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)

The in vitro intracellular daunorubicin accumulation (IDA) of blast cells from 69 patients with newly diagnosed acute myeloid leukaemia (AML) was correlated with the expression and functional activity of the multidrug resistance (MDR) proteins, P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP). An inverse and significant association was found between IDA and Pgp-related efflux activity (r = -0.31, P = 0.01) and also MRP (r = -0.25, P = 0.04) but not with LRP (r = -0.13, P = 0.28). Coexpression of the MDR proteins had an additive effect in further lowering of IDA levels, suggesting that the clinical MDR phenotype is dependent on the sum of multiple MDR factors available to the leukaemic cell. Thus, the median IDA of leukaemic cells without any MDR proteins was significantly higher than that of blasts carrying two MDR proteins (0.466 vs. 0.296, P = 0.046). Seven patients with no expression of Pgp, MRP and LRP still had low IDA levels, suggesting the presence of efflux MDR mechanisms other than those studied. The relation of IDA to clinical parameters known to be associated with poor prognosis, such as age, secondary AML, karyotype, peripheral blood blast and CD34 counts, was also studied, but no significance was found on multifactorial analysis. There was a non-significant trend for earlier relapse in patients with low IDA levels (leukaemia-free survival of 16.3 months compared with 21.1 months in patients with high IDA levels). Our data suggest that, while the IDA assay is a quick and relatively easy test for the combined efflux MDR phenotype, it is unable to detect other MDR mechanisms, such as LRP, which may be important to the clinical outcome of patients with AML.
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PMID:P-glycoprotein and multidrug resistance-associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myeloid leukaemic cells. 1065 23

Immunophenotype might be an important indicator for multidrug resistance (MDR) profiles in childhood acute lymphoblastic leukemia (ALL). The authors analyzed the messenger RNA (mRNA) levels of MDR1, multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP) by reverse transcriptase-polymerase chain reaction (RT-PCR) in childhood pre-B ALL, T-cell ALL, and acute nonlymphoblastic leukemia (ANLL). Results showed that MRP and LRP, but not MDR1, mRNAs are overexpressed, particularly in children with pre-B ALL compared with T-cell ALL and ANLL tested. In addition, the MRP and LRP mRNA expression levels in initial diagnosis and first relapse samples of one patient with pre-B ALL were similar. Consequently, these preliminary results suggest that the expression of these MDR-related genes in childhood ALL might be regulated differently in a lineage dependent manner.
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PMID:Increased expression of lung resistance-related protein and multidrug resistance-associated protein messenger RNA in childhood acute lymphoblastic leukemia. 1069 21

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 may be conferred by P-glycoprotein (Pgp, ABCB1) or the multidrug resistance associated protein (MRP). These membrane proteins are members of the ATP binding cassette transporter superfamily and are responsible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among the most potent modulators of Pgp with a Ki of 59 nM. LY335979 is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 (ABCC1) and MRP2 (ABCC2). LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide. Coadministration of LY335979 with paclitaxel compared to paclitaxel alone significantly reduced the tumor mass of the Pgp-expressing UCLA-P3.003VLB lung carcinoma in a xenograph model and delayed the development of tumors in mice implanted with the parental drug-sensitive UCLA-P3 tumor. LY335979 was without significant effect on the pharmacokinetics of these anticancer agents. This may be due impart to its poor inhibition of four major cytochrome P450 isozymes important in metabolizing doxorubicin and other oncolytics. The selectivity and potency of this modulator allows the clinical evaluation of the role of Pgp in multidrug resistance. LY335979 is currently in clinical trials.
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PMID:Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. 1117 91

Multidrug resistance parameters, tissue infiltration parameters, receptors for colony-stimulating factors (CSFr) and cell cycle parameters were analyzed using flow cytometry in 145, 109 initial and 36 relapsed or refractory, acute nonlymphoblastic leukemia (ANLL) patients to find out clinically more reliable functional parameters. Lung resistance-associated protein (LRP) was most frequently expressed in ANLL (44.1%) followed by P-glycoprotein (PGP) (35.9%) and multidrug resistance-associated protein (MRP) (8.3%). LRP and PGP were expressed more frequently in relapsed or refractory ANLL than initial ANLL cases. Complete remission rate after standard chemotherapy falls in PGP-positive cases (p = 0.001). CD44-positive ANLL cases relapsed more frequently. The organ tropism is different depending on the infiltration parameters, vascular cell adhesion molecule to splenomegaly, matrix metalloprotease-2 to hepatomegaly and to extramedullary infiltration other than spleen, liver or lymph node. The percentage of the granulocyte-macrophage-CSFr expression was high in M4 and M5, and granulocyte-CSFr-positive ANLL showed less extramedullary infiltration (p = 0.007) and more PGP expression. Ki-67 was expressed significantly less in refractory ANLL than initial ANLL and DNA topisomerase IIalpha was expressed significantly more in the surviving patients group. In conclusion, analysis of these new functional parameters could help to predict and overcome the clinical behavior of each ANLL at the time of diagnosis.
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PMID:Expression of functional markers in acute nonlymphoblastic leukemia. 1127 7

P-glycoprotein (P-gp), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression, and blast cell intracellular daunorubicin accumulation (IDA) were evaluated in 95 previously untreated cases of adult acute lymphoblastic leukaemia (ALL) using flow cytometry. Forty-five out of 95 (47%) patients were P-gp positive (+), 12/66 (18%) were LRP+ and 11/66 (17%) were MRP+. Eighteen out of 66 (28%) patients showed a simultaneous multidrug resistance (MDR)-related protein expression higher than controls for more than one protein, while 24/66 (36%) cases did not overexpress any protein. Twenty-one out of 24 (87%) cases overexpressing at least one MDR-related protein had a defect in accumulating daunorubicin into their blast cells, while only 4/24 (16%) cases who did not overexpress any protein had similar features. The complete remission rates were similar in MDR-positive and -negative (-) patients but relapses within 6 months were more frequent in P-gp+ cases, and therefore the disease-free survival duration was shorter in P-gp+ than in P-gp- patients (P = 0.01). The number of MRP+ and/or LRP+ cases was too small to be able to draw any conclusion on their role in affecting or predicting therapy outcome. In conclusion, P-gp overexpression associated with a defect in daunorubicin accumulation is a frequent feature in adult ALL at onset and seems to be related to poorer therapy outcome and, consequently, a shorter disease-free survival. LRP and MRP overexpression seems to be a rare event and no conclusion can be drawn on its prognostic role.
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PMID:P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia. 1184 7

A major problem in the treatment of leukemia is the development of resistance to chemotherapeutic agents. Assessing the drug resistance of leukemic cells is therefore an important aspect of treatment. One of the main mechanisms of resistance is rapid drug efflux mediated by various members of the ATP-binding cassette transporter superfamily, such as multidrug resistance gene 1 (MDR1), which encodes P-glycoprotein, multidrug resistance-associated protein (MRP) 1 and lung resistance protein. To quantify the degree of acquisition of resistance, several techniques, including drug-sensitivity studies, flow cytometry assay and quantitative gene analysis, have been developed to detect MDR1 and MRP1 gene expression in leukemic cells. However, a significant number of patients may relapse in spite of low expression of MDR1 or MRP1, suggesting the involvement of other intracellular mechanisms, possibly related to cytarabine resistance. This review focuses on the methods aimed at the assessment of drug resistance in acute myeloid leukemia.
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PMID:Assessment of drug resistance in acute myeloid leukemia. 1534 63

Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.
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PMID:Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. 1597 Jun 68

Multidrug resistance is a major obstacle to cancer treatment and leads to poor prognosis for the patient. Multidrug resistance-associated protein 1 (MRP1) can confer drug resistance in vitro and MRP1 may play a role in the development of drug resistance in several cancers including acute myeloid leukaemia, small cell lung cancer, T-cell leukaemia and neuroblastoma. The majority of patients with neuroblastoma present with widely disseminated disease at diagnosis and despite intensive treatment, the prognosis for such patients is dismal. There is increasing evidence for the involvement of the MYCN oncogene, and its down-stream target, MRP1, in the development of multidrug resistance in neuroblastoma. Given the importance of MRP1 overexpression in neuroblastoma, MRP1 inhibition may be a clinically relevant approach to improving patient outcome in this disease.
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PMID:The role of the multidrug resistance-associated protein 1 gene in neuroblastoma biology and clinical outcome. 1597 85

Over the past decades, numerous reports have covered the crucial role of multidrug resistance (MDR) transporters in the efficacy of various chemotherapeutic drugs. Specific cell membrane-associated transporters mediate drug resistance by effluxing a wide spectrum of toxic agents. Although several excellent reviews have addressed general aspects of drug resistance, this current review aims to highlight implications for the efficacy of folate-based and other types of chemotherapeutic drugs. Folates are vitamins that are daily required for many biosynthetic processes. Folate supplementation in our diet may convey protective effects against several diseases, including cancers, but folate supplementation also makes up an essential part of several current cancer chemotherapeutic regimens. Traditionally, the folate leucovorin, for instance, is used to reduce antifolate toxicity in leukemia or to enhance the effect of the fluoropyrimidine 5-fluorouracil in some solid tumors. More recently, it has also been noted that folic acid has the ability to increase antitumor activity of several structurally unrelated regimens, such as alimta/pemetrexed and cisplatin. Moreover, studies from our laboratory demonstrated that folates could modulate the expression and activity of at least two members of the MDR transporters: MRP1/ABCC1, and the breast cancer resistance protein BCRP/ABCG2. Thus, folate supplementation may have differential effects on chemotherapy: (1) reduction of toxicity, (2) increase of antitumor activity, and (3) induction of MRP1 and BCRP associated cellular drug resistance. In this review the role of MDR proteins is discussed in further detail for each of these three items from the perspective to optimally exploit folate supplementation for enhanced chemotherapeutic efficacy of both antifolate-based chemotherapy and other classes of chemotherapeutic drugs.
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PMID:Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment. 1636 98


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