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)

A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including failure of the cell to undergo apoptosis in response to chemotherapy, or failure of the drug to reach and/or affect its intracellular target. This review focuses on the latter mechanism, and on intracellular drug transport resistance mechanisms in particular. Expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) has generally been reported to correlate with prognosis in acute myeloid leukemia (AML). Additionally, but more controversial, expression of the ABC transporter multidrug resistance protein (MRP) and the vault-transporter lung resistance protein (LRP) have been correlated with outcome in AML. Despite these findings, functional efflux assays indicate the presence of non-Pgp, non-MRP transporters in AML. Recently, a novel ABC transporter, breast cancer resistance protein (BCRP) was cloned and sequenced in our laboratory. Transfection and overexpression of BCRP in drug-sensitive cells confers drug-resistance to the cells. BCRP is a half-transporter, and may homodimerize or form heterodimers (with a yet unknown half-transporter) to produce an active transport complex. Relatively high expression of BCRP mRNA is observed in approximately 30% of AML cases, suggesting a potential role for this new transporter in drug resistance in leukemia.
Leukemia 2000 Mar
PMID:Novel mechanisms of drug resistance in leukemia. 1072 Jan 43

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

U-937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P-glycoprotein (Pgp), encoded by the multidrug-resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug-resistance-associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin-resistant cell lines were selected. Both drug-resistant cell lines upregulated the MVP mRNA level 1.5-fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug-selected cells. MVP induction is therefore the rate-limiting step for vault particle formation in U-937 cells. By passage 25 and thereafter, the selected cells were resistant to doxorubicin, etoposide, mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1, MRP1, MRP2 and breast cancer resistance protein. In summary, U-937 doxorubicin-selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant.
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PMID:A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells. 1177 57

The breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MXR) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). BCRP has been detected in acute myeloid leukaemia and in breast, colon and gastric cancer but there has been no reports regarding BCRP expression in acute lymphoblastic leukaemia (ALL). We report the first results of BCRP expression in childhood ALL. Sixty-seven children (47 initial stage, 20 relapses) with ALL were analysed for BCRP gene expression by TaqMan real-time polymerase chain reaction. The expression of BCRP in mononuclear cells obtained from the bone marrow (BM) and peripheral blood (PB) of healthy donors was also investigated. There was no relationship between BCRP expression and age, sex, initial blast cell count, prednisolone response or BM response on d 15 and 33. Patients with T-lineage ALL showed a lower expression of BCRP (P = 0.044). Kaplan-Meier analysis of the relapse-free interval showed no prognostic significance of BCRP expression when different levels of BCRP expression were used as cut-off points. No significant difference in expression of BCRP mRNA was measured between initial-stage and relapsed-stage ALL or between normal MNC obtained from BM and ALL patients. The results indicate a low expression of BCRP in childhood ALL. Relationships between BCRP and clinical, molecular or in vivo resistance characteristics of the patients were not observed.
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PMID:Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia. 1210 Jan 41

Breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MRX) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). Transfection and enforced expression of BCRP in drug-sensitive cells confers resistance to mitoxantrone, doxorubicin, daunorubicin and topotecan. In this study the expression of BCRP gene was measured using TaqMan real-time PCR in 59 children with newly diagnosed AML. Nine patients were also analyzed in relapse. The median of BCRP gene expression was more than 10 times higher in patients who did not achieve remission after the first phase of chemotherapy (n = 24) as compared to patients who did achieve remission at this stage (n = 21; P = 0.012). In first relapse the expression of the BCRP gene was higher than at diagnosis (P = 0.038). Although high levels of BCRP gene expression were more frequent in subtypes of AML with a favorable prognosis, we found that within both risk groups (high and low risk), patients who expressed high levels of BCRP had a worse prognosis (P = 0.023). Our results strongly suggest that the expression of the BCRP gene reduces the response to chemotherapy in AML and that BCRP expression is higher at the time of relapse.
Leukemia 2002 Aug
PMID:BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. 1214 83

Our study examines the ability of LY335979 (Zosuquidar trihydrochloride) to modulate 3 distinct ABC transporters that are mechanisms of drug resistance: P-glycoprotein (Pgp, ABCB1), multidrug resistance associated protein (MRP1, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). Pgp-mediated resistance can be modulated by coadministration with the highly potent, selective inhibitor, LY335979. Modulation of resistance by mitoxantrone and vinorelbine, 2 drugs used to treat certain solid tumors, was examined in a 3-day cytotoxicity assay using a panel of HL60 leukemia cell lines or MCF-7 breast cancer transfectants. LY335979, at 0.5 microM, substantially reversed mitoxantrone resistance and fully reversed vinorelbine resistance of Pgp-expressing HL60/Vinc cells. However, LY335979 did not modulate drug resistance in the MRP1-expressing HL60/ADR or drug-sensitive parental HL60 cells. To ascertain if LY335979 modulates BCRP-mediated drug resistance, the sensitivity of 26-fold mitoxantrone resistant, BCRP-transfected MCF-7 cells was evaluated. Addition of 5 microM LY335979, a concentration approximately 100-fold higher than the affinity of Pgp, had little to no effect on the BCRP transfectant. [(125)I]Iodomycin photolabeled Pgp in CEM/VLB(100) membranes and was inhibited by 5 microM LY335979 and GF120918. No photolabeling of MRP or BCRP occurred in H69AR or MCF-7/BCRP membranes, respectively. These results further demonstrate that LY335979 is highly specific for Pgp and does not modulate MRP1- or BCRP-mediated resistance and can be used in combination with mitoxantrone and vinorelbine in tumor cells.
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PMID:Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. 1245 64

We studied the molecular basis of the up to 46-fold increased accumulation of folates and methotrexate (MTX) in human leukemia CEM-7A cells established by gradual deprivation of leucovorin (LCV). CEM-7A cells consequently exhibited 10- and 68-fold decreased LCV and folic acid growth requirements and 23-25-fold hypersensitivity to MTX and edatrexate. Although CEM-7A cells displayed a 74-86-fold increase in the reduced folate carrier (RFC)-mediated influx of LCV and MTX, RFC overexpression per se cannot induce a prominently increased folate/MTX accumulation because RFC functions as a nonconcentrative anion exchanger. We therefore explored the possibility that folate efflux activity mediated by members of the multidrug resistance protein (MRP) family was impaired in CEM-7A cells. Parental CEM cells expressed substantial levels of MRP1, MRP4, poor MRP5 levels, whereas MRP2, MRP3 and breast cancer resistance protein were undetectable. In contrast, CEM-7A cells lost 95% of MRP1 levels while retaining parental expression of MRP4 and MRP5. Consequently, CEM-7A cells displayed a 5-fold decrease in the [(3)H]folic acid efflux rate constant, which was identical to that obtained with parental CEM cells, when their folic acid efflux was blocked (78%) with probenecid. Furthermore, when compared with parental CEM, CEM-7A cells accumulated 2-fold more calcein fluorescence. Treatment of parental cells with the MRP1 efflux inhibitors MK571 and probenecid resulted in a 60-100% increase in calcein fluorescence. In contrast, these inhibitors failed to alter the calcein fluorescence in CEM-7A cells, which markedly lost MRP1 expression. Replenishment of LCV in the growth medium of CEM-7A cells resulted in resumption of normal MRP1 expression. These results establish for the first time that MRP1 is the primary folate efflux route in CEM leukemia cells and that the loss of folate efflux activity is an efficient means of markedly augmenting cellular folate pools. These findings suggest a functional role for MRP1 in the maintenance of cellular folate homeostasis.
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PMID:Loss of multidrug resistance protein 1 expression and folate efflux activity results in a highly concentrative folate transport in human leukemia cells. 1248 26

The recent treatment of hematological malignancies appears to be unsatisfactory in child and adult patients with acute myeloid leukemia and adult patients with acute lymphocytic leukemia. A major problem in the treatment of leukemia is caused by the development of drug resistance to chemotherapeutic agents, which is already present at diagnosis or after chemotherapy as a minimal residual disease, their resistance having originated from genetic or epigenetic mutations during prior growth of the leukemia clone. It was suggested that the mechanisms of drug resistance consist of drug resistance proteins, which work as a drug efflux pump. These are the permeability-related glycoprotein (P-Gp), the multidrug-resistance associated protein (MRP), the lung resistance protein (LRP), and other MDR proteins such as the transporter associated with antigen processing (TAP), anthracyclin resistance associated protein (ARA), MRP 2-7, and breast cancer resistance protein (BCRP). In addition, anti-apoptosis mechanisms, alterations of tumor suppressor genes, altered immunogenicity, drug resistance mechanisms for individual drugs, and clinical risk factors such as white blood cell count, age, and other factors have been reported to act in drug resistance singly or in combinations. Here we describe the update of research on the biology of MDR in the hematological malignancies and also discuss how to overcome MDR and adapt the updated treatment methods in the clinical medical field.
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PMID:Multidrug resistance in hematological malignancy. 1367 81

Infants with acute lymphoblastic leukemia (ALL) are more resistant to chemotherapeutic drugs than older children with ALL, except for Ara-C. Drug resistance mechanisms in infant ALL, however, remain unknown. Possibly, multidrug resistance (MDR) proteins like P-glycoprotein, MDR-associated protein (MRP1), lung resistance-related protein (LRP/MVP) and the breast cancer resistance protein (BCRP) play a role. Accordingly, we measured the mRNA levels of these proteins in infants (n=13) and non-infants (n=13) with ALL, using quantitative RT-PCR. Infants expressed 2.4-fold less BCRP mRNA (P=0.009) than non-infants with ALL. MDR1, MRP1 and LRP/MVP expression did not differ between both groups. MDR gene expression levels did not correlate to prednisolone, vincristine, daunorubicin or Ara-C cytotoxicity, except for BCRP expression, which correlated with resistance to Ara-C (Rs=0.53, P=0.012), suggesting that Ara-C might be a BCRP substrate. However, culturing patients ALL cells in the presence of the BCRP inhibitor Ko143 had no effect on Ara-C sensitivity. Inhibiting Bcrp1 in the Mdr1a-, Mdr1b- and Mrp1-deficient and Bcrp1-overexpressing mouse cell line Mef3.8/T6400, also did not modulate Ara-C cytotoxicity. Therefore, we conclude that Ara-C is not a substrate for BCRP and that MDR proteins do not play a significant role in drug resistance in infant ALL.
Leukemia 2004 Jan
PMID:Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein. 1457 27

Data on breast cancer resistance protein (BCRP, MXR, ABCG2) expression in acute myeloid leukemia (AML) have been inconsistent, possibly due to use of different assays in different studies. BCRP mRNA was studied by the reverse-transcription polymerase chain reaction and BCRP protein expression (BXP-21, BXP-34 or anti-ABCG2 antibody, with anti-CD34 and anti-CD33) and function (fumitremorgin C modulation of mitoxantrone retention) by flow cytometry in eight cell lines and in pretreatment blasts from 31 AML patients. BCRP mRNA levels, antibody staining and function correlated strongly in cell lines (Pearson r values, 0.73-0.97), but not in AML samples. AML sample BCRP mRNA levels were between those in parental 8226 and 35-fold mitoxantrone-resistant 8226/MR20 cells in all but one case, and BCRP mRNA had the wild-type sequence at codon 482 in all. In AML, unlike in cell lines, BCRP protein expression or function, when present, was only detected in small subpopulations. BCRP mRNA and protein expression did not correlate, nor did staining with different BCRP antibodies, and function did not correlate with mRNA nor protein expression. Presence of BCRP only in subpopulations and discordance among BCRP measurements suggest complex biology of BCRP in AML and incomplete modeling by cell lines.
Leukemia 2004 Jul
PMID:Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function. 1520 43


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