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)

The human multidrug resistance protein (MRP) family contains at least six members: MRP1, the gene encoding the multidrug resistance protein; cMOAT or MRP2, encoding the canalicular multispecific organic anion transporter; and four homologues, called MRP3, MRP4, MRP5, and MRP6. The most recently discovered member of the family, MRP6, is analyzed in this report. The MRP6 gene is located on chromosome 16, immediately next to MRP1, and encodes a protein of 1503 amino acids with a predicted molecular weight of Mr 165,000. The 3' end of the MRP6 protein was found to be almost identical with the anthracycline resistance associated (ARA) protein identified previously in epirubicin-selected leukemia cells. Using both 3'- and 5'-derived MRP6 probes, we found that MRP6 is highly expressed in liver and kidney and to a low or very low extent in a few other tissues. No evidence was obtained for an independent expression of the ARA part of the MRP6 gene in normal tissues. To assess a possible role for MRP6 in multidrug resistance, we examined a large panel of resistant cell lines for the (over)expression of MRP6. We found overexpression of the complete MRP6 gene or part of it only in those cell lines with high overexpression and amplification of the MRP1 gene. DNA blot (Southern) analysis showed that MRP6 or a part of it is also amplified in these cell lines. Our results suggest that MRP6 does not play a role in the resistance of the resistant cells analyzed, and that MRP6/ARA is only coamplified with MRP1 because of its location immediately next to it on the same chromosome.
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PMID:Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. 989 4

Two proteins that have been correlated with the occurrence of multidrug resistance in acute myeloid leukemia (AML) are P-glycoprotein (Pgp) and the major vault protein (Mvp/LRP). With the purpose of further quantifying the potential contributions of Pgp-mediated drug efflux and Mvp/LRP to drug resistance in AML we have investigated whether the transport function of Pgp and the expression of Mvp/LRP correlated with the accumulation of daunorubicin (DNR) and the in vitro resistance to DNR cytotoxicity (LC50 by MTT assay) in AML cells. In de novo adult AML, the steady-state DNR accumulation (in pmol/10(6) cells) correlated with Pgp activity or expression, whereas the LC50 for DNR did not correlate with Pgp activity (measured as the modulation of rhodamine 123 or DNR accumulation by the Pgp inhibitor PSC833) or Pgp expression (measured by flow cytometry with the MRK-16 antibody). The contribution of MRP1 expression to a reduced DNR accumulation seems minor compared to Pgp. In addition, the modulation of the DNR LC50 by PSC833 did not correlate with Pgp protein or activity. The steady-state DNR accumulation showed no correlation with the DNR LC50. The Mvp/LRP expression (immunocytochemical staining) did neither correlate with DNR accumulation nor with the DNR LC50. A significant negative correlation was seen between the Mvp/LRP immunocytochemical staining and Pgp activity, indicating that both markers define (partially) different populations. In conclusion, it is shown that Pgp function, but not Mvp/LRP or MRP1 expression correlate with a low steady-state DNR accumulation in de novo AML. The Pgp activity does, however, not predict the DNR sensitivity in AML measured as in vitro DNR LC50 with an MTT-based assay. The reason for that seems to be that a low DNR accumulation may not be the most important factor in determining the LC50. While the clinical usefulness of these drug resistance tests remains to be proven they do not seem to provide as yet a straightforward explanation for the major cause(s) of clinical chemotherapy failure.
Leukemia 1999 Feb
PMID:Do P-glycoprotein and major vault protein (MVP/LRP) expression correlate with in vitro daunorubicin resistance in acute myeloid leukemia? 1048 3

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

Currently available data regarding the substrate specificity of the multi-drug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-associated protein (MRP1) for idarubicin are inconclusive. A multiparameter flow cytometry method was developed which allows simultaneous quantitative measurement of total cellular fluorescence and the amount of anthracyclines intercalated into the DNA. Anthracycline DNA intercalation was measured by fluorescence resonance energy transfer (FRET) between Hoechst 33342 and anthracyclines. Daunorubicin and idarubicin accumulation were studied and compared in established cell lines expressing Pgp and MRP1. The data demonstrate that daunorubicin DNA intercalation is affected by both Pgp and MRP1 whereas idarubicin DNA intercalation is affected only by MRP1. MRP1 and Pgp function could be blocked completely by 5 microM PAK 104P, while higher concentrations of verapamil, PSC 833 and cyclosporin A were necessary to attain complete blocking of MRP1 compared to Pgp. Daunorubicin DNA intercalation correlates better with cell survival and is more sensitive at physiological MDR expression as observed in hematopoietic progenitors than daunorubicin levels measured by total cellular fluorescence. In conclusion, idarubicin DNA intercalation is reduced by MRP1 but not by Pgp. PAK-104P is an effective modulator for both Pgp and MRP1 and may further improve idarubicin efficacy.
Leukemia 1999 Sep
PMID:Idarubicin DNA intercalation is reduced by MRP1 and not Pgp. 1048 90

Thirteen cell lines with different levels of Pgp and MRP1 expression were used to assess the ability of calcein-AM uptake and calcein efflux to measure Pgp and MRP1 functions, respectively. There was a good correlation between MRP1 expression and the modulatory effect of probenecid (a specific modulator of MRP1) on the calcein efflux (r = 0.91, p = 0.0003) and between Pgp expression and the modulatory effect of CsA on calcein-AM uptake (r = 0.96, p < 0.0001). On light of the high correlations for both proteins, we tested calcein-AM uptake and efflux in fresh myeloid leukemic cells. In 53 AML patients, there was also a good correlation between MRP1 expression (measured by RT/PCR and by MRPm6 expression by flow cytometry) and the modulatory effect of probenecid on the calcein fluorescence (r = 0.92, p < 0.0001) and between Pgp expression as measured by UIC2 antibody binding on flow cytometry and the modulatory effect of CsA on calcein-AM uptake (r = 0.83, p < 0.0001). Pgp activity was higher in CD34+ leukemia than in CD34- leukemia (2.26 +/- 1.50 vs 1.46 +/- 1.21 respectively, p = 0.003) and MRP1 activity was higher in CD34- leukemia than in CD34+ leukemia (1.77 +/- 0.40 vs 1.4 +/- 0.29 respectively, p = 0.004). Pgp expression and activity (p = 0.004 and p = 0.01, respectively), MRP1 activity (p = 0.03) but not MRP1 expression were prognostic factors for achievement of CR. The effect of probenecid and CsA together were higher than the effect of either probenecid or CsA alone on calcein-AM uptake. These results suggest that functional testing (with calcein-AM +/- modulators) for the presence of both MRP1 and Pgp activities is of prognostic value and that MRP1 contributes to drug resistance in AML.
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PMID:Both Pgp and MRP1 activities using calcein-AM contribute to drug resistance in AML. 1050 Jul 91

To compare the clinical relevance of drug resistance factors in de novo acute myeloid leukemia (AML), we determined their relationship to both response to induction chemotherapy and survival of the patients in univariate as well as multivariate analyses. The drug resistance factors immunocytochemically studied in 111 patients at the time of diagnosis included the lung resistance protein (LRP), P-glycoprotein (P-gp), multidrug resistance protein (MRP1) and bcl-2. In the univariate analyses, age (P = 0.005), karyotype (P = 0.03), LRP (P = 0.003), P-gp (P = 0.02) and bcl-2 (P = 0.03) predicted for response to induction chemotherapy, whereas MRP1 had no predictive value. Age (P = 0.05), karyotype (P = 0.05) and LRP (P = 0.03) retained their predictive value in the multivariate logistic regression analyses. With regard to overall survival, age (P = 0. 008), karyotype (P = 0.006), LRP (P = 0.001) and P-gp (P = 0.01) were of prognostic value in the univariate Cox regression analyses but only age (P = 0.01), karyotype (P = 0.02) and LRP (P = 0.01) retained their prognostic significance in the multivariate analyses. A risk score based on the number of independent prognostic factors allowed division of patients into four groups with different outcome. In these groups, the complete remission rates were 93%, 75%, 47% and 33%, respectively, and median overall survival was 2.4, 1.2, 0.6 and 0.2 years, respectively. Thus, several drug resistance factors did predict outcome in the univariate analyses but LRP was the only drug resistance factor with independent predictive and prognostic significance. The proposed risk score might be useful for risk-adapted treatment in the future. Leukemia (2000) 14, 68-76.
Leukemia 2000 Jan
PMID:Drug resistance factors in acute myeloid leukemia: a comparative analysis. 1063 79

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

Multidrug resistance protein (MRP1) is a member of the ATP-binding cassette (ABC) transmembrane transporter superfamily that confers multidrug resistance. The transfer and expression of the MRP1 gene in human hematopoietic stem cells may be a useful alternative to multidrug resistance (MDR1) gene transfer for protection from the myelosuppressive effects of chemotherapy in cancer patients. We constructed a gibbon ape leukemia virus packaging cell line (PG13) using the human MRP1 cDNA in a Moloney murine leukemia virus (MoMuLV) backbone containing a modified LTR. This PG13-based cell line, designated MRP1-PG13, produces retroviral vectors bearing the MRP1 gene at a titer of 1.7x10(5) viral particles/ml. Transduction of the human leukemic cell line K562 showed that viral MRP1-PG13 supernatants routinely transfer the MRP1 gene to approximately 35% of target K562 cells, of which at least one third are capable of proliferating in the presence of otherwise toxic concentrations of etoposide. Southern blot analyses indicated that most clones had only one proviral integration. Northern blot analysis of expanded K562 clones showed the presence of a major full-length approximately 8-kb MRP1 transcript as well as a minor approximately 6-kb transcript in all clones. Flow cytometric analysis of the producer cells and clones of transduced K562 cells demonstrated significantly increased MRP1 expression in these cells (approximately 30-fold increase). Human bone marrow mononuclear cells and CD34+ cells were also transduced with MRP1-PG13 supernatants on fibronectin-coated culture flasks in the presence of SCF, IL-3, and IL-6. PCR analysis of individual hematopoietic colonies in methylcellulose cultures demonstrated proviral DNA in approximately 10% of unselected human hematopoietic progenitor cells cultured from nonsorted mononuclear cell samples and in up to approximately 75% of progenitors when CD34-enriched cell populations were targeted. To assess functional MRP1 gene expression, normal human hematopoietic progenitors and K562 cells were cultured in methylcellulose assays containing vincristine or etoposide. All transduced samples gave rise to approximately 10% drug-resistant colonies, which were shown to be provirus-positive by PCR. Our studies document the development of an amphotropic MRP1 retroviral vector producer cell line and pave the way for large animal and preclinical studies of chemoprotection by MRP1 gene transfer.
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PMID:Retroviral-mediated transfer and expression of the multidrug resistance protein 1 gene (MRP1) protect human hematopoietic cells from antineoplastic drugs. 1079 1

We analysed the expression of three drug transporter proteins [p-glycoprotein (PGP), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP1)] involved in anthracycline resistance that are frequently overexpressed in poor-risk adult acute non-lymphocytic leukaemia (ANLL), in 23 acute promyelocytic leukaemia (APL) patients at onset managed at a single institution. Cellular daunorubicin accumulation was also evaluated. At onset, no case had PGP or MRP1 expression that exceeded that of non-multidrug-resistant (MDR) cell lines. Only one case showed LRP overexpression. No peculiar MDR features distinguished the seven patients who relapsed from those who maintained complete remission. In the onset vs. first relapse, only one patient showed an increased (threefold) PGP expression at relapse. At second relapse, three out of four patients showed a PGP expression two- to threefold higher than baseline values. These results are consistent with the view that low PGP, LRP and MRP1 expression and the absence of defects in intracellular drug accumulation may account for the peculiarly high sensitivity of APLs to anthracycline. It does not support the screening of MDR markers in APL patients at onset as predicting factors of early relapse. The results suggest that no significant changes in PGP, LRP or MRP1 expression are likely to occur at first relapse. In contrast, PGP expression is likely to increase later in the patient history as a result of additional chemotherapy courses.
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PMID:P-glycoprotein (PGP), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression in acute promyelocytic leukaemia. 1079 72

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


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