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 monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein-negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.
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PMID:Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. 863 Apr 12

Since some multidrug-resistant (MDR) tumor cell lines show drug accumulation defects but do not over-express Pgp or MDR protein (MRP), a search was made for novel MDR-related transporter proteins by immunizing rats with non-small cell lung cancer SW- 1573/2R120 cells to produce monoclonal antibodies (MAbs). Five rat MAbs (LMR-4, -12, -42, -44 and -94) were generated, showing strong membranous staining of non-Pgp MDR SW- 1573/2R120 tumor cells and minimal reactivity to the corresponding parental and revertant cell lines. In addition, a 6th MAb (LMR-5) was isolated, recognizing the MDR-related lung resistance protein (LRP), previously identified as the major vault protein. The first 5 LMR MAbs show predominantly membranous staining of several non-Pgp MDR tumor cell lines of different histogenetic origins, except for LMR-4, which recognizes only MDR sublines of the SW- 1573 cell line. Flow-cytometric analysis revealed that all MAbs, except LMR-4 and -5, detect outside epitopes. Functional studies showed that these MAbs did not restore the daunorubicin accumulation defect. All but one of the MAbs (LMR-42) showed staining of distinct normal human tissues, notably epithelial cells lining the airways and digestive tract. In addition, staining of vascular endothelial cells was found with all MAbs except LMR-4. Three MAbs (LMR-12, -44 and -94) showed remarkable immunoreactivity with vincristine-selected SW- 1573 sublines. By immunoblotting and precipitation, the LMR antigens were found to be in the 42-69 kDa range.
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PMID:Identification of novel drug resistance-associated proteins by a panel of rat monoclonal antibodies. 933 51

Resistance to natural product-derived anti-cancer drugs, such as the anthracyclines and etoposide, contributes to the failure of chemotherapeutic treatment of leukaemia. One biological resistance mechanism of potential importance is the overexpression of the plasma membrane drug transporter proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP). Many studies have reported evidence for a correlation of Pgp/MDR1 expression with unfavourable prognostic features in acute myeloid leukaemia (AML). Failure to achieve complete remission (CR) is correlated with Pgp and the CD34+ phenotype. For MRP fewer data are available, which suggest a basal expression level in most AMLs. Another protein reported to correlate with treatment failure in AML is the lung resistance protein or major vault protein (LRP), a protein with a still unknown function. Co-expression of Pgp and LRP especially seems to define an adverse prognostic population. Further progress towards the understanding of the clinical importance of these proteins is hampered by the lack of validation of methods to determine their expression. A reliable way to measure Pgp seems to be the assessment of the active transport of fluorescent Pgp substrates, such as rhodamine 123 out of AML cells. Such functional Pgp assays can be used to validate mRNA or protein measurements and to quantify the effect of Pgp or the magnitude of the effect of a blocker of the Pgp-mediated drug efflux on the intracellular drug concentration. The prognostic value of such methods has still to be shown.
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PMID:Transport proteins in drug resistance: detection and prognostic significance in acute myeloid leukemia. 935 Jan 97

The discovery of the Multidrug Resistance-associated Protein (MRP or MRP1) as a GS-X pump able to transport both anionic drug conjugates and unmodified anti-cancer drugs out of the cell, has raised the question whether other members of the MRP family might contribute to drug resistance of human tumours. The most extensively studied member of this family is cMOAT, the canalicular Multispecific Organic Anion Transporter. The substrate specificity of this pump was originally defined by an inborn error in rats, lacking this protein. These rats are mildly hyperbilirubinemic, because of their inability to secrete bilirubin glucuronides into their bile. In addition, they have diminished capacity to secrete a variety of other organic anions. Absence of cMOAT in humans results in an analogous inborn error of metabolism, the Dubin-Johnson syndrome. Attempts to determine the effect of cMOAT on the sensitivity of cells to anti-cancer drugs have run into technical problems. Most cells transfected with a cMOAT cDNA construct and overproducing cMOAT seem unable to transport the protein to the cell surface and are not MDR. However, in polarized kidney cell monolayers cMOAT is correctly routed to the apical cell surface and able to transport vinblastine. Hence, overexpression of cMOAT in cancer cells could potentially lead to drug resistance. In studies of cells selected for drug resistance no correlation was found thus far between cMOAT overexpression and MDR, but there was a positive association with cisplatin resistance, raising the possibility that cMOAT might contribute to cisplatin resistance by mediating excretion of cisplatin-glutathione complexes. This remains to be verified by more direct experiments and clinical studies, however. Database searches have yielded four additional MRP family members, MRP3-6. The physiological functions of these putative transporters are not yet known and whether they can contribute to drug resistance needs to be determined. Another putative transporter found in many MDR cells not overproducing P-glycoprotein is the Lung Resistance Protein (LRP), which is the major vault protein. Scheper et al have detected LRP in many MDR cell lines and they have shown that elevated LRP values are a strong and independent predictor of unfavourable outcome for several types of drug-treated human tumours. LRP is a cytoplasmic protein and attempts to demonstrate its involvement in drug transport have failed thus far. The possibility that this protein is only an indicator of resistance caused by upregulation of other proteins, rather than a drug transporter, remains open.
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PMID:Do cMOAT (MRP2), other MRP homologues, and LRP play a role in MDR? 944 49

Cellular drug resistance is related to a poor prognosis in childhood leukemia, but little is known about the underlying mechanisms. We studied the expression of P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein (MRP), and major vault protein/lung resistance protein (LRP) in 141 children with acute lymphoblastic leukemia (ALL) and 27 with acute myeloid leukemia (AML) by flow cytometry. The expression was compared between different types of leukemia and was studied in relation with clinical risk indicators and in vitro cytotoxicity of the MDR-related drugs daunorubicin (DNR), vincristine (VCR), and etoposide (VP16) and the non-MDR-related drugs prednisolone (PRD) and L-asparaginase (ASP). In ALL, P-gp, MRP, and LRP expression did not differ between 112 initial and 29 unrelated relapse samples nor between paired initial and relapse samples from 9 patients. In multiple relapse samples, LRP expression was 1.6-fold higher compared with both initial (P = .026) and first relapse samples (P = .050), which was not observed for P-gp and MRP. LRP expression was weakly but significantly related to in vitro resistance to DNR (Spearman's rank correlation coefficient 0.25, P = .016) but not to VCR, VP16, PRD, and ASP. No significant correlations were found between P-gp or MRP expression and in vitro drug resistance. Samples with a marked expression of two or three resistance proteins did not show increased resistance to the tested drugs compared with the remaining samples. The expression of P-gp, MRP, and LRP was not higher in initial ALL patients with prognostically unfavorable immunophenotype, white blood cell count, or age. The expression of P-gp and MRP in 20 initial AML samples did not differ or was even lower compared with 112 initial ALL samples. However, LRP expression was twofold higher in the AML samples (P < .001), which are more resistant to a variety of drugs compared with ALL samples. In conclusion, P-gp and MRP are unlikely to be involved in drug resistance in childhood leukemia. LRP might contribute to drug resistance but only in specific subsets of children with leukemia.
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PMID:Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. 949 Jun 95

Vaults are 13-MDa ribonucleoprotein particles composed largely of a 104-kDa protein, termed major vault protein or MVP, and a small vault RNA, vRNA. While MVP levels have been found to increase up to 15-fold in non-P-glycoprotein multidrug-resistant cell lines, the levels of vault particles have not been investigated. As both the function of vault particles and the mechanism of drug resistance in non-P-glycoprotein cells are unknown, we decided to determine whether vault synthesis was coupled to MDR. By cloning the human gene for vRNA and careful quantitation of the MVP and vRNA levels in MDR cells, we find that vRNA is in considerable excess to MVP. Sedimentation measurements of vault particles in multidrug resistance cells have indeed revealed up to a 15-fold increase in vault synthesis, coupled with a comparable shift of associated vRNA, demonstrating that vault formation is limited by expression of MVP or the minor vault proteins. The observation that vault synthesis is linked directly to multidrug resistance supports a direct role for vaults in drug resistance.
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PMID:Vaults are up-regulated in multidrug-resistant cancer cell lines. 953 82

Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 microM PSC 833 (P = 0.025), 1.5-fold using 4 microM CsA (P = 0.003) and 1.6-fold using 6 microM Vp (P = 0.012) whereas the adverse effect of 25 microM genistein was median 1.8-fold (P < 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of P-gp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.
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PMID:The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia. 963 20

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.
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PMID:Do P-glycoprotein and major vault protein (MVP/LRP) expression correlate with in vitro daunorubicin resistance in acute myeloid leukemia? 1048 3

Contradictory data have been reported about the prognostic value of myeloid antigen co-expression (My+) in childhood acute lymphoblastic leukaemia (ALL). In the present study the methyl thiazol tetrazoliumbromide (MTT) assay was used to compare the in vitro cytotoxicity of 14 drugs between 60 My+ (CD13+ and/or CD33+) and 107 My- ALL children at initial diagnosis. P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), major vault protein/lung resistance protein (LRP) and the intracellular daunorubicin concentration were studied by flow cytometry. My+ ALL samples were significantly more resistant, i.e. between 1.1- and 2.9-fold, to daunorubicin, doxorubicin, idarubicin, mitoxantrone, vincristine, 6-thioguanine, 6-mercaptopurine, teniposide, etoposide and ifosfamide compared with My- ALL samples. My- and My+ ALL did not significantly differ in sensitivity to prednisolone, dexamethasone, L-asparaginase and cytarabine. Comparable results were found when only common and preB ALL cases were analysed. Drug resistance in My+ ALL was not related to increased expression of P-gp, MRP or LRP compared with My- ALL (ratio My+/My-:P-gp 0.8, MRP 1.0, LRP 1.1). Accumulation and retention of daunorubicin did not significantly differ between My- and My+ ALL cells (ratio My+/My-: accumulation 1.2, retention 1.3). Therefore the nature of drug resistance in My+ ALL remains unknown. The lack of prognostic value for My+ in childhood ALL may be explained by the responsiveness of My+ ALL to glucocorticoids, L-asparaginase and cytarabine. In addition, the currently intensive treatment regimens may apply drug doses which are simply high enough to overcome the mild resistance to anthracyclines, mitoxantrone, vincristine, thiopurines, epipodophyllotoxins and ifosfamide in childhood My+ ALL.
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PMID:Myeloid antigen co-expression in childhood acute lymphoblastic leukaemia: relationship with in vitro drug resistance. 1055 96

In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.
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PMID:Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. 1060 24


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