Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of P-glycoprotein (P-gp) in AML has been well documented. Resistance to the anthracyclines can be overcome by several agents including Cyclosporin A (CsA), PSC833 and GF120918. We describe an investigation into the expression, using MRK16 and UIC2, and function of P-gp using daunorubicin with and without modulators by flow cytometric analysis on previously frozen blast cells from 27 patients with primary or secondary AML. We compared this with the in vitro chemosensitivity, using the MTT assay, of fresh blast cells from the same patients. Whilst we found a correlation between P-gp function using CsA and GF120918 and expression using MRK16 (p < 0.05) and (p < 0.02) respectively, we were unable to find any overall correlation between expression and function of P-gp with either in vitro sensitivity to the anthracyclines, previous treatment, or 1 degree or 2 degrees disease. However it was possible to identify individual patients whose cells exhibited P-gp expression and function teamed with in vitro resistance to, and modification of, the anthracyclines. Furthermore, it is possible to identify which modulator had the greatest effect. The fact that we obtained higher indications of resistance reversal using the MTT assay along with finding P-gp expression and function in patients sensitive to the anthracyclines, suggests studies of P-gp should be teemed with chemosensitivity testing to identify specific patients who will benefit.
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PMID:Comparison of P-glycoprotein expression and function with in vitro sensitivity to anthracyclines in AML. 1050 Jul 77

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr 1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24 h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.
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PMID:Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). 1050 Jul 79

Drug resistance often results in failure of anticancer chemotherapy in leukemias. A large number of studies have been published on the effect of P-glycoprotein (Pgp) expression on prognosis in AML. However, a consensus has been difficult to reach, due to the variable results obtained by different laboratories. Pgp expression was investigated here in bone marrow samples from 34 patients with AML including 19 newly diagnosed cases and 15 relapsing patients. Pgp expression was performed by immunocytochemistry (ICC) using the aviding-biotin-peroxydase technique with JSB1 and UIC2 MoAbs. Flow cytometry (FCM) analysis of Pgp expression was performed using UCI2 MoAbs in an indirect immunofluorescent assay without cell permeabilization. Rhodamine 123 (Rh 123) uptake was measured in the presence or absence of verapamil. Result was discordant in only 1/20 samples studied with both JSB1 and UIC2 by ICC. Results of Pgp expression were consistent on FCM and ICC in 23 of the 28 (82%) samples tested. Overall, Pgp expression was observed by ICC or FCM in 23 (67%) patients, including 11 (58%) newly diagnosed patients and 12 (80%) patients in relapse. Functional Rh123 efflux (Rh123+) was observed in 20 cases (59%): 10 de novo AML (53%) vs 10 AML in relapse (67%). The functional efflux was correlated with Pgp expression in 25 of the 34 cases analyzed (p = 0.013). 3 (9%) and 6 (18%) samples were Pgp-/Rh123+ and Pgp+/Rh123- respectively. Nine of the 14 pts (64%) treated with intensive anthracyclin-Ara C chemotherapy achieved complete remission, including 5/5 (100%) Pgp- cases vs 4/9 (44%) Pgp+ cases (p = 0.04) and 4/6 (67%) Rh 123- vs 4/7 (57%) Rh123+ cases (p = 0.5). In conclusion, assessment of Pgp expression by ICC and FMC using 2 different MoAbs coupled with functional efflux analysis confirms that Pgp expression is correlated with disease stage and response to treatment in AML. Discordant Pgp/Rh123 cases suggest a non functional Pgp or another alteration of drug transport.
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PMID:Assessment of P-glycoprotein expression by immunocytochemistry and flow cytometry using two different monoclonal antibodies coupled with functional efflux analysis in 34 patients with acute myeloid leukemia. 1050 Jul 80

In order to bring MDR analysis into a clinical setting, reproducible assays with clear cut off points to define MDR positivity must be used. Sensitivity can also be increased by combining the results of more than one assay. We have used a combination of flow cytometric assays to define MDR positive and negative blasts in 47 AML patients entered into MRC trials. Our primary test is a standardised and reproducible assay for anthracycline accumulation in which we use carboxylate microspheres to bind the fluorescent drug daunorubicin (dnr). Cells and beads are incubated concurrently with dnr. Cellular dnr accumulation is quantified as a cell:bead fluorescence ratio. Confirmatory assays for MDR comprise the cyclosporin modulation assay for rhodamine 123 uptake and also measurement of lung resistance protein and multidrug resistance associated protein (with LRP-56 and MRPr1 respectively). 27/47 (57%) samples had both low and accumulation and at least one positive confirmatory test (a modulated functional assay and/or protein overexpression) and were categorised as "confirmed MDR". 15/47 patients (32%) were MDR negative in all 4 assays. 5/47 (11%) patients had unconfirmed low dnr accumulation. None of the patients in this cohort had high dnr accumulation alongside overexpressed LRP or MRP or functional P-glycoprotein. We believe that this approach to MDR analysis enhances the value of the highly reproducible functional assays. The use of a primary and confirmatory tests is also likely to improve specificity.
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PMID:Reproducible flow cytometric methodology for measuring multidrug resistance in leukaemic blasts. 1050 Jul 83

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

New combination therapies against hematological malignancies have recently been reported. Anti-CD20 chimeric antibody adds a therapeutic benefit to standard-dose CHOP therapy without causing significant additional toxicity in the treatment of indolent B cell lymphoma. Multidrug resistant modifiers such as PSC833 and MS209 in combination with chemotherapy are useful for treating poor risk AML patients, whose leukemia/lymphoma cells express P-glycoprotein. Fludarabine containing FL and FLAG therapy were effective in patients with AML in relapse. The early addition of chemotherapy to ATRA, and maintenance therapy with chemotherapy and intermittent ATRA, can reduce the incidence of relapse in cases of acute promyelocytic leukemia.
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PMID:[New combination therapies in hematological malignancies]. 1074 Jun 32

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

Breast cancer resistance protein (BCRP) is a novel member of the adenosine triphosphate-binding cassette superfamily of transport proteins. Transfection and enforced expression of BCRP in drug-sensitive cells confer resistance to mitoxantrone, doxorubicin, daunorubicin, and topotecan. We studied blast cells from 21 acute leukemia patients (20 acute myeloid leukemia, 1 acute lymphocytic leukemia) for the expression of BCRP mRNA using a quantitative reverse-transcription polymerase chain reaction assay. BCRP mRNA expression varied more than 1000-fold among the samples tested, with low or barely detectable expression in half of the samples. Seven samples (33%) had relatively high expression of BCRP mRNA. High expression of BCRP did not correlate strongly with high expression of P-glycoprotein, suggesting that BCRP may cause resistance to certain antileukemic drugs in P-glycoprotein-negative cases. High expression of BCRP mRNA is sufficiently frequent in AML to warrant more extensive investigations to determine the relation of disease subtype and treatment outcome to BCRP expression and function.
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PMID:Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. 1089 76

In the myelodysplastic syndromes (MDS), P-glycoprotein (P-gp) expression is clinically associated with drug resistance, whereas the clinical significance of multidrug resistance-associated protein (MRP1) is uncertain. Bone marrow from 56 patients with MDS, including six with refractory anaemia (RA)/RA with ringed sideroblasts (RARS), 23 cases of RA with excess blasts/in transformation (RAEB/T), four patients with chronic myelomonocytic leukaemia (CMML) and 23 cases of MDS having progressed to acute myeloid leukaemia (MDS-AML), were studied. MRP1 expression was investigated by immunocytochemistry (ICC) and by flow cytometry using MRPm6 monoclonal antibody. The efflux test using calcein-AM (CAM) +/- probenecid to evaluate MRP1 activity was performed in ten of the 56 patients. Twenty-eight of the 56 cases (50%) expressed MRP1. MRP1 expression was more frequent in MDS-AML than in MDS (70% vs. 36%). The efflux test using CAM was positive in three out of the ten patients tested. The results were in agreement with expression of MRP1 in six cases, and were discordant in four cases (1 MRP-/CAM+, 3 MRP+/CAM-). No correlation was observed between MRP1 expression and P-gp, lung resistance-associated protein (LRP) or CD34 expression, although there was a trend for more frequent MRP1 expression in P-gp-positive cases in MDS-AML (P = 0.08). Ten of the 26 patients treated with intensive chemotherapy achieved complete remission including six out of 16 MRP1+ and four out of ten MRP1- cases (P = NS). In conclusion, MRP1 expression was correlated with disease stage in MDS in our study. As for P-gp, discordant expression/function of MRP1 could be found in some cases, suggesting the existence of non-functional transport proteins in MDS. MRP1 expression did not seem to be a prognostic factor in MDS in our experience.
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PMID:Expression of the multidrug resistance-associated protein in myelodysplastic syndromes. 1099 69

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR). The previous study revealed that a doxorubicin-resistant AML subline (AML-2/DX100) overexpressed an MDR-associated protein (MRP) but not P-glycoprotein. The AML-2/DX100 also showed various levels of resistance to daunorubicin and vincristine but was paradoxically sensitive to hydrogen peroxide (5-fold), t-butyl hydroperoxide (3-fold), and paraquat (2-fold) when compared to the drug-sensitive parental AML-2 cells (AML-2/WT). We compared the activities of antioxidant enzymes to detoxify reactive oxygen species (ROS), including superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase in both AML-2/WT and AML-2/DX100. Interestingly, of these antioxidant enzymes, catalase activity of AML-2/DX100 decreased significantly to about one-third that of AML-2/WT (P < 0.000005). The decreased activity of catalase was due to reduced expression of the catalase gene; confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses. The decreased activity of catalase was maintained even in the absence of doxorubicin for 3 months as well as by the treatment of probenecid, an MRP inhibitor. In addition, there was no difference in catalase activity between HL-60 and another MRP-overexpressing subline HL-60/Adr. Taken together, the paradoxical increase in the sensitivity of an MRP-overexpressing AML-2/DX100 in response to peroxides and paraquat is due to the down-regulation of catalase gene expression, which totally independent of overexpression of MRP. It is therefore possible that decreased catalase activity could be exploited as an Achilles' heel in resistant cells such as this.
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PMID:Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100. 1117 67


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