Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Native resistance to conventional chemotherapy remains an important cause of treatment failure in the adult acute leukemias. Delineation of cellular mechanisms of drug resistance therefore represents a prerequisite to the development of more effective treatment strategies. The multidrug resistance (MDR) phenotype represents one such mechanism of resistance with direct clinical relevance. This phenotype occurs normally in certain mammalian tissues, and is detectable in tumor cell lines selected for resistance to naturally occurring antineoplastics. The mdr1 gene or its glycoprotein product, P-glycoprotein, is detected with high frequency in secondary acute myeloid leukemia (AML) and poor-risk subsets of acute lymphoblastic leukemia. In prospective studies in AML, MDR overexpression is an independent determinant of response to treatment and overall survival with conventional-dose induction regimens. Investigations of mdr1 regulation in normal hematopoietic elements has shown a pattern which corresponds to its regulation in acute leukemia, explaining the linkage of mdr1 to specific cellular phenotypes. Therapeutic trials are now in progress to test the ability of various MDR-reversal agents to restore chemotherapy sensitivity in high-risk acute leukemias.
...
PMID:Multidrug resistance in acute leukemia: a conserved physiologic function. 128 51

Despite more effective treatment for younger patients with acute myeloid leukemia (AML), resistance to conventional antineoplastics has limited such advances in the elderly. Overexpression of the multidrug transporter, P-glycoprotein (Pgp), appears to contribute to treatment failure in de novo AML and has been detected in up to 70 percent of elderly patients. Data also indicate linkage between Pgp and many adverse prognostic features, including cytogenetic pattern, surface phenotype, and evolution from an antecedent hematologic disorder. Pharmacologic inhibitors of Pgp function have been targeted for investigation in elderly AML patients. Non-Pgp mechanisms responsible for multidrug resistance (MDR) phenotypes that are only weakly sensitive to classic Pgp modulators, however, may limit the success of such strategies. Overexpression of the lung-resistance protein (LRP) in AML has also been linked to advanced age, secondary leukemia, and Pgp overexpression. In a study of 66 patients at the Arizona Cancer Center, LRP overexpression was a more important predictor of response to induction therapy for AML than was Pgp. Recent investigations indicate that overexpression of the gene encoding the MDR-related protein (MRP), though rare in de novo AML, may be common in high-risk groups such as relapsed patients and secondary AML. Use of monoclonal antibodies specific for the MRP gene product may further define its prognostic relevance in AML.
...
PMID:The role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. 861 69

Clinical and biological features have recognized prognostic significance in acute myeloid leukemia (AML). To evaluate the interaction of these variables and weighted effect on treatment outcome, prognostic variables from 96 previously untreated patients were analyzed for association with expression of the MDR1 gene product P-glycoprotein (Pgp), and effect on response to induction chemotherapy, progression-free survival and overall survival. Multivariate relationships were analyzed using six prognostic variables, including age, cytogenetic pattern, gender, CD34+ surface phenotype, AML type (de novo versus secondary) and Pgp. Univariate comparisons indicate that Pgp (P = 0.0001), cytogenetic pattern (P = 0.0004) and a Cd34+ phenotype (P = 0.0005) are predictive of primary treatment failure, whereas Pgp (P = 0.0001) had the greatest predictive value in multivariate analysis. Only cytogenetic pattern retained prognostic significance (P = 0.0143) for response to induction therapy after adjustment for Pgp. Although all variable except gender were associated with Pgp, specimens harboring the favorable karyotypic abnormalities t(15;17), t(8;21) and inv(16) exclusively lacked Pgp expression. In a multivariate model, both Pgp and cytogenetic pattern predicted response and overall survival, whereas secondary AML and cytogenetic pattern influenced remission duration. These findings indicate that cytogenetic has prognostic relevance that is independent of Pgp, and implies the presence of undefined biological mechanisms affecting chemotherapy resistance.
...
PMID:Cytogenetics and P-glycoprotein (PGP) are independent predictors of treatment outcome in acute myeloid leukemia (AML). 862 17

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.
...
PMID:Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. 863 Apr 12

Cellular expression of the multidrug transporter, P-glycoprotein (Pgp) is recognized as a biological mechanism possibly contributing to treatment failure in acute myeloid leukemia (AML). Correlative studies indicate its association with poor risk features including secondary AML, CD34+ surface phenotype, unfavorable karyotype and advanced age. Reported disparity in the prognostic impact of Pgp relates in part to variance in drug transport capacity. In Pgp expressing cells, capacity for drug extrusion is governed by maturation phenotype and is largely restricted to CD34+ populations lacking myeloid maturation antigens. Three competitive inhibitors of Pgp function showing promise in pilot studies, cyclosporin A (CsA), quinine and the cyclosporin D analogue PSC 833, have entered testing in phase III trials. The presence of non-Pgp-related mechanisms of multidrug resistance, relatively insensitive to Pgp modulators, may limit the success of such treatment strategies. Preliminary investigations indicate that overexpression of the gene encoding the multidrug resistance-related protein (MRP) occurs infrequently in de novo AML, but relative increases in gene message are evident in relapsed specimens. Overexpression of lung resistance protein (LRP) is associated with adverse prognostic variables such as age, secondary disease and Pgp, and has demonstrated prognostic relevance. Because treatment with Pgp modulators may select for this drug resistance phenotype, LRP merits evaluation in randomized trials of Pgp antagonists. These observations indicate that multiple biological mechanisms contribute to anthracycline resistance in AML, thereby warranting development of multifunctional modulators or chemotherapeutic agents with novel mechanisms of action.
...
PMID:Role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. 866 48

Resistance to chemotherapy is a major obstacle in the treatment of patients with acute myeloid leukemia (AML). The majority of AML patients are intrinsically resistant to chemotherapy at initial diagnosis before chemotherapeutic exposure; such intrinsic resistance frequently results from expression of the multidrug resistance gene (MDR-1), which encodes a membrane transporter protein, P-glycoprotein (P-gp), that mediates drug efflux in leukemic cells. Expression of novel transporter proteins that confer alternative forms of multidrug resistance (MDR), such as the lung-resistance protein (LRP) and the MDR-associated protein (MRP), occurs more frequently in leukemic patients at relapse. Preliminary studies indicate that these proteins may also confer therapeutic resistance in leukemia. In patients older than 55 years of age, AML is characterized by a high frequency of unfavorable cytogenetics, P-gp expression, and functional drug efflux, which contribute to poor clinical outcome. In a multivariate analysis, secondary AML, unfavorable cytogenetics, and P-gp expression/function were each significantly and independently associated with a lower complete remission (CR) rate. Resistant disease was associated with P-gp expression and unfavorable cytogenetics. Strikingly, elderly patients with P-gp- de novo AML and favorable or intermediate cytogenetics had a CR rate of 81%. Patients with P-gp+ secondary AML with unfavorable cytogenetics had a CR rate of only 12%. Therefore, characterization of elderly AML patients at diagnosis using biologic parameters may help identify those patients who are likely to achieve a CR with conventional regimens, as well as those patients who require alternate treatment designed to overcome MDR. In contrast, expression of P-gp and functional drug efflux is detected in only 25% to 30% of AML patients less than 50 years of age. While P-gp expression is less strongly associated with a poor outcome in younger versus older AML patients, it remains strongly associated with resistant disease. Studies are ongoing to determine the prognostic significance of LRP and MRP in various forms of leukemia.
...
PMID:The prognostic significance of the expression and function of multidrug resistance transporter proteins in acute myeloid leukemia: studies of the Southwest Oncology Group Leukemia Research Program. 940 58

The importance of P-glycoprotein (P-gp) in AML has been well documented. Resistance to the anthracyclines can be overcome by several agents including Cyclosporin A (CsA), PSC833 and GF120918. We describe an investigation into the expression, using MRK16 and UIC2, and function of P-gp using daunorubicin with and without modulators by flow cytometric analysis on previously frozen blast cells from 27 patients with primary or secondary AML. We compared this with the in vitro chemosensitivity, using the MTT assay, of fresh blast cells from the same patients. Whilst we found a correlation between P-gp function using CsA and GF120918 and expression using MRK16 (p < 0.05) and (p < 0.02) respectively, we were unable to find any overall correlation between expression and function of P-gp with either in vitro sensitivity to the anthracyclines, previous treatment, or 1 degree or 2 degrees disease. However it was possible to identify individual patients whose cells exhibited P-gp expression and function teamed with in vitro resistance to, and modification of, the anthracyclines. Furthermore, it is possible to identify which modulator had the greatest effect. The fact that we obtained higher indications of resistance reversal using the MTT assay along with finding P-gp expression and function in patients sensitive to the anthracyclines, suggests studies of P-gp should be teemed with chemosensitivity testing to identify specific patients who will benefit.
...
PMID:Comparison of P-glycoprotein expression and function with in vitro sensitivity to anthracyclines in AML. 1050 Jul 77

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr 1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24 h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.
...
PMID:Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). 1050 Jul 79

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.
...
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

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.
...
PMID:A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617. 1086 30


1 2 Next >>

---