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: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nowadays about two-thirds of children with acute lymphoblastic leukemia (ALL) can be cured with chemotherapy, but one-third die from the disease. The clinical response of leukemic cells to chemotherapy is roughly due to two factors: the effective drug levels reaching the cells and the resistance of these cells to the drugs. The clinical value of cellular drug resistance in children with ALL is not known. We developed an in vitro assay to study drug resistance in these children. In this article, the main results obtained with this MTT assay on samples from 137 children with ALL are summarized: (1) patients whose cells are resistant to several drugs at initial diagnosis have a poor prognosis; (2) relapsed leukemias show a considerable drug resistance which might partly explain the poor prognosis. Relapsed cases differ in their type and degree of resistance; (3) the poor outcome of high risk groups as defined by age and immunophenotype can partly be explained by specific patterns of drug resistance; (4) P-glycoprotein-mediated multidrug resistance is not an important cause of resistance in childhood ALL; and (5) no relation exists between the activities of the purine enzymes HGPRT, 5'NT, ADA, and PNP and drug resistance in childhood ALL. The conclusion is that in vitro drug resistance data have clinical relevance and can be used to develop more effective and less toxic treatment strategies in childhood ALL.
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PMID:Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: the state of the art. 812 53

We examined the expression of the genes encoding topoisomerases I and II and those associated with V(D)J [variable(diversity)joining] recombination in two human T-cell acute lymphoblastic leukemia (T.ALL) cell lines, CEM and CEM/DOX. In CEM/DOX cells, which are resistant to doxorubicin, the topoisomerase I gene was found to be 4-fold overexpressed and nuclear topoisomerase I relaxation activity was 2-fold greater in CEM/DOX than in CEM cells. Furthermore, the cleavable complex reaction induced by camptothecin, a specific topoisomerase I inhibitor, was found to be 2.5-increased in the presence of topoisomerase I extracted from CEM/DOX, in comparison to that in CEM cells. Conversely, the topoisomerase II mRNA levels, nuclear decatenation activities and (mAMSA) 4'(9-acridinylamino)methanesulfon-m-anisidide-induced cleavable complex formation in CEM/DOX were similar to those of the doxorubicin-sensitive cells. The results indicate that topoisomerase I activity is elevated in CEM/DOX cells. Nevertheless, CEM/DOX cells were 11-fold more resistant to camptothecin than were CEM cells, and cross-resistance to camptothecin was not reversed by verapamil. Furthermore, using an intact cell assay for DNA-protein complexes, we found that camptothecin-stimulated cleavable complexes formed in CEM/DOX cells were increased in correlation with the elevated topoisomerase I activity. These results suggest that camptothecin resistance in CEM/DOX cells is due to different mechanism(s) than topoisomerase- or P-glycoprotein-associated multidrug resistance. The recombination activating gene, RAG1, which is one of the components of the site-specific V(D)J recombination complex, was 20-fold overexpressed in CEM/DOX cells. In contrast, RAG2 and T160 gene transcripts, other components of the V(D)J complex, were at best poorly detected in both sensitive and resistant cells. No specific V(D)J recombinase activity was found in CEM or CEM/DOX cells when the pJH201 transfection assay was used. The results indicate that CEM/DOX cells failed to generate V(D)J recombination although RAG1 gene is overexpressed. The mechanism of the RAG1 gene activation was not gene amplification, and no rearrangement was detected in the RAG1 gene locus. RAG1 presents homology with the yeast gene HPR1, itself homologous to yeast topoisomerase I and responsible for the control of recombination in somatic cells. Since DNA topoisomerases are themselves involved in the control of DNA topology, recombination and DNA repair, the possible coactivation of RAG1 and topoisomerase I genes in CEM/DOX cells is discussed.
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PMID:Altered topoisomerase I activity and recombination activating gene expression in a human leukemia cell line resistant to doxorubicin. 839 37

Multidrug resistance gene (mdr1) RNA levels were determined in 55, and P-glycoprotein expression in 37 samples of peripheral leukemic cells from 17 patients with acute myeloblastic leukemia (AML) and 7 patients with acute lymphocytic leukemia (ALL). Between sample collections, patients were treated with various chemotherapy regimens. Mdr1 RNA levels were quantified by a RNA-RNA solution hybridization assay. P-glycoprotein was determined by Western blot analysis. Samples from 14 patients (9 AML, 5 ALL) had undetectable mdr1 RNA levels at initial analysis. Only two of these had detectable levels after chemotherapy. Ten patients (8 AML, 2 ALL) had detectable mdr1 RNA levels at initial analysis (median 1.0 transcript per cell, range 0.2-1.4). Increase of mdr1 RNA levels after chemotherapy were observed in cells from 3 patients, one patient had a lower level after chemotherapy and the 6 remaining patients had essentially unchanged mdr1 RNA levels in their leukemic cells. Samples from 13 patients were sequentially analysed for P-glycoprotein expression. In one patient, no P-glycoprotein was detectable at initial analysis but was weakly positive after chemotherapy. In the remaining 12 patients, P-glycoprotein levels stayed stable during disease progression. In conclusion, combination chemotherapy seems only rarely to be associated with an increase of mdr1 gene expression in residual leukemic cells. The addition of resistance modifiers to chemotherapy in order to overcome P-glycoprotein mediated resistance might therefore be more effective in chemotherapy naive patients since it is possible that during later disease progression additional mechanisms of resistance may be more operative.
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PMID:Multidrug resistance (Mdr1) gene expression in peripheral blasts from patients with acute leukemia only rarely increases during disease progression after combination chemotherapy. 852 50

Daunorubucin (DNR) accumulation studies as functional tests of the multidrug resistance (MDR1) gene product P-glycoprotein have produced diverging results when correlated to response to chemotherapy in acute leukaemia. To investigate possible reasons for this diversity a starvation experiment, based upon prolongation of medium exchange, was set up in the multidrug resistant cell line CEM/VBL100. DNR accumulation (1 microgram/ml) was measured flow cytometrically in the presence or absence of Verapamil (10 micromol/l). In cells permanently kept under ideal growth conditions, addition of Verapamil resulted in an average 90% increase in DNR enhancement in five successive experiments. In contrast, DNR accumulation increased by only 26% when the medium exchange was prolonged by 30 h to 42 h. This effect was not accompanied by changes in the MDR1 gene expression at the RNA or protein level. Consequently, 53 leukaemic blast samples of 30 newly diagnosed and 18 relapsed or refractory patients with acute leukaemia (ALL-18, AML-37) were processed without any delay and under the most stringent conditions possible. Evidence of the classical MDR phenotype was arbitrarily defined by a greater than 20% enhancement in DNR accumulation in response to Verapamil (10 micromol/l) or Cyclosporin A (3 micromol/l). Using this cutoff point for analysis of newly diagnosed leukaemia we found DNR uptake better correlated to response to treatment (p = 0.002) than P-gp detection by means of immunocytochemistry, using a panel of monoclonal antibodies (p = 0.03). We conclude that DNR accumulation studies are a sensitive method for predicting therapy outcome in acute leukaemia when performed with necessary precautions.
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PMID:Prolongation of medium exchange is associated with a decrease in function but not expression of the P-glycoprotein pump in leukaemic cells. 859 88

P-glycoprotein (P-gp) is a crucial factor in the development of chemotherapy resistance in malignant disorders. Between 1989 and 1995, P-gp expression was studied in bone marrow blast cells of 322 (239 AML; 83 ALL) acute leukemia patients. 166 AML patients with the AML-6 protocol (EORTC), containing daunorubicin, vincristine and conventional-dose cytarabine (ara-C), and 63 AML patients treated with intermediate-does Ara-C plus amsacrine. Further 71 ALL patients were treated according to a German standard polychemotherapy protocol (BMFT04/1989). P-gp was determined by using monoclonal antibodies C219 and 4E3, and the cutoff point for P-gp overexpression was set at >/= 10%. A significant (P < 0.06) difference in P-gp overexpression was demonstrated between AML (21.6%) and ALL (10.2%) patients at primary diagnosis and between primary diagnosis and relapse/refractoriness in AML (21.6%; 51.0%) and ALL (10.2%; 27.2%) patients. According to FAB classification P-gp overexpression was detected in AML patients significantly (P < 0.05) more frequently in classes M4, M5a and M5b and less frequently in M3, as compared to other types. For AML patients with P-gp overexpression at primary diagnosis or early relapse/refractoriness, the predictive value for nonresponse to the AML-6 protocol was 91 and 95%, respectively, while late-relapsed AML patients with P-gp overexpression had a significantly (P < 0.05) lower predictive value of 73% for nonresponse. Additionally, in refractory and late-relapsed P-gp--overexpressing AML patients treated with intermediate-dose ara-C plus amsacrine the predictive values for nonresponse were 44 and 39%, respectively, significantly (P < 0.05) lower as compared to AML-6 protocol-treated refractory or late-relapsed AML patients. In P-gp-overexpressing treated ALL patients the predictive values of 50 and 55% for non-response were calculated at primary diagnosis and late relapse, respectively. We conclude that P-gp overexpression is a common phenomenon in AML patients at primary diagnosis or relapse, has an inverse influence on AML-6 treatment outcome and should be taken into consideration in the development of new therapy strategies.
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PMID:P-glycoprotein expression in patients with acute leukemia-clinical relevance. 865 97

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor-risk ALs.
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PMID:Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. 869 37

Eighty six of 430 acute myeloblastic leukemia (AML) patients (20.0%) and forty of 173 acute lymphoblastic leukemia (ALL) patients (23.1%) had CD7 on their leukemia cells. CD7(+) AML occurred at a younger age than CD7(-) AML, and is more frequent in males. Hepatomegaly and central nervous system involvement were also more frequent in CD7(+) AML than in CD7(-) AML. The age of onset of CD7(+) ALL is also younger than that of CD7(-) ALL. Phenotypically, CD(+) AML expressed CD34, HLA-DR, and TdT more frequently than CD7(-) AML while CD7(+) ALL expressed CD13/33 more often than CD7(-) ALL cells responded most significantly to interleukin 3 (IL-3), whereas most CD7(-) AML cells responded more significantly to granulocyte macrophage-colony stimulating factor (GM-CSF) and/or granulocyte (G)-CSF than to IL-3. CD7(+)sCD3(-)CD4(-)CD8(-) ALL expressed G-CSF receptor and c-kit mRNA more frequently, which is not usual in other types of ALL. P-glycoprotein (P-gp)/multi-drug resistance gene (MDR1), thought to be expressed in hematopoietic stem cells, is expressed in CD7(+) AML and CD7(+)sCD3(-) CD4(-)CD8(-) ALL significantly more often than in CD7(-) acute leukemias and the CR rate and overall survival of CD7(+)AML was worse than CD7(-) AML. These data, collectively, suggest the close association of CD7(+) AML and CD7(+)sCD3(-)CD4(-)CD8(-) ALL, not only the common expression of CD7 itself but also because their phenotypical immaturity, cytokine receptor expression, P-gp/MDR1 expression and clinical manifestations including the frequent occurrence in males and the poor prognosis. We propose that CD7(+) acute leukemia is an hematopoietic stem cell leukemia which may be separate entity.
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PMID:Biological characteristics of CD7(+) acute leukemia. 872 5

Confocal microspectrofluorometry allows the analysis of fluorescent molecules such as anthracylines in isolated living cells. An optical microscope fitted with a phase-contrast 100 X water-immersion objective enables simultaneous observation of the sample, focusing of the laser beam on the selected cell fraction (nucleus) and collection of the fluorescence emitted from the sample. The resulting intranuclear spectra are interpreted according to a quantitative model of the fluorescence spectra of both free and DNA-bound anthracycline. The intranuclear drug concentration can thus be determined. This technique has been applied to blast cells collected in patients with acute leukemia. Leukemic cells are aspirated from bone marrow, separated by Ficoll sedimentation and resuspended in RPMI-1640 containing 10% fetal calf serum and 200 nM tetrahydropyranyl-doxorubicin (THP-DOX). After one hour, 20 cells are analyzed and the mean nuclear drug content is determined (C1). Cells are then resuspended in the same medium but without anthracycline for 3 hours and the mean intranuclear drug concentration is then also determined (C3). From C1 and C3 the retention rate (RR) is calculated. Firstly, the accuracy of the method was checked. In 4 AML patients, two different samples aspirated on the same day were divided into two portions. Thus, two measurements were made on each one (4 values per patient). Coefficients of variation were satisfactory (4, 6, 12, and 12%). Secondly, blast cells collected in patients with AML and ALL at diagnosis or in relapse were studied. P-glycoprotein (P-gp) and CD34 expression was also studied using respectively immunohistochemistry land flow cytometry. Results obtained from the first 21 patients showed that there was no correlation between RR and either P-gp or CD34 expression. This could result from the efflux of THP-DOX by other mechanisms and/or low sensitivity of the staining technique.
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PMID:[Evaluation of multidrug resistance phenotype on medullary specimens from patients with acute leukemia by determination of nuclear efflux of tetrahydropyranyl-doxorubicin. Approach by confocal laser microspectrofluorometry]. 873 89

In acute lymphoblastic leukemia (ALL) the apoptosis of blast cells in peripheral blood (PB) and bone marrow before and/or during treatment, is of great interest. As the morphological changes during apoptosis provide the most reliable markers, in the present study we utilized a nuclear stain based on ethidium bromide (EtBr) for the rapid qualitative and quantitative measurement of circulating apoptotic cells directly in PB suspensions without fractionation. By using a fluorescent microscope the apoptotic cells appeared clearly visible, making the estimation of their percentage straightforward. We studied apoptosis before and during the onset of chemotherapy in PB from 16 children with ALL at diagnosis, and one upon relapse. In the cases studied at diagnosis the circulating apoptotic cells were found in variable percentages after 24 hours of treatment. Maximal apoptosis was observed after 24 hours of treatment in five cases and after 48 hours in two cases. After 96 hours of treatment the cases studied at diagnosis could be divided into three groups: those with a) negligible apoptotic cells, b) between 8% and 12% apoptotic cells and c) a high percentage of apoptotic cells (more than 20%). The relapsed case was characterized by P-glycoprotein positive blast cells, and circulating apoptotic cells which remained very low at all time points. Thus, it is possible to evaluate the response to treatment by studying apoptosis directly in peripheral blood. Therefore, the maximum apoptotic effect and the percentage of circulating apoptotic cells at the different time intervals must be considered.
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PMID:Study of apoptosis in peripheral blood of patients with acute lymphoblastic leukemia during induction therapy. 892 Jul 81

In this investigation, untreated non-B-type acute lymphoblastic leukemia (ALL) of 104 children was analyzed using immunocytochemistry for expression of protein kinase C, proto-oncogene products (Fos, Jun, Ras) and resistance-related proteins (topoisomerase II, P-glycoprotein, glutathione S-transferase-pi, metallothionein, dihydrofolate-reductase, thymidylate-synthase). The aim of the analysis was to find out whether combining those factors with the most important clinical prognostic factor (blast cell count) can improve the prognostic value (relapse-free interval). Univariate analysis shows that protein kinase D (PKC), Fos, P-glycoprotein (P-170) and glutathione S-transferase-pi (GST-pi) are significant prognostic factors independent of blast cell count (PBC) for the relapse-free intervals of children with ALL. The presence of the proteins Fos, PKC, P-170 and GST-pi was not independent within the patient population. The multivariate analysis showed that in combination with PBC and PKC, both P-170 and GST-pi have only limited prognostic influence. Combining the factors PKC, Fos and GST-pi as a categorical variable showed that this variable is a strong prognostic factor in addition to PBC.
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PMID:Prognostic value of protein kinase C, proto-oncogene products and resistance-related proteins in newly diagnosed childhood acute lymphoblastic leukemia. 898 47


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