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

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

The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Resistance varies. Although regulatory approval may require efficacy in as few as 20% of trial cohorts, a drug may subsequently be used in unselected patients displaying resistance to the treatment. Principal mechanisms may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme (e.g. mutated topoisomerase II), decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptose as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and, in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in abrogating or delaying onset of resistance. Gene knockout using antisense molecules may be another effective way of blocking drug resistance genes. Conversely, drug resistance may also be used to good purpose by transplanting retrovirally transformed CD34 cells expressing the MDR gene to protect the bone marrow during high-dose chemotherapy.
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PMID:Mechanisms of drug resistance in cancer chemotherapy. 1610 12

Acute myeloid leukaemia (AML) is a heterogenous malignant disease with diverse biological features in which disease progression at the level of CD34+ cells has a major impact on the resistance to chemotherapy and relapse. The AML blast cells in these elderly patients are often characterised by several unfavourable covariates that predict the poor treatment outcome, including high stem cell marker CD34 expression, minimally or undifferentiated features, high P-glycoprotein expression, high bcl-2/bax ratio, unfavourable karyotype and more frequent internal tandem duplications (ITDs) and mutations of class III receptor-type tyrosine kinase for key haematopoietic cytokines: Flt-3 (receptor for Flt-ligand), c-kit (receptor for stem cell factor) and fms (receptor for M-CSF). Testing the new and more specific molecular-targeted therapeutic approaches in CD34+ AML cells can provide the basis for a more effective combined molecular/chemotherapy regimen and may consequently improve the treatment outcome in elderly AML patients. Therefore, the present study was performed to evaluate whether stem cell factor-antibody (anti-SCF) can enhance the efficacy of the two main chemotherapeutic drugs used in AML therapy: cytarabine and daunorubicin at low doses in human-resistant CD34+ AML cells, in an attempt to identify a novel effective regimen with tolerable side-effects for elderly AML patients. The effect of anti-SCF on each of the two chemotherapeutic drugs-induced apoptosis and necrosis was investigated in KG1a human-resistant CD34+ AML cells expressing P-glycoprotein to determine its enhancing activity. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells from 12.0+/-1.7 to 40.9+/-5.9% and from 16.3+/-0.9 to 48.9+/-1.0%, respectively, p<0.01. It has also exerted its significant enhancement activity on the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells in the presence of SCF, p<0.05. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells from 26.7+/-0.6 to 64.6+/-1.0% and from 59.8+/-3.1 to 80.1+/-7.9%, respectively, p<0.01. The addition of SCF has not altered the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells (Table 4). Anti-SCF has also significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells in the presence of SCF, p<0.05. The unique potent enhancing activity of anti-SCF on low dose chemotherapy-induced apoptosis and necrosis in extremely resistant AML cells suggest a novel promising role for the treatment of elderly AML patients. Further studies are warranted to evaluate a similar enhancing effect for anti-SCF in blast cells from elderly AML patients in primary cultures before its introduction in a pilot clinical study. In conclusion, the combination of anti-SCF and the low dose cytarabine provides a promising solution for the dilemma of therapy in elderly AML patients.
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PMID:Human stem cell factor-antibody [anti-SCF] enhances chemotherapy cytotoxicity in human CD34+ resistant myeloid leukaemia cells. 1611 92

Multidrug transporters, such as P-glycoprotein (P-gp), multidrug-resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), are associated with multidrug resistance in cancers; other molecules, such as major vault protein (MVP), have a similar association with drug-resistant cancer. These proteins are postulated to generate drug resistance in epilepsy. They have been shown individually to be up-regulated in epileptogenic brain tissue. In any consideration of the function, inhibition or evasion of the activity of such proteins, the colocalization of such proteins needs to be understood. We systematically determined the presence of such colocalization, focusing on microvascular endothelium from epileptogenic human brain tissue. Double labelling immunofluorescence and confocal laser scanning microscopy were used to determine colocalization of P-gp, MRP1, BCRP and MVP in one case of hippocampal sclerosis and two cases of focal cortical dysplasia type IIb. Endothelial colocalization was examined with double labelling using antibodies to CD34 and Factor VIII. The presence of P-gp, BCRP and MVP in microvascular endothelium was confirmed. P-gp, BCRP and MVP colocalized in microvascular endothelium, though not all proteins appeared to be identically distributed within this tissue. MRP1 did not colocalize to endothelium. These findings were not unexpected but required formal confirmation. The demonstrated colocalization of P-gp, BCRP and MVP in microvascular endothelium in epileptogenic human brain tissue has important implications for functional experiments (including single knock-out mice studies), work with specific and broad-spectrum inhibitors of transport function, and any eventual trials of treatment of refractory epilepsy involving modulation of the function of these proteins.
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PMID:Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies. 1640 53

Multidrug resistance is a major cause of treatment failure in acute myeloid leukemia (AML). P-glycoprotein (PGP) over-expression has an unfavorable prognostic significance, while the role of breast cancer resistance protein (BCRP) is less clear, especially in AML patients with a normal karyotype. We studied 73 consecutive AML patients with a normal karyotype. BCRP was over-expressed in 24 patients (33%) and was significantly co-expressed with PGP (13/24 vs 11/49, p=0.006) and with CD56. Only PGP, along with age and CD34, affected the achievement of complete remission (p=0.02), while BCRP-positive cases showed an increased risk of relapse (p=0.005) and a shorter disease-free survival (p=0.027). BCRP over-expression did not influence the achievement of remission, but significantly affected the duration of complete remissions. BCRP may, therefore, be regarded as a prognostic factor in patients with normal karyotype AML, for the design of risk-adapted post-remission therapy.
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PMID:The prognostic value of P-glycoprotein (ABCB) and breast cancer resistance protein (ABCG2) in adults with de novo acute myeloid leukemia with normal karyotype. 1670 62

Multi drug resistance(MDR) is a major problem in the treatment ofcancer and hematological malignancies. This resistance is multi factorial and is the result of decreased intra cellular drug accumulation. This is partly due to the presence of a 170KD intra membranous protein termed P-glycoprotein(P-gp) that is an energy- dependent efflux pump which has increased expression on drug-resistance cells. In this study we identified the presence of P-gp by staining with Fluorescent Iso Thio Cyanate (FITC) conjugated anti P-gp in acute leukemia patients and flow cytometry in addition to performing immunophenotype analysis and French, American British (FAB) classification. Results revealed that one fifth of leukemic patients expressed P-gp and this phenotype was more prevalent in Acute Undifferentiated Leukemia(AUL) and Acute Myelogenous Leukemia (AML) than in Acute Lymphoblastic Leukemia(ALL). Other findings showed a logical relationship between this phenotype and age groups. There was not any association between P-gp+ phenotype and FAB and Immunophenotyping sub classification, but there was a linear relationship between CD34 and CD7 expression and P-gp+ phenotype. The accumulation of P-gp molecule that was stated as Mean Fluorescence Intensity (MFI) on the blasts' membrane of AUL and AML patients showed marked increase in comparison to ALL. Furthermore MFI in P-gp+ relapsed patients was much more than P-gp+ pretreatment patients. Kepvords: Leukemia, Drug resistance, P-glycoprotein, Flowcytometry, FAB classification, Immunophenotyping, Mean Fluorescence Intensity.
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PMID:P-glycoprotein quantitation in acute leukemia. 1730 57

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients >or=60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients.
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PMID:CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age. 1734 Jan 37

P-glycoprotein (P-gp), which is encoded by the multidrug resistance gene (MDR-1); alpha fetoprotein (AFP); and vascular endothelium-associated antigens are well-known markers for human and canine hepatic diseases. We obtained liver tissues from 5 dogs with hepatocellular carcinoma (HCC) and 12 dogs with cirrhosis, and we performed histopathologic and immunohistochemical evaluations using anti-P-gp, anti-AFP, anti-CD31, and anti-CD34 antibodies. P-gp was expressed at higher levels in HCC than in cirrhotic livers ( P < .01), and was most commonly localized in biliary canaliculi and small ductuli. AFP was localized mainly in the cytoplasm in HCC ( P < .01) and in a few cases of cirrhosis. In both HCC and cirrhosis, the AFP-positive cells were morphologically similar to normal hepatocytes and showed an even cytoplasmic distribution of AFP. The endothelial markers CD31 and CD34 were used to investigate vascular distribution. CD31 was expressed strongly in the portal area and parenchyma in HCC, but it was rarely observed in the parenchyma in cirrhosis. CD34 expression could not be detected in both HCC and cirrhosis. This study constitutes the first comprehensive study of P-gp, AFP, and endothelial markers in canine HCC and cirrhosis. The importance of these markers in HCC and cirrhosis in dogs was demonstrated and provides a more accurate basis for a definitive diagnosis of HCC and cirrhosis in dogs.
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PMID:Cellular characterization of multidrug resistance P-glycoprotein, alpha fetoprotein, and neovascular endothelium-associated antigens in canine hepatocellular carcinoma and cirrhotic liver. 1784 32

A total of 49 newly diagnosed patients with acute leukemia were studied in order to assess the diagnostic value of clone AC141 of CD133 antibody by flow cytometry. AC141 expression was further compared to CD34 and P-glycoprotein, immunophenotype, morphology and cytogenetic/molecular data. Flow cytometry allowed for the detection of AC141 expression in 42.8% of the patients. A strong correlation with myeloid lineage was observed. All AC141(+) acute myeloid leukemia (AML) cases were of immature morphology and a strong concordance with CD34 expression was found. However, discordant patterns were also observed. Besides, AC141 expression correlated with CD7 in the absence of mature markers (CD14, CD15 and CD64). Similarly to CD34, P-glycoprotein levels were also significantly higher in AC141(+) AML cases. No correlation was found with cytogenetic/molecular data of the patients. In conclusion, membrane expression of AC141, in combination with other antigens, might facilitate a more precise immunologic characterization of acute leukemias and may serve as an alternative to CD34 for purging purposes in selected patients.
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PMID:CD133-2 (AC141) expression analysis in acute leukemia immunophenotyping in correlation to CD34 and P-glycoprotein. 1870 70

Human acute leukemias (AL) are classified as myeloid or lymphoid according to cytomorphology and the expression of leukocyte differentiation antigens/CD-markers. However, in the minority of cases leukemic cells express markers of more than one lineage, which has led to the introduction of a new subgroup of acute leukemias termed mixed or biphenotypic acute leukemias (BAL). In an effort to distinguish between BAL and those AL with aberrant expression of markers of other lineage, the European Group for the Immunological Characterization of Acute Leukemias (EGIL) has proposed a scoring system in which CD-markers are assigned a score of 0.5, 1.0 or 2.0, depending on the specificity of a particular antigen for myeloid, B- and/or T-lymphoid lineage, respectively. The new WHO classification of hematologic tumors has adopted the EGIL criteria for BAL and introduced a new group of AL termed 'AL of ambiguous lineage'. In addition to BAL in which a single cell population expresses both myeloid and lymphoid differentiation markers, this new group of leukemias also comprises cases that present with two separate blast populations (acute bilineal leukemia, aBLL). In general, BAL accounts for less than 5% of all AL cases, whereas aBLL is a rare disease constituting 1%-2% of AL cases that contains B- or T-lymphoid along with myeloid blasts. Chromosome abnormalities are frequent in both entities with a relatively high incidence of Philadelphia chromosome and rearrangements involving 11q23, especially in cases with B- and myeloid involvement. Other biological features include CD34 expression and multi-drug resistance P-glycoprotein overexpression. The prognosis of BAL and aBLL is unfavorable, with poor prognostic factors being age, high WBC and the presence of Philadelphia chromosome. Unfortunately, optimal therapy is not known, although regimens designed for acute lymphoblastic leukemia may result in a better response rate. Collaborative studies are needed for better understanding of the biology of these entities and establishment of standard therapeutic protocols.
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PMID:[Biphenotypic and bilineal acute leukemias]. 1920 64

Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma. Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated regarding angiogenesis (CD34), proliferative activity (MIB-1), and the expression of p53 and MDR (P-glycoprotein (Pgp); clones JSB-1, C494, and MRK16). Quantitative and semiquantitative scores of immunoreactive cells were analyzed statistically along with retrospectively obtained clinicopathologic variables. Results. Chemotherapy reduced the rate of amputations (P = .00002). The Pgp was overexpressed (score >/=2) in 48% of the primary, diagnostic biopsies, and high Pgp correlated with high Pgp in postsurgical specimens (P = .003). In contrast, no such associations were disclosed for estimates of angiogenesis (P = .64) and p53 (P > .32), whereas the MIB-1 index was reduced in the post-chemotherapy specimens (P = .02). The overall, disease-specific survival was 47%, increasing to 54% in patients receiving pre-operative chemotherapy. Statistical analyses showed prognostic impact exclusively by patient age and type of osteosarcoma. Discussion. The studied series of patients documented already prior to the chemotherapy era, a rather excellent survival and estimates of angiogenesis, proliferation, p53, and Pgp expressions, did not demonstrate sufficient power to serve as predictors of treatment response or survival.
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PMID:Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation. 1926 50


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