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)

Our purpose was to study the role of the expression of P-glycoprotein (Pgp) and glutathione S transferase-pi (GST-pi) in predicting the response to chemotherapy, relapse-free interval, and survival of patients with synovial sarcoma (SS). Thirty-seven cases of primary SS, without regional lymph node or distant metastases, were studied. There were 17 females and 20 males, ranging in age from 7 to 81 years (median, 31 years) with tumors located in the lower extremity (n = 24) upper extremity (n = 5) and trunchus (n = 8). The cases were retrospectively studied without knowledge of clinical course to compare the immunohistochemical expression of Pgp and GST-pi, flow cytometry parameters (ploidy and % of cells in S+G2 phases), and PCNA and Ki-67 labeling of primary tumors before any therapy, with that observed in local recurrences and metastases after chemotherapy. The relationship of the aforementioned parameters with clinicopathological features (gender, age, and histo-blood group of the patients, size, location, histological subtype. TNM stage, and clinical response to chemotherapy of the tumors) was also evaluated. Results revealed that Pgp and GST-pi were expressed in 29.7% and 40.5% of the cases, respectively. In 48.6% of the tumors there was expression of a least one of the drug resistance markers. The markers were coexpressed in 25.0% of the tumors. The prevalence of Pgp expression was lower, but not significantly, in stage I-II (17.6%) than in stage III (40.0%) tumors, and also in cases without clinical progression (16.7%), than in cases with (36.0%). No such differences were observed for GST-pi expression. Pgp and GST-pi expressions were significantly associated with biphasic SS and were particularly noticeable in solid/glandular areas of biphasic SS. The expression of the drug resistance markers was not significantly associated with gender, age, and histo-blood group of the patients, dimension, location, and proliferative activity of the tumors; it was also not significantly related to relapse-free interval and survival of the patients. The expression of Pgp and GST-pi was not significantly associated either to response to chemotherapy or influenced by chemotherapy. We conclude that Pgp and GST-pi expressions are not good predictors response to of the chemotherapy in patients with localized SS. Other drug resistance mechanisms may be active in SS.
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PMID:Synovial sarcoma: immunohistochemical expression of P-glycoprotein and glutathione S transferase-pi and clinical drug resistance. 911 70

Hepatocellular carcinomas (HCCs) from 31 patients, cirrhotic livers from 7 patients and normal liver from 8 patients were immunohistochemically assessed in frozen sections using anti-P-glycoprotein (Pgp) monoclonal antibody C219. Immunohistochemical staining with anti-Ki-67 monoclonal antibody MIB-1 was performed for 22 HCCs to assess proliferative activity. Tumor tissues expressed Pgp on the biliary surface and on the luminal surface of cancer cells, which was less extensive than in normal and cirrhotic liver hepatocytes. Expression of Pgp was closely associated with the degree of histological differentiation and the histological type of HCC. Labeling indices (LI) of Pgp expression were 0.68 +/- 0.06 (mean +/- SD) in well, 0.51 +/- 0.14 in moderately and 0.04 +/- 0.06 in poorly differentiated HCC (significant differences among the three groups). LI of Pgp expression in the trabecular (0.55 +/- 0.15) and in the pseudoglandular types (0.44 +/- 0.10) were remarkably higher than in the compact type (0.04 +/- 0.06). The extent of Pgp expression in HCC was significantly inversely related to the extent of Ki-67 expression, in which Pgp expression decreased in highly proliferating tumors. In conclusion, Pgp expression in HCC was clearly related to its proliferative activity.
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PMID:Inverse relationship between P-glycoprotein expression and its proliferative activity in hepatocellular carcinoma. 914 5

Recently reported morphologic and molecular genetic evidence suggests that some ovarian carcinomas arise from their benign and low malignant potential (LMP) counterparts. In order to help reach a better understanding of ovarian tumorigenesis, we studied a wide range of gene products involved in cellular growth regulation in archival material obtained from three groups of tumors with graduated malignant potential. Immunohistochemical staining was performed for Ki-67, proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), HER-2/neu-encoded receptor protein, p53 gene product, and multidrug resistance gene product (P-glycoprotein). The expression of EGFR, HER-2/neu-encoded receptor protein, and mutant p53 product was significantly lower in LMP tumors than in carcinomas (p < 0.05). HER-2/neu immunopositivity was more prevalent in adenocarcinomas than in LMP tumors, and the proportion of HER-2/neu-positive adenocarcinomas increased with the progression of the disease. The staining differences between LMP tumors and adenocarcinomas with antibodies against Ki-67, PCNA, and P-glycoprotein were not statistically significant. Immunohistochemical detection of EGFR, HER-2/neu, and p53 in ovarian epithelial tumor is relevant to ovarian tumorigenesis. It could serve as a powerful tool for the pursuit of retrospective studies focused on these important biologic markers.
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PMID:Immunohistochemical assessment of proliferation markers and altered gene expression in archival specimens of ovarian epithelial tumors. 939 93

Resistance of tumor cells to chemotherapeutic drugs can not only be caused by treatment with antineoplastic agents but also by radiotherapy. The aim of this study was to analyze whether ionizing radiation can influence the mRNA expression of proteins which have been found to be involved in drug resistance of tumor cells. Human tumor cell lines (MCF-7, LXF and Sk-Mel) were treated with single doses of irradiation (5, 10 and 20 Gy). The expression of the resistance related proteins glutathione S-transferase-pi (GST-pi), topoisomerase II alpha (Topo II), thymidylate synthase (TS), O6-methylguanine-DNA-methyltransferase (MGMT), P-glycoprotein (Pgp), glutathione peroxidase (GPX) multidrug resistance-associated protein (MRP) and also of the heat-shock protein 70 (HSP 70) were determined at the mRNA level during the time interval from 1.5 to 72 h post-irradiation and compared with their corresponding controls. We also examined whether a relationship exists between these proteins and the proliferative activity (histone 3, Ki-67, statin) of the cells. We found that exposure of MCF-7, LXF and Sk-Mel cells to ionizing radiation increases the expression of the mRNA of GST-pi. Topo II, TS, HSP 70 and proliferation markers were also altered by exposure to ionizing radiation, but there was no common response of the three cell lines. No significant changes were observed in the expression of MGMT, Pgp, GPX and MRP after radiation treatment. Drug resistance tests revealed that irradiated MCF 7 cells were less sensitive to doxorubicin than non-irradiated control cells. Our results indicate that ionizing irradiation modifies the expression of some proteins involved in drug resistance and the response of MCF 7 cells to doxorubicin and may, therefore, play a role in clinical drug response.
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PMID:Messenger RNA expression of resistance factors in human tumor cell lines after single exposure to radiation. 941 87

Forty-two patients with clinical stage IIIA or IIIB breast cancer were treated with neoadjuvant chemotherapy followed by mastectomy and radiotherapy. The median follow-up was 32 months (range 10-72 months) and the median time to progression was 17 months (range 10-30 months). A multivariate analysis showed that a longer disease-free survival (DFS) was related to more chemotherapy cycles given (P = 0.003), a better pathological response to chemotherapy (P = 0.04) and fewer positive axillary lymph nodes (P = 0.05). A better overall survival (OS) was related to more chemotherapy cycles given (P = 0.03) and better pathological response to chemotherapy (P = 0.04). In patients with residual tumour after neoadjuvant chemotherapy, high levels of staining for Ki-67 was correlated with a worse DFS (P = 0.008). Other biological characteristics, including oestrogen receptor status, microvessel density (CD31 staining), P-glycoprotein (P-gp) staining and nuclear accumulation of p53, were not independent prognostic factors for either DFS or OS. If both P-gp and p53 were expressed, DFS and OS were worse in the uni- and multivariate analysis. The preliminary results of this phase II study suggest that coexpression of P-gp/p53 and a high level of staining for Ki-67 after chemotherapy are associated with a worse prognosis, and that prolonged neoadjuvant chemotherapy and the attainment of a pathological complete remission are important factors in determining outcome for patients with this disease.
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PMID:Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer. 948 20

Growing multicellular prostate tumor spheroids develop quiescent cell subpopulations in central regions with features of intrinsic multicell-mediated drug resistance. Doxorubicin (dox) uptake was significantly reduced in large spheroids (diameter 400+/-70 microm), which consist predominantly of quiescent cells, as compared to small spheroids (diameter 100+/-50 microm), which consist entirely of proliferating cells. After removal of dox from the incubation medium, dox fluorescence declined more efficiently in large spheroids, which led to a decreased dox toxicity as revealed by colony-forming assays. Verapamil significantly increased dox retention in large spheroids and, consequently, augmented dox toxicity. At a depth 80 microm from the spheroid periphery, a significantly decreased dox fluorescence was observed in the deep, quiescent cell layers of large spheroids. The P-glycoprotein-mediated multidrug resistance (MDR)-reversing agents verapamil, cyclosporin A, quinidine, sodium orthovanadate and tamoxifen significantly increased dox fluorescence at this depth, whereas genistein, indomethacin, probenecid and brefeldin A, which reverse multidrug-resistance-associated protein (MRP) function, exerted no effect. Anti-P-glycoprotein immunohistochemistry of multicellular tumor spheroids revealed an increase of P-glycoprotein expression in large speroids as compared to small spheroids, which was most prominent in the Ki-67-negative, quiescent cell layers 60 to 100 microm distant from the periphery of the spheroid, indicating that the MDR phenotype is related to cell quiescence. This was corroborated by whole-cell patch-clamp experiments, where the C219 antibody, which is directed against the ATP-binding site of P-glycoprotein, significantly inhibited P-glycoprotein-associated, volume-activated chloride currents in quiescent, but not proliferating cells from multicellular tumor spheroids.
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PMID:Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids. 950 30

ELAM is an E-Selectin adhesion molecule involved in the inflammatory process but it is also thought to potentially participate in the development of blood borne metastases, by facilitating tumour cell adhesion to vessels wall. ELAM expression in tumours was immunohistochemically investigated in 203 breast carcinomas. Frozen tissue sections were probed with monoclonal anti ELAM (Clone 1.2B6) using automated and quantitative immunoperoxidase systems. A positive anti-ELAM immunoreaction was observed in 113 tumours (57%). The mean surface of positive tumours varied from 3% to 50% (mean = 11.75%, SD = 8.7) and was correlated with histoprognostic indicators and tumour expression of various antigens detected according to the same method as ELAM. The results showed that ELAM immunoexpression was independent of the tumour size, grade and type and of the nodal status but significantly increased parallel to patients' age (p<0. 01). ELAM expression was independent of Ki-67/MIB1, anti-P53 and anti-Bcl2, anti-CD44v, anti-c-erbB-2, anti-CD31, anti-RE/RP, anti-PS2, and anti-VLA3 immunoreactions. But ELAM expression correlated with that of the VCAM vascular cell adhesion molecule (p=0.0004), VLA2 (p<0.0001), P-glycoprotein (p=0.025), and of Cathepsin D to a lower degree (p=0.06) and inversely correlated with E-cadherin (p=0.03). The results suggest that endothelial cell activation is independent of tumour cell proliferative activity and of stromal angiogenesis and that the precise role and regulation of ELAM in tumours remains to be elucidated. Also the clinical relevance of ELAM immunohistochemical expression requires further investigation and correlation with patients' follow-up.
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PMID:ELAM selectin expression in breast carcinomas detected by automated and quantitative immunohistochemical assays. 953 26

A consensus has emerged that early imaging (within 20 min post-injection [p.i.] of sestamibi) has the highest diagnostic yield. Tc-99m-sestamibi uptake has been associated with P-glycoprotein-mediated multi-drug resistance (MDR), tumor vascularization, invasiveness, and cell proliferation. The aim of this study was to assess whether these parameters affect tumor uptake in current imaging protocols. Twenty-three patients with squamous cell carcinoma (SCC) of the mouth floor who were scheduled for surgery were imaged 5 min. p.i. with a triple-head gamma camera (360 degrees, 3 degrees/step SPECT, UHRPAR collimators). Tumor:nontumor tissue (TBR), tumor:gingiva (TGR), tumor:salivary gland (TSR), and tumor:nuchal muscle ratios (TNR) were calculated based on the cts/pix values of ROIs in the axial slices. The expression of the MDR gene was determined histochemically from biopsies. Cell proliferation was quantitated by the histochemical analysis of the Ki-67 protein (Ki-67 index); additionally, the p53 tumor suppressor gene (p53 index), a posttranslational stabilizer of the cell cycle at the G1 stage, was assessed. No significant differences were found for the uptake indices between MDR+ and MDR- tumors. Moreover, no significant correlation between sestamibi uptake and the Ki-67 and p53 indices could be demonstrated. The diagnostic information content of currently applied imaging protocols for sestamibi in SCC of the mouth floor is not affected by tumor-specific properties.
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PMID:Is early sestamibi imaging in head and neck cancer affected by MDR status, p53 expression, or cell proliferation? 975 20

Intrinsic expression of the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) may be regulated by reactive oxygen species (ROS). A transient expression of Pgp was observed during the growth of multicellular tumor spheroids. Maximum Pgp expression occurred in tumor spheroids with a high percentage of quiescent, Ki-67-negative cells, elevated glutathione levels, increased expression of the cyclin-dependent kinase inhibitors p27Kip1 and p21WAF-1 as well as reduced ROS levels and minor activity of the mitogen-activated kinase (MAPK) members c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase ERK1,2, and p38 MAPK. Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated. Down-regulation of Pgp was furthermore observed with low concentrations of hydrogen peroxide and epidermal growth factor, indicating that ROS may regulate Pgp expression. The down-regulation of Pgp following BSO treatment was abolished by agents interfering with receptor tyrosine kinase signaling pathways, i.e. the protein kinase C inhibitors bisindolylmaleimide I (BIM-1) and Ro-31-8220, the p21ras farnesyl protein transferase inhibitor III, the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1,2 activation. ROS involved as second messengers in receptor tyrosine kinase signaling pathways may act as negative regulators of Pgp expression.
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PMID:Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. 1127 18

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


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