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)

The diagnosis of 'ALL with maturation' (ALLm) is proposed. One hundred and one patients with untreated ALL were entered into this study. The diagnosis of ALLm was made when more than 20% of all nucleated elements in the bone marrow showed maturation beyond prolymphocytes by light microscopic examination. The mature-appearing leukemic cells showed the same immunophenotype to remaining lymphoblasts. The number of ALLm cases was 19 (18.8%). The mean age at presentation of ALLm was 29 +/- 18, older than that of 18 +/- 16 of the remaining typical ALL (ALLt) (P = 0.015). Remission was induced with daunorubicin, vincristine, prednisone and L-asparaginase. Only two of 19 ALLm patients achieved CR after 4 weeks induction chemotherapy. In contrast, 57 of 82 (69.5%) ALLt patients achieved CR after the same induction chemotherapy. There was no significant difference in immunophenotype of ALLm compared with ALLt. Labeling index of DNA topoisomerase IIalpha (TopoLI) was studied by immunohistochemistry. Initial TopoLI of ALLm (221 +/- 147) was much lower than that of ALLt (609 +/- 262, P = 0.005). Furthermore, the remaining leukemic cells after chemotherapy were not labeled with anti-DNA topoisomerase IIalpha. The P53 protein was expressed in nine of 18 ALLm cases (50.0%) and P-glycoprotein was not expressed in ALLm cases. Twelve of 19 ALLm cases were studied for carrying bcr/abl fusion by karyotyping and/or fluorescent in situ hybridization. Only two cases revealed bcr/abl fusion. In conclusion, ALLm is a separate entity of ALL which has a very poor clinical course and is independent of other prognostic factors. The morphologically mature leukemic cells are in resting GO phase.
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PMID:Acute lymphoblastic leukemia with maturation--a new entity with clinical significance. 963 14

Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 microM PSC 833 (P = 0.025), 1.5-fold using 4 microM CsA (P = 0.003) and 1.6-fold using 6 microM Vp (P = 0.012) whereas the adverse effect of 25 microM genistein was median 1.8-fold (P < 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of P-gp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.
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PMID:The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia. 963 20

The measurement of rhodamine 123 (Rho123) efflux in hematological malignancies, using flow-cytometry, provides an accurate assessment of multidrug resistance (MDR) of both P-glycoprotein and MRP. While their normal counterparts display high levels of PgP and Rho123 efflux, we investigated the MDR status of marked T/NK proliferations. When diagnosed according to natural killer (NK) markers (CD16, CD56, CD57) 8 of nine NK lymphoproliferative disorders (LPD) were markedly positive (3 NK non Hodgkin's lymphomas (NHL), 1 NK lymphoproliferative disease of large granular lymphocytes (LGL), and 5 T/NK LGL). These results are in accordance with the observed response to chemotherapy in the treated cases. Mature T LPD (prolymphocytic leukemia (PLL), and NHL) cells gave varying results, as did cells from Sezary syndromes. Marked Rho123 efflux was detected in the two cases of T-PLL suggesting the expression of MRP as previously described. Immature T-lymphomas or leukemias (6 cases) were all negative. These data should be considered in relation to NK proliferations which clearly display an MDR phenotype and therefore raise the question, of the relevance of this phenotype in normal cells, and secondly of the negativity of immature T-LPD. The latter could indicate that MDR inhibitors may be superfluous in the initial treatment of acute lymphoblastic leukemia (ALL). Finally the resistance to treatment of T-ALL or mature T cells LPD invokes the importance of exploring other mechanisms of drug resistance such as the lung resistance related protein (LRP).
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PMID:Multidrug resistance in aggressive lymphoproliferative disorders of T and natural-killer origin. 971 68

Drug resistance, both primary and acquired, is a major obstacle to advances in cancer chemotherapy. In vitro, multidrug resistance can be mediated by P-glycoprotein (PGY1), a cell surface phosphoglycoprotein that acts to efflux natural products from cells. PGY1 is encoded by the MDR1 gene located at 7q21.1. Overexpression of MDR1 has been demonstrated in many cancers, both in patient tumors and in cell lines selected with a variety of chemotherapeutic agents. Recent studies in drug-selected cell lines and patients samples have identified hybrid mRNAs comprised of an active, but apparently random, gene fused 5' to MDR1. This observation indicates that random chromosomal rearrangements, such as translocations and inversions, leading to "capture" of MDR1 by constitutively expressed genes may be a mechanism for activation of this gene following drug exposure. In this study, fluorescence in situ hybridization (FISH) using whole chromosome paints (WCP) and bacterial artificial chromosome (BAC)-derived probes showed structural rearrangements involving 7q in metaphase and interphase cells, and comparative genomic hybridization (CGH) revealed high levels of amplification at chromosomal breakpoints. In an adriamycin-selected resistant colon cancer line (S48-3s/Adr), WCP4/WCP7 revealed t(4;7)(q31;q21) and BAC-derived probes demonstrated that the breakpoint lay between MDR1 and sequences 500-1000 KB telomeric to it. Similarly, in a subline isolated following exposure to actinomycin D (S48-3s/ActD), a hybrid MDR1 gene composed of heme oxygenase-2 sequences (at 16p13) fused to MDR1 was identified and a rearrangement confirmed with WCP7 and a subtelomeric 16p probe. Likewise, in a paclitaxel-selected MCF-7 subline where CASP sequences (at 7q22) were shown to be fused to MDR1, WCP7 showed an elongated chromosome 7 with a homogeneously staining regions (hsr); BAC-derived probes demonstrated that the hsr was composed of highly amplified MDR1 and CASP sequences. In all three selected cell lines, CGH demonstrated amplification at breakpoints involving MDR1 (at 7q21) and genes fused to MDR1 at 4q31, 7q22, and 16p13.3. Finally, in samples obtained from two patients with drug refractory ALL, BAC-derived probes applied to archived marrow cells demonstrated that a breakpoint occurred between MDR1 and sequences 500-1000 KB telomeric to MDR1, consistent with a random chromosomal rearrangement. These results support the proposal that random chromosomal rearrangement leading to capture and activation of MDR1 is a mechanism of acquired drug resistance.
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PMID:Cytogenetic and molecular characterization of random chromosomal rearrangements activating the drug resistance gene, MDR1/P-glycoprotein, in drug-selected cell lines and patients with drug refractory ALL. 971 96

Paclitaxel (Taxol) has been shown to be clinically effective in treatment of patients with breast and ovarian cancer. It has also shown promising results in various other solid tumours. Paclitaxel has induced apoptosis in the G2/M phase of the cell cycle in both HL-60 and U937 human leukaemia cells. A recent study has shown a dose-dependent cytotoxicity for both taxanes: paclitaxel (taxol) and docetaxel (Taxotere) on fresh leukaemia cells in primary culture from 16 ALL and four AML patients and proposed their use in treatment of acute leukaemia patients. AML is a heterogeneous disease in which malignant transformation and disease progression occur at the level of CD34 positive cells. Also, the multi-drug resistance gene product, P-glycoprotein is expressed only in CD34 positive AML cells. Therefore, an in vitro evaluation of the efficacy of paclitaxel, a P-glycoprotein substrate, in CD34 positive AML cells is warranted before considering its clinical use in acute leukaemia patients. Since all in vitro studies of paclitaxel reported so far have involved only CD34 negative (HL-60, U937, K562) human AML cells, the aim of the present study was to evaluate paclitaxel efficacy against CD34 positive AML cells. The IC50 of paclitaxel for apoptosis was significantly higher in MHH225 CD34 positive cells (12 +/- 2 microM) than in U937 CD34 negative cells (1.7 +/- 0.2 microM), P < 0.001. Paclitaxel has a significantly weaker cytotoxic effect on CD34 positive AML cells. One log higher concentration of paclitaxel was required in MHH225 CD34 positive AML cells to achieve the same apoptosis level achieved in U937 CD34 negative leukaemia cells. Also, at the high concentration achievable in vivo: 10 microM paclitaxel, only half the MHH225 CD34 positive AML cells were apoptotic versus 72% of U937 CD34 negative leukaemia cells. Clearly, paclitaxel has only weak or modest in vitro efficacy compared with several conventional anti-leukaemia drugs used in AML treatment. The present results support the poor level of in vivo induction of apoptosis achieved during a phase I clinical study with paclitaxel therapy in 26 leukaemia patients. Also, the present results have shown a significant increase in nitric oxide production during paclitaxel-induced apoptosis in U937 monocytic leukaemia cells, confirming the vital role of nitric oxide in mediating paclitaxel-induced apoptosis by monocytic cells. In conclusion, the present study has demonstrated a clear difference between the effect of paclitaxel on CD34 negative and CD34 positive AML cells. Given its poor performance in the phase I clinical study of 26 acute leukaemia patients and the present weak in vitro cytotoxic effect, it is unlikely that paclitaxel will have a role in the treatment of acute leukaemia. Also, the present study emphasises the need to use CD34 positive AML cells such as MHH225 rather than the unsuitable lineage-specific CD34 negative cells such as HL-60 or U937 for in vitro pre-clinical screening of potential novel effective anti-leukaemia agents.
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PMID:Divergent effect of taxol on proliferation, apoptosis and nitric oxide production in MHH225 CD34 positive and U937 CD34 negative human leukaemia cells. 976 54

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

P-glycoprotein (P-gp) is often expressed (40-50%) on leukemic cells at diagnosis in acute myelogenous leukemia (AML), and is even more frequently present after treatment failure. Several large cohorts of newly diagnosed AML patients treated with a classical anthracycline + standard doses of cytosine arabinoside were tested for the prognosis value of MDR1 phenotype, and demonstrated an high correlation between a significant increase of MDR1 gene expression and treatment failure (or, better, drug resistance). This P-gp(+) drug resistance could be due either to a particular phenotype of bad prognosis AML, as it is suggested by the association of myelodysplasia, complex karyotype and advanced age with MDR1 phenotype, or due primarily to the active efflux of anthracyclines and VP16 in P-gp(+) leukemic cells. Several observations tend to confirm the functional role of the P-gp in clinical drug resistance; (i) using multivariate analysis, MDR1 phenotype appears to be an independent variable, as potent (or higher) as karyotype and age for predicting in vivo drug resistance; (ii) the prognostic value is limited to the CD34(+)/P-gp(+) phenotype, wich is linked to a functional P-gp; (iii) the in vitro sensitivity to anthracyclines and VP16 is highly correlated with P-gp expression. All these data argue for an early use of P-gp modifier agents in the treatment of AML. The role of the MDR1 gene in ALL resistance is controversial and marginal compared to the sensitivity of ALL blasts to glucocorticoids, and the frequency of MDR1 phenotype is low at diagnosis, and is increasing only after repetitive chemotherapies.
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PMID:MDR1/P-GP expression as a prognostic factor in acute leukemias. 1050 Jul 74

In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.
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PMID:Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. 1060 24

A major problem in the treatment of leukemia is the development of resistance to chemotherapeutic agents. There are several ways for cancer cells to develop resistance or defense mechanisms against cytotoxic drugs. This review paper will focus on membrane transport-associated multidrug resistance (MDR). The proteins involved, P-glycoprotein (P-gp), MRP1 and LRP/MVP, share the ability to act as drug transport proteins. Following upregulation of the mdr-1 gene, the energy-dependent transmembrane P-gp overexpression results in diminished intracellular concentrations of anthracyclins, vinca-alkaloids and epipodophyllotoxins. The other transmembrane protein, MRP1, also has intracellular epitopes which are involved in intracellular redistribution and sequestration of drugs. The last named mechanism has also been ascribed to LRP, a protein which only occurs intracellularly. In leukemia patients, cellular drug resistance profiles determined in vitro at the time of presentation show a strong correlation with outcome. In AML, mdr-1 overexpression at diagnosis is a strong independent predictor for CR and long-term survival. In ALL, mdr-1 expression is of minor importance for prediction of outcome. In AML, MRP1 expression at diagnosis is not correlated with clinical response and survival in most studies. In ALL, MRP1 expression at diagnosis is not associated with response and long-term survival in the few studies on this aspect which have been published. The studies on LRP in AML emphasize the importance of the correlation between LRP-expression and anthracycline accumulation and suggest that LRP-expression has prognostic value at diagnosis. However, there is an equal number of studies where a predictive value in the case of LRP-expression in de novo AML cannot be shown. The highest levels of LRP have been reported in multiple relapses of ALL. Furthermore, new membrane-associated drug transport proteins have been reported including the transporter associated with antigen processing (TAP), the anthracyclin resistance-associated protein (ARA), five new homologues of MRP (MRP2, or MOAT, MRP3, MRP4, MRP5, and MRP6), the sister of P-glycoprotein (sP-gp) and breast cancer resistance protein (BCRP). Studies on the (clinical) significance of these proteins have not yet been reported.
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PMID:The prognostic significance of membrane transport-associated multidrug resistance (MDR) proteins in leukemia. 1073 13

The development of refractory disease in acute myeloid or lymphoblastic leukaemias (AML, ALL) and multiple myeloma (MM) is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, MRP1 and LRP have been identified as important adverse prognostic factors in AML, T-ALL and MM. Recently, it has become possible to reverse clinical multidrug resistance by blocking P-glycoprotein-mediated drug efflux. The potential relevance of these reversal agents of MDR and potential new approaches to treat refractory disease are discussed.
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PMID:Multidrug resistance in haematological malignancies. 1080 91


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