Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed P glycoprotein (PGP) expression and its correlation with hematological parameters and outcome in 50 cases of newly diagnosed adult acute lymphoblastic leukemia (ALL). PGP expression was evaluated by flow cytometry using MRK16 monoclonal antibody (MoAb) and/or immunocytochemistry on marrow slides, using JSB1 MoAb. Thirty-two of the 50 patients (64%) were PGP positive by at least one of the two methods, which gave concordant results in 15 of the 18 cases in which they were both used. No correlation between PGP expression and clinical and hematological parameters including WBC counts, immunophenotype and karyotype was seen, although there was a trend for more frequent CD34 expression in PGP-positive cases. All patients were treated with intensive chemotherapy. We found no difference in complete remission (CR) rate, actuarial disease-free survival and survival in PGP-positive and PGP-negative cases. Our findings suggest that the clinical significance of PGP expression is less clear in ALL than in AML. Wider use of functional techniques of evaluation of mdr1 gene expression, which assess the 'pumping' activity of PGP, and their correlation with quantitative analysis of mdr1 mRNA and protein, would probably improve knowledge of the role of PGP in ALL. Analysis of other mechanisms of drug resistance, especially multidrug resistance-associated protein (MRP) expression, would also be useful.
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PMID:Expression of the multidrug resistance P glycoprotein in newly diagnosed adult acute lymphoblastic leukemia: absence of correlation with response to treatment. 747 77

Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine relative levels of transcripts for MDR1 and the recently described multidrug resistance-associated protein (MRP) in normal lymphohematopoietic cells and in 62 bone marrow aspirates of newly diagnosed and recurrent acute leukemia. Levels of MRP expression in newly diagnosed AML samples were similar to those observed in normal bone marrow cells (CD34-negative and CD34-positive) and in unselected HL60 human promyelocytic leukemia cells, which were used as an internal control throughout this study. In contrast, samples of AML obtained at the time of relapse contained approximately twofold higher levels of MRP RNA (P < .01). Analysis of paired samples, the first obtained at diagnosis and the second at relapse, from 13 acute myelogenous leukemia (AML) and four acute lymphocytic leukemia (ALL) patients showed that MRP expression was increased at the time of relapse in greater than 80% of patients. In contrast, no consistent changes of MDR1 expression at relapse were observed. These results raise the possibility that increased MRP expression might contribute to leukemic relapse.
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PMID:Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia. 752 66

High spontaneous proliferation of acute myeloid leukemia (AML) in vitro is an unfavorable, tumor-specific prognostic factor. We investigated the frequency of drug-resistant tumor cells with high proliferating capacity in de novo AML and analyzed the expression of multiple resistance parameters in relation to the response to chemotherapy and overall survival. Thirty-eight patients were included in this study. P-glycoprotein (P-gp) expression was found in 28/38 patients and was associated with lower intracellular accumulation of DNR (P = 0.0001). Thirty-five out of 38 patients were treated with 1-2 regimens of daunorubicin (DNR)/cytarabine (Ara-C), and 57% attained a complete remission (CR). Failure to achieve a CR correlated with autonomous growth (P = 0.0064), CD34 and P-gp expression alone (P = 0.0005 and P = 0.048 respectively), and with simultaneous expression of P-gp and CD34 (P = 0.0001), but not with expression of the non-P-gp drug resistance associated-protein (p110), the multidrug resistance-associated protein (MRP), Ara-CTP formation or Ara-C incorporation, respectively. AML cells with CD34/P-gp double expression were more frequently observed in samples with high autonomous growth (P = 0.003). The median survival was 6 months in CD34+/P-gp+ patients as compared with 15 months in other AML patients (P = 0.003). In patients with de novo AML who fail on chemotherapy, a population of autonomously proliferating, immature AML cells with a multidrug resistant phenotype can be recognized. These cells thus show primary resistance to chemotherapy and have the potential for rapid regrowth, leading to resistant disease.
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PMID:Multidrug resistant cells with high proliferative capacity determine response to therapy in acute myeloid leukemia. 754 Oct 95

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.
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PMID:Expression of the multidrug resistance-associated protein (MRP) in acute leukaemia. 780 5

We determined the expression of the multidrug resistance-associated protein (MRP), a new putative transmembrane drug transporter, in peripheral blood cells from healthy volunteers as well as from 60 patients with acute or chronic leukemia, using an RNase protection assay. MRP appeared to be ubiquitously expressed at low levels in all nonmalignant hemopoietic cell types, reflecting its basal constitutive expression. In acute myelocytic leukemia (AML) (n = 16), one of nine untreated patients and two of seven patients with prior chemotherapy showed significant hyperexpression of MRP. In chronic lymphocytic leukemia (CLL) (n = 21), either treated (n = 8) or untreated (n = 13), a high percentage (15 of 21: 71% had relatively high expression levels of the MRP gene. In contrast, low MRP expression levels were detected in acute lymphocytic leukemia (n = 14), and in chronic myelocytic leukemia (n = 9). DNA analysis by Southern blotting did not reveal amplification of the MRP gene in the leukemia samples, including those with elevated MRP mRNA levels. We conclude that relatively high expression of MRP is occasionally observed in AML and at high frequency in CLL, irrespective of treatment, probably due to transcriptional activation and/or increased mRNA stability.
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PMID:Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias. 791 48

The multidrug resistance-associated protein (MRP) gene is a member of the ATP-binding cassette transporter gene superfamily and may be partially responsible for clinical drug resistance. Reverse transcriptase-polymerase chain reaction was used to measure MRP mRNA in normal hematopoietic cells from bone marrow and peripheral blood as well as patients with high risk acute myelocytic leukemia and multiple myeloma. All normal peripheral blood cells, regardless of cell lineage (CD4, CD8, CD14, CD15, CD19, CD56), expressed a similar basal level of MRP mRNA. Specimens from bone marrow containing mixed lineages also expressed a similar basal level of MRP expression. In patients with acute myelocytic leukemia, 10 of 12 (83%) of the specimens had detectable MRP mRNA, but the level of expression was similar to that of normal blood cells and low compared to a cell line known to overexpress MRP (H69/AR). All myeloma patients (12 of 12) had detectable MRP mRNA expression at levels comparable to normal peripheral blood and bone marrow cells. We conclude that MRP is commonly expressed in normal hematopoietic cells as well as certain hematopoietic malignancies. The therapeutic relevance of MRP expression is unknown, but these studies emphasize the importance of measuring MRP expression in normal cells as a point of reference and comparison for detection in malignant cells. We also recommend obtaining sequential specimens from patients, which may reveal an increased expression of MRP from baseline as the disease progresses and becomes resistant.
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PMID:Analysis of multidrug resistance-associated protein (MRP) messenger RNA in normal and malignant hematopoietic cells. 806 63

A specific and quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay was developed for measuring the mRNA of the multidrug resistance-associated protein (MRP). A region corresponding to bp 3897-4471 of MRP cDNA is amplified, which encompasses approximately half of the second nucleotide-binding domain (NBD2). In two multidrug resistant (MDR) sublines of the HL-60 human acute myeloid leukemia (AML) cell line which overexpress MRP but not P-glycoprotein, the assay detects elevated levels of MRP mRNA (4- to 8-fold) relative to the drug-sensitive parental cells (designated HL-60/W). Blast cells from 24 patients with AML were also studied for MRP expression using this RT-PCR method. Expression of MRP was normalized for that of beta-actin in the blast cells, which was also determined by RT-PCR. All of these blast cell samples had MRP expression that was detectable after 35 PCR cycles. Eighteen of these patients samples had levels of expression of MRP mRNA equal to or less than that expressed by HL-60/W cells. In six patient blast cell specimens, the expression of MRP mRNA was up to 1.7-fold higher than that of HL-60/W cells. In 21 specimens, the steady-state intracellular accumulation of daunorubicin (1 microgram/ml, 3h) was also determined. The blast cells with MRP mRNA expression higher than HL-60/W had a lower median accumulation of daunorubicin compared to those whose MRP expression was less than HL-60/W, suggesting a functional defect in drug transport in the cells with higher MRP expression; a similar trend toward lower daunorubicin accumulation was also noted in the one-third of samples that displayed the highest expression of MDR1 mRNA (also determined by RT-PCR). These studies illustrate the range of expression of MRP in AML blast cell specimens. The identification of MRP overexpression in MDR AML cell lines and in some AML patient blast cells with low intracellular daunorubicin accumulation warrants further study of MRP as a component of clinical drug resistance in AML.
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PMID:Expression of multidrug resistance-associated protein (MRP) mRNA in blast cells from acute myeloid leukemia (AML) patients. 855 37

Homoharringtonine (HHT) is a cytotoxic alkaloid isolated from the evergreen tree cephalotaxus harringtonia native to the southern provinces of China. The principal mechanism of action of HHT is the inhibition of protein synthesis in a dose- and time-dependent manner by acting on the ribosomes of cancer cells. It blocks the progression of cells from G1 phase into S phase and from G2 phase into M phase. It is synergestic or additive in vitro with AraC, amsacrine, actinomycin D and dexamethasone. Clinical studies have indicated that HHT is effective in treating acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS), but not acute lymphoblastic leukemia (ALL) and solid tumors. The dose limiting toxicities are hypotention and myelosuppression. Homoharringtonine has relatively mild extramedullary toxicities and no anthracycline-like cardiac toxicity, which make it a suitable candidate for the treatment of aged patients. Pharmacological studies indicate that HHT belongs to the category of multidrug resistance (MDR)-related drugs. The cells resistant to HHT are cross-resistant to anthracycline, vinca alkaloids, mitoxantrone, but not cis-platine and AraC. Multiple mechanisms, including the sequential emergence of overexpression of multidrug resistance-associated protein (MRP) and MDR1 genes, are involved in the cross-resistance of tumor cells to HHT.
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PMID:Homoharringtonine: an effective new natural product in cancer chemotherapy. 874 64

We studied the expression of multidrug resistance-associated protein (MRP) in normal haemopoietic cells from peripheral blood and bone marrow. The MRP mRNA levels were estimated by RT/PCR and in situ hybridization (ISH) assay, and the protein levels by flow cytometry. 21 samples of peripheral blood and 21 samples of bone marrow (11 normal bone marrow donors, 10 patients in complete remission after chemotherapy for large cell lymphoma or acute myeloid leukaemia) were analysed. In peripheral blood the mean MRP mRNA level in CD3+ cells was statistically higher than in the other cells (3-fold by the methods used). The levels of MRP in CD3+ varied from one individual to another (4.5-34.8 units by RT/PCR and 5-23 grains/cell by ISH); however, this was proportional to the variation in all the cell lineages of same individual (r = 0.84). In bone marrow the mean MRP levels of the various cell lineages (including CD34+) were similar to the basal level in HL60 cells. Individual expression levels were again variable; however, there was no difference between untreated normal bone marrow and post chemotherapy normal bone marrow. MRP protein expression was determined by flow cytometry with the monoclonal antibody MRPm6. The CD4+ lymphocytes exhibited a higher MRP protein expression than the other cell lineages, including CD8+ cells. There was a good correlation between the three methods used (RT/PCR and ISH, P = 0.0001, r = 0.87; RT/PCR and flow cytometry, P = 0.0001, r = 0.85; ISH and flow cytometry, P = 0.002, r = 0.67).
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PMID:Expression of the multidrug resistance-associated protein (MRP) mRNA and protein in normal peripheral blood and bone marrow haemopoietic cells. 875 4

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating sequestration of the drugs into intracellular compartments, both leading to a reduction in effective intracellular drug concentrations. For the classical MDR phenotype, evidence is accumulating that it plays a role indeed, in clinical drug resistance, especially in some hematological malignancies (acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma) and solid tumors (soft tissue sarcomas and neuroblastoma). The association of MRP with clinical drug resistance has not been elaborated, yet, and studies on MRP expression in human cancer have just begun. We found that overexpression of MRP, as determined by RNase protection assay as well as by immunohistochemistry, occurs in several human cancers, among which are cancer of the lung, esophagus, breast and ovary, and leukemias. Further studies are indicated to establish whether elevated MRP expression at diagnosis is an unfavorable prognostic factor for clinical outcome of chemotherapy.
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PMID:Molecular mechanisms of multidrug resistance in cancer chemotherapy. 888 Aug 78


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