cell lines were selected in vitro for resistance to adriamycin or vincristine, P388/ADR and P388/VCR-600, respectively, from P388 murine leukemia cells. These cells were demonstrated by immunoblot studies with P-glycoprotein specific monoclonal antibody (C219) to overexpress not only P-glycoprotein but also approximately 65 kDa protein, and the expression levels were found to correlate with the degree of resistance. Furthermore, in Northern blot analysis with an MDR1 cDNA as a probe, an overexpressed transcript with the length of about 2.4 kilobases which might encode this previously uncharacterized protein was also detected in the multidrug resistant cell line. Thus, it is suggested that this protein might be associated with multidrug resistant phenotype and be related to P-glycoprotein.
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PMID:Identification of a P-glycoprotein-related protein (mini-P-glycoprotein) which is overexpressed in multidrug resistant cells. 790 66

Overexpression of the human multidrug resistance gene (MDR1) on acute myelogenous leukemia (AML) correlates with poor prognosis. We evaluated several methods for mRNA estimation to standardize simple and reliable techniques for identifying MDR1 positive leukemia among untreated AMLs in large scale studies. Northern blot detection of MDR1 mRNA suffered from low signal-to-noise ratio under the conventional conditions, that was improved mainly by removing unincorporated radioactivity. The amount of MDR1 transcripts on positive cells was estimated less than 10% of that of constitutive mRNA species. A modified method seemed useful in estimating the total amount of the MDR1 mRNA in a whole leukemic cell population, and suitable to study stock samples or for large prospective clinical trials. RT-PCR was more sensitive in detecting MDR1 mRNA than Northern blot analysis, and the very feature made it virtually impossible to exclude contamination with normal hematopoietic cells. This procedure showed that FAB M3 leukemias were essentially MDR1 negative, and there existed frequently myelodysplastic syndrome subpopulation which had excessive MDR1 transcripts. In situ hybridization of the mRNA with a FITC-labeled phosphorothioate oligonucleotide probe was visualized using flowcytometry or con-focus lightmicroscopy, enabled us to recognize the difference between multidrug resistant K562/ADM and its wild type.
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PMID:Methods for detection of MDR1 mRNA expression on acute myelogenous leukemia cells. 796 78

A retrospective analysis was performed on 235 elderly acute myelogenous leukaemia (AML) patients aged 60 years or more, consecutively admitted to a single haematological department during a 10-year period from 1980 to 1989. 46% of patients received only conventional induction chemotherapy. The rate of inclusion in EORTC cooperative clinical trials was significantly lower than for younger patients despite specific protocols proposed for the elderly since 1983, thus confirming the important selection bias of most published series on elderly AML patients. Compared with treatment results in patients < 60 years, complete remission (CR) rate was lower (33.3% v 65.4%, P < 0.0001), with a marked drop in patients older than 70, and induction death rate was higher (21.3% v 12.5%, P = 0.04). Intrinsic characteristics of leukaemic cells, especially expression of the MDR1 gene, in vitro growth of the leukaemic clonogenic cells and sensitivity to daunorubicin-(+)cytosine arabinoside, did not differ according to age, except that there was a higher incidence of previous myelodysplastic syndromes and a lower incidence of good prognostic cytogenetics in the elderly patients. Thus, treatment failure in elderly AML patients appears to be mainly due to host-related factors (especially performance status and age < or > or = 70 years), and to inadequate treatments. Some elderly patients may have been undertreated because of the planned anthracycline dose reduction, resulting in a higher rate of 'resistant' AML, i.e. patients surviving the induction period without entering into CR, than in younger patients (45.4% v 22.1%, P < 0.0001). 11 patients (4.7%) with untreated or 'resistant' AML survived more than 1 year, while receiving only supportive care. These slowly progressive AML patients were characterized by a good performance status, and lower circulating blast cells and bone marrow blast counts.
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PMID:Acute myelogenous leukaemia in the elderly: retrospective study of 235 consecutive patients. 801 51

Resistance to multiple chemotherapeutic agents is related to the production of P-glycoprotein, a transmembrane drug efflux pump that is encoded by the multidrug resistance gene (MDR1). To detect low-level or heterogenous expression of the MDR1 gene in acute leukemia, we have developed sensitive, specific and semi-quantitative protocols for measuring levels of MDR1 mRNA, based on the polymerase chain reaction. Using this assay, we screened blasts from 20 patients with untreated adult acute leukemia for evidence of MDR1 gene expression. The level of MDR1 mRNA was normalized to beta 2-microglobulin mRNA and was defined by reference to the highly resistant trimetrexate-selected leukemia cells MOLT-3/TMQ200 (1.80). MDR1 mRNA was observed in 14 out of 20 patients. Higher MDR1 mRNAs were observed in three patients with phenotypes of undifferentiated or minimally differentiated nonlymphocytic acute leukemia, as compared with other types of acute leukemia (0.98 vs. 0.25). In contrast, lower MDR1 mRNAs were found in five patients with acute promyelocytic leukemia, as compared with other types of acute leukemia (0.08 vs. 0.45). These findings suggest that MDR1 gene expression is correlated with the leucocyte differentiation stage of leukemia. MDR1 gene expression may, in part, explain the responsiveness to chemotherapy in these distinct subtypes of acute leukemia.
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PMID:MDR1 (multidrug resistance) gene expression in adult acute leukemia: correlations with blast phenotype. 847 61

We have established a novel ascites tumour model (MDA435/LCC6) from the oestrogen receptor-negative, invasive and metastatic MDA-MB-435 human breast cancer cell line. MDA435/LCC6 cells grow as both malignant ascites and solid tumours in vivo in nude mice and nude rats, with a tumour incidence of approximately 100%. Untreated mice develop ascites following i.p. inoculation of 1 x 10(6) cells and have a reproducible life span of approximately 30 days, with all animals dying within a 48 h period. The in vivo response of MDA435/LCC6 ascites to several cytotoxic drugs, including doxorubicin, etoposide (VP-16), BCNU and mitomycin C, closely reflects the activity of these single agents in previously untreated breast cancer patients. MDA435/LCC6 cells also retain the anchorage-dependent and anchorage-independent in vitro growth properties of the parental MDA-MB-435 cells, and can be used in standard in vitro drug screening assays. The drug resistance pattern of the MDA435/LCC6 cells suggests that they may have few active endogenous drug resistance mechanisms. To generate a model for the screening of MDR1-reversing agents, MDA435/LCC6 were transduced with a retroviral vector directing the constitutive expression of the MDR1 cDNA, producing a cell line with a classical MDR1 resistance pattern (MDA435/LCC6MDR1). THese ascites models may be a viable alternative to the murine leukaemia ascites (L1210, P388) and, in conjunction with other breast cancer cell lines, facilitate the in vitro and in vivo screening of new cytotoxic drugs and drug combinations.
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PMID:MDA435/LCC6 and MDA435/LCC6MDR1: ascites models of human breast cancer. 854

The method of reverse transcription coupled with polymerase chain reaction (RT-PCR) has been used to detect multidrug resistance gene MDR1 expression in 73 leukemia patients. Specificity of MDR1 PCR product was identified by a probe labelled with biotin. In this paper, beta 2M mRNA (a 120bp of PCR product) was selected as an internal control for semi-quantitative analysis of MDR1 mRNA (a 157bp of PCR product). Detection of MDR1 expression was positive in 31 of the 73 patients with leukemia. The percentage of MDR1+ and the value of MDR1/beta 2M in the relapsed acute leukemia and CML in blast crisis were 76.00% and 0.798 +/- 0.266, they were significantly higher than those in newly diagnosed acute leukemia (25.00% and 0.386 +/- 0.128) and complete remission leukemia (25.00% and 0.151 +/- 0.059), MDR1/beta 2M in newly diagnosed was significantly higher than that in complete remission. We found that MDR1 gene expression correlated well with response to chemotherapy in 53 cases of acute leukemia. The refractory rate in patients with MDR1+ was 75.00%, while it was 15.00% in MDR1- (P < 0.01). We thought that the determination of MDR1 expression level in acute leukemia could provide a valuble information for designing chemotherapeutic regimen in individual patient, and a high level of MDR1 expression correlated closely with drug resistance in clinical leukemia chemotherapy.
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PMID:[Analysis of the multidrug resistance MDR1 gene expression in clinical leukemia with RT-PCR]. 855 28


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