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 expression of the protooncogene encoded proteins (c-erbB1, c-erb B2, c-myc, c-fos) and the suppressor gene product p53 was analyzed in 81 human squamous cell carcinomas of the lung and correlated with clinical parameters of the patients (patient survival, presence of metastases and tumor stage) and with biological characteristics of the tumors (tumor growth in nude mice, DNA-ploidy, proliferative activity, drug-resistance and P-glycoprotein or gluathione S-transferase expression). By means of immunohistochemistry, expression of c-erbB1 oncoprotein (EGF-receptor) was detected in 79% of the tumors, c-erbB2 (c-neu) proteins in 35%, c-myc proteins in 48%, c-fos proteins in 41%, and p53 in 43% of the tumors. Patients with c-erbB1 positive tumors had a poor prognosis (p = 0.021). In addition, these tumors were more frequently drug resistant (p = 0.0067). A significant correlation between the growth of the squamous lung carcinomas in nude mice and c-fos oncoprotein expression was demonstrated (p = 0.017). Therefore, EGF-receptor and c-fos products may serve as prognostic factors for the aggressiveness of squamous cell carcinomas of the lung and for the response of these tumors to chemotherapy. No significant correlation was found between the expression of the c-erbB1 or c-fos gene products and stage, metastasis and DNA-ploidy. In contrast to these results, no relationship was found between c-neu or c-myc gene products expression and any of the clinical or biological parameters examined. Aneuploid squamous cell carcinomas of the lung expressed p53 more frequently than diploid tumors (p = 0.027). However, there was no significant difference between p53 expression and stage, survival of patients, metastasis, growth of the tumors in nude mice, proliferative activity and drug-resistance of the tumors.
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PMID:Oncoprotein (c-myc, c-erbB1, c-erbB2, c-fos) and suppressor gene product (p53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations. 134 20

P-glycoprotein mediates classic multidrug resistance by functioning as an efflux pump that excretes lipophilic chemotherapeutic drugs from cancer cells. We now report an association of P-glycoprotein in colon carcinomas with another tumor property, i.e., enhancement of local tumor aggressiveness. P-glycoprotein was detected with monoclonal antibody immunohistochemistry in 65 of 95 primary colon adenocarcinomas, which were stage B1 or greater. In all but 1 of the 95 cases, solitary invading carcinoma cells were present at the leading edge of the tumor. This subpopulation of invasive carcinoma cells expressed P-glycoprotein (P-Gp+) in 47 of the 95 surgically resected colon specimens. Cases were grouped on the basis of the presence (Group 1, 47 cases) or absence (Group 2, 48 cases) of P-Gp+ invasive carcinoma cells. There was a significantly greater incidence of vessel invasion (P less than 0.001) and lymph node metastases (P less than 0.01) in Group 1 cases. Groups 1 and 2 did not differ with respect to tumor size, depth of invasion of the bowel wall, histological grade, maximum tumor size, mitotic index, mucin production, or presence of perineural invasion (P greater than 0.1). Our findings indicate that P-Gp+ invasive colon cancer cells may have an increased potential for dissemination, suggesting that P-glycoprotein may influence cell behavior.
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PMID:Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. 167 39

Drug resistance to multiple chemotherapeutic agents is considered a major cause of chemotherapy failure. An extensively studied and relatively well understood type of cellular drug resistance is P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). Pgp acts as an energy-dependent drug efflux pump, thereby decreasing the intracellular drug concentration and causing drug resistance, in in vitro experiments. Colorectal cancer and colorectal mucosa generally express high levels of Pgp, and this may contribute to the general unresponsiveness of colorectal cancer to natural product, anticancer drugs. The controversies concerning the prognostic role of Pgp expression and its contribution to tumour aggressiveness, and possible reasons for the disappointing results of clinical MDR reversal trials in colorectal cancer are discussed.
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PMID:MDR1/P-glycoprotein expression in colorectal cancer. 757 38

In osteosarcoma, resistance to chemotherapy and metastatic spread are the most important mechanisms responsible for the failure of current multimodal therapeutic programs. We have shown previously that overexpression of the MDR1 gene product P-glycoprotein is the most important predictor of an adverse clinical course in patients with osteosarcoma. treated with chemotherapy. In this study, we analyzed the relationship between P-glycoprotein expression and local aggressiveness and systemic dissemination of multidrug-resistant (MDR) human osteosarcoma cells. Compared to parental sensitive cells, MDR cells showed a decreased tumorigenicity,and metastatic ability in athymic mice, together with a reduced migratory and invasive ability and a lower homotypic adhesion ability in vitro, suggesting that P-glycoprotein overexpression is associated with a less malignant phenotype. These experimental observations were confirmed by clinical data. In fact, the time of appearance of lung metastases in a series of osteosarcoma patients treated with chemotherapy was significantly shorter in the group of cases with no expression of P-glycoprotein in the primary lesion compared to the group with P-glycoprotein overexpression. Moreover, the incidence of P-glycoprotein overexpression was found to be higher among patients with localized disease at the clinical onset than in patients with evidence of metastasis at the time of diagnosis. These data indicate that, in osteosarcoma, the MDR phenotype is not associated with a more aggressive behavior both in vitro and in clinical settings, suggesting that the previously shown association of the MDR phenotype with a worse outcome in osteosarcoma is not related to a higher metastatic ability of cells with P-glycoprotein overexpression but is more likely due to their lack of responsiveness to cytotoxic drugs.
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PMID:Multidrug resistance and malignancy in human osteosarcoma. 862 24

We investigated immunohistochemical localization of P-glycoprotein (P-gp) on paraffin-embedded sections from 103 cases of previously untreated pancreatic tumors and also analyzed multidrug resistance-1 (MDR1) gene expression by polymerase chain reaction after reverse transcription in 35 cases. High positive staining for P-gp was observed in 72.8% of pancreatic tumors and in 73.2% of ductal adenocarcinoma. In ductal adenocarcinoma, immunoreactivity of P-gp was inversely correlated with biological aggressiveness of tumors determined by histologic grading (P<0.01), tumor size (P < 0.01), retroperitoneal invasion (P < 0.01) and portal invasion (P < 0.05). Expression of the MDR1 gene was detected in all the pancreatic tumors examined and was significantly higher than that in normal pancreas (P < 0.05). The levels of MDR1 mRNA showed a moderate correlation with those of P-gp (r=0.62, P<0.0001). Higher expression levels of MDR1/P-gp significantly correlated with better prognosis of patients with ductal carcinoma (P < 0.05). Among patients with ductal carcinoma, the high staining group for P-gp revealed a 3.5-fold better prognosis compared with the low staining group (HR=3.47, 95% CI=1.62, 7.45; P=0.0016). In conclusion, MDR1 gene/P-gp expression in pancreatic cancer without chemotherapy inversely correlates with biological aggressiveness and is an independent indicator of favorable prognosis.
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PMID:Immunohistochemical localization of P-glycoprotein and expression of the multidrug resistance-1 gene in human pancreatic cancer: relevance to indicator of better prognosis. 876 29

The expression of the MDR1 gene has been shown to correlate with tumor aggressiveness and oncogenic activation both in experimental tumor models and in human clinical specimens In order to verify whether this association also takes place in ovarian carcinoma, we studied tumor samples from 39 patients by means of immunohistochemistry for the overexpression of P-glycoprotein (MDR1), nm23, c-erb-B2 and p53. MDR1 (p = 0.023), nm 23 (p = 0.037) and c-erb-B2 (p = 0.015) were expressed significantly more in specimens from patients with advanced stage of disease. There were no differences in p53 expression between both groups of patients. Furthermore, we found a significant coexpression of MDR1 and nm23 (p = 0.028), and of MDR1 and c-erb-B2 (p = 0.0077). There was no association between the expression of the MDR1 gene and p53. These results parallel those previously reported by us for mammary carcinoma, and seem to indicate that expression of the multidrug resistance gene (MDR1) is inherent to the development of the malignant phenotype in several human tumors.
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PMID:Correlation of MDR1 expression and oncogenic activation in human epithelial ovarian carcinoma. 921 79

Because P-glycoprotein expression might be associated with a more aggressive behaviour of colorectal carcinomas (Weinstein et al., Cancer Res, 1991, 51, 2720-2726), we determined the relationship between MDR1 RNA expression of the carcinomas and the survival of the patients. At a median duration of follow-up of 86 months, event-free survival of patients with MDR1 RNA-negative tumours (n = 35) was not significantly different to that of patients with MDR1 RNA positive tumours (n = 67). Among the different tumour stages, event-free survival of the patients was also independent of MDR1 gene expression of the tumours. Thus, these findings do not support the hypothesis that local aggressiveness of P-glycoprotein positive tumour cells translates into worse clinical outcome.
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PMID:MDR1 RNA transcripts do not indicate long-term prognosis in colorectal carcinomas. 933 99

In the study described here we investigated the possibility of an association between the aggressiveness of melanoma and multidrug resistance phenotype by analyzing the expression and activity of P-glycoprotein (Pgp) in two genetically related transplantable hamster melanomas--a melanotic (Ma) and an amelanotic (Ab) form --which differed in aggressiveness and metastatic potential. Flow cytometric analysis of Pgp activity (using a verapamil-sensitive rhodamine R123 exclusion test) as well as Western blotting of cellular lysates showed its preferential (although not very marked) expression in the Ab melanoma cells. The Ab melanoma cells also exhibited a higher proportion of tumor-infiltrating lymphocytes (TIL), mostly of T cell phenotype, that may have reflected a higher immunogenicity of the tumor. In conclusion, Pgp activity appeared to be associated with less-differentiated more aggressively metastasizing melanoma (the Ab variant) although its role in maintaining this phenotype remains to be established.
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PMID:Expression and activity of P-glycoprotein in transplantable hamster melanomas. 1096 60

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making.
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PMID:Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1. 1177 77

Vinblastine, vincristine and doxorubicyn are currently used in chemotherapeutic treatments of several malignancies including HIV-1 associated tumours Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL). Hence, AIDS patients also affected by KS and NHL may be simultaneously subjected to highly active antiretroviral therapy (HAART) and cytotoxic drugs to combat HIV-1 infection and cancer aggressiveness. In order to assess if the combination of these therapies may affect cell growth and survival of P-glycoprotein expressing MDR variants of the human CD4+ T-lymphoblastoid CEM cell line, the protease inhibitors (PI's) ritonavir, saquinavir and indinavir were tested in an in vitro assay for their ability to potentiate the vinblastine, vincristine and doxorubicyn cytotoxicity. The results we obtained demonstrated that at the concentration of 10 micrograms/ml, ritonavir and in a lesser extent saquinavir act as MDR reversing agents. By contrast, the PI indinavir at least in the CEM cell system, does not affect the patterns of drug resistance. The level of chemosensitization exerted by ritonavir and saquinavir suggests that these PI's may render P-glycoprotein expressing MDR cells de novo susceptible to the antineoplastic drugs vinblastine, vincristine and doxorubicyn.
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PMID:Modulation of the multidrug resistance (MDR) phenotype in CEM MDR cells simultaneously exposed to anti HIV-1 protease inhibitors (PI's) and cytotoxic drugs. 1276 Mar 35


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