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)

VLA2 is thought to be involved in the metastatic process in malignant tumours, in particular in carcinomatous cell adhesion to vessel basement membrane. VLA2 expression was immunohistochemically investigated in 204 breast carcinomas. Frozen tissue sections were probed with monoclonal anti-VLA2 using automated (Ventana ES 320 System) and quantitative (SAMBA 2005 image processor) immunoperoxidase. A positive anti-VLA2 immunoreaction was observed in 48 tumours (23.5%), within epithelial carcinomatous cells. The VLA2-positive surface in tumours varied from 3% to 20% (mean 8.75, S.D. 7.17) and was correlated with histoprognostic indicators and tumour expression of various antigens detected using the same method as that for VLA2. The results show that VLA2 immunoexpression was independent of the tumour size, grade, type and aneuploidy, and of the nodal status. VLA2 significantly correlated with ELAM, VCAM, VLA3 and P-glycoprotein (P-gp) (P < 0.01) and inversely correlated with cathepsin D (P < 0.001), but was independent of Ki67/MIB1, p53, bcl-2, c-erbB-2, E cadherin, CD44v, CD31, oestrogen and progesterone receptors' (ER, PR) antigenic sites and pS2. The exact role, if any, of VLA2 in tumour cell dissemination remains to be elucidated and the clinical relevance of VLA2 immunodetection in breast carcinomas requires further investigation of the correlation between VLA2 immunocytochemical expression and patients' outcome and response to chemotherapy.
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PMID:VLA2 integrin expression in breast carcinomas evaluated by automated and quantitative immunohistochemistry. 964 45

Non-Hodgkin's lymphomas (NHL) are B-cell malignancies which generally present molecular abnormalities, such as bcl-2 translocation t(14; 18) predominantly in the follicular subgroup. Other molecular events have been described in NHL, including p53 gene mutation and overexpression of one chemoresistance mechanism, the multidrug resistance system, P-glycoprotein (MDR 1/P-gp). In this study, we analysed samples from 44 NHL patients with the presence of the bcl-2 major breakpoint region (MBR) rearrangement in 29 and without in 15. Immunochemical analysis revealed that 39 samples were positive for bcl-2 protein expression in tumoral cells (88.6%). Seventeen (38.6%) patients expressed P-gp and 9 (20.5%) expressed p53 proteins. Eleven patients expressed both bcl-2 and P-gp proteins, four expressed bcl-2 and p53 proteins whereas four expressed bcl-2, p53 and P-gp proteins. Our results confirm the importance of p53 expression as a key prognostic factor, and no objective response (OR) was found in patients with p53 positivity. MBR rearrangement was not associated with poor response to chemotherapy (62.1% OR in MBR positive patients v. 60% OR in MBR negative patients). The clinical impact of P-gp cannot be identified because no relationship was observed between P-gp expression and prognosis (58.8% OR in P-gp positive patients v. 63% OR in P-gp negative patients).
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PMID:MBR rearrangement and P-glycoprotein expression are not independent prognostic factors like p53 protein in malignant lymphoma. 968 Dec 18

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

Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.
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PMID:Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. 981 81

Multidrug resistance-associated protein (MRP) is one of the major factors for non-P-glycoprotein (PGp)-mediated multidrug resistance. We reported previously that overexpression of the MRP gene was related to the prognosis of non-small cell lung cancer (NSCLC). It is unclear how MRP expression is regulated in NSCLC. In this study, we examined MRP and mutant p53 expression in 107 NSCLCs by immunohistochemical procedures. Forty-seven (43.9%) of these 107 NSCLCs were positive for MRP in the cytoplasm. Mutant p53-positive NSCLC showed a significant correlation with MRP overexpression (P=.011). Coexpression of MRP and p53 in the same cells of NSCLC was confirmed by double-staining procedures. Twenty-six patients with MRP-positive tumors who underwent postoperative chemotherapy with MRP-related anticancer drugs (vindesine and etoposide) had significantly poorer prognoses than did those with MRP-negative tumors (P=.017). This correlation between MRP expression and prognosis was also seen in Stage III patients (P=.022) and in patients with squamous cell carcinoma (P=.062). NSCLC patients with coexpression of MRP and p53 showed poorer prognoses than did those without MRP and p53 (P=.014). These results suggested that MRP overexpression affected by mutant p53 had a significant effect on prognosis through atypical non-PGp-mediated multidrug resistance in NSCLC.
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PMID:Multidrug resistance-associated protein and mutant p53 protein expression in non-small cell lung cancer. 983 Dec 2

While resistance to chemotherapy is a major problem in lung cancer treatment, there is no useful predictor of treatment response. We thus designed this study to determine the utility of p53 and P-glycoprotein expression in predicting the response to chemotherapy in patients with primary lung cancer, retrospectively. We evaluated transbronchial biopsy (TBB) specimens from 60 patients with lung cancer, who were previously untreated. Formalin-fixed, paraffin-embedded TBB specimens were immunostained using anti-p53 antibody (DO-1) and anti-P-glycoprotein antibody (JSB-1). The positivity of p53 was 63%, and that of P-glycoprotein was 17%. No correlation was observed between p53 and P-glycoprotein immunostaining. Positivity of p53 correlated significantly (P = 0.004) with a lack of response to chemotherapy in non-small cell lung cancer (NSCLC), but not in small cell lung cancer (SCLC). In contrast, positivity of P-glycoprotein was correlated with chemotherapy resistance in SCLC (P = 0.003), but not in NSCLC. Multiple logistic regression analysis revealed that positive immunostaining for p53 was a significant risk factor for chemotherapy resistance in NSCLC. These results suggest that immunostaining of p53 and P-glycoprotein for TBB specimens may help to predict response to chemotherapy in NSCLC and SCLC, although the results should be confirmed in a larger, more homogeneous series.
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PMID:Immunohistochemically detected p53 and P-glycoprotein predict the response to chemotherapy in lung cancer. 984 16

We previously reported the pharmacodynamics of antiproliferative and apoptotic effects of paclitaxel in histocultures of bladder, breast, head and neck, ovarian, and prostate tumors obtained from patients. This study examined the relationship between paclitaxel pharmacodynamics and tumor pathobiological parameters [i.e., stage, grade, proliferation status, expression of P-glycoprotein (Pgp), p53, and Bcl-2]. Pgp, p53, and Bcl-2 proteins were detected by immunohistochemical methods. The drug sensitivity rank order of the five tumor types is as follows: prostate > or = head and neck = bladder > breast > ovarian for the antiproliferative effect and breast = ovarian = head and neck > prostate = bladder for the apoptotic effect. When the pathobiological parameters were considered as single parameters, the antiproliferative effect was inversely correlated with tumor stage, grade, labeling index (LI), and expression of Pgp, p53, and Bcl-2 (P < 0.05 in all cases). The apoptotic effect was positively correlated with Pgp expression, LI, and tumor grade (P < 0.01) but was not related to tumor stage and expression of p53 and Bcl-2 (P > 0.2). Results of multivariate analysis indicated that the maximum antiproliferative effect was best predicted by the combination of tumor stage and expression of Pgp and p53 (inverse correlation) and that the maximum apoptotic effect was best predicted by the combination of tumor LI and Pgp expression (positive correlation). In summary, these results indicate that the two major effects of paclitaxel in human solid tumors, i.e., antiproliferation and apoptosis, correlate with different tumor properties. The second finding that drug-induced apoptosis was equal or higher in tumors that expressed Pgp, p53, and Bcl-2 compared to tumors that did not express these proteins supports the use of paclitaxel in treating Pgp-, p53- and Bcl-2-positive tumors.
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PMID:Relationship between paclitaxel activity and pathobiology of human solid tumors. 986 5

We investigated the antitumour effects of 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3,4-a]benzimidazole (TBZ) a new anti-HIV-1 agent, on human promyelocytic HL60 leukaemia, both a parental and a multidrug resistant form (HL60R). HL60R overexpresses P-glycoprotein and, like HL60, lacks p53 protein expression. HL60 and HL60R show similar levels of Bcl-2 protein. In contrast to the conventional chemotherapeutic agents daunorubicin, etoposide and mitoxantrone, TBZ caused equal or even greater cytotoxicity in HL60R than in HL60, and this result was associated with a more marked induction of apoptosis in the drug resistant cells. The antitumour activity of TBZ occurred in the range of concentrations higher than those required to exert antiviral activity. TBZ seems to act in the presence of P-glycoprotein and Bcl-2 and in the absence of p53 and is able to circumvent the mechanisms of drug resistance and anti-apoptosis present in HL60R cells.
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PMID:Selective induction of apoptosis in multidrug resistant HL60R cells by the thiazolobenzoimidazole derivative 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3,4-a] benzimidazole (TBZ). 989 65

The transcription of MDR1 gene may be increased by mutation or loss of function of p53 gene. In this study, we investigated whether in osteosarcoma, the p53 status is correlated with overexpression of the MDR1 gene product P-glycoprotein. The relationship between P-glycoprotein expression and p53 status was analyzed by immunohistochemistry in 64 primary and 11 metastatic high-grade osteosarcomas. In the same series, we also assessed the nuclear accumulation of MDM2 protein, whose binding to p53 protein provides an alternative mechanism of p53 inactivation. No association was found between mutant-p53 and MDM2 nuclear accumulation either with P-glycoprotein expression or with clinical course. Only increased expression of P-glycoprotein in tumor cells was significantly associated with a poor outcome, further supporting the adverse prognostic value of this marker in osteosarcoma.
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PMID:Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma. 991 6

P-glycoprotein (Pgp) encoded by the MDR1 gene, a predictor of chemoresistance, may also serve as a prognosticator of clinical outcome in cancer patients. The mutant tumour-suppressor p53 protein has been shown to activate the MDR1 promoter, whereas the wild-type p53 represses this activity in cultured cells. We have described the differential expression of Pgp and p53 proteins in betel- and tobacco-related oral tumorigenesis in the Indian population. Herein, Pgp expression was analysed in relation to p53 protein accumulation in pre-malignant and malignant oral lesions by immunohistochemical and flow-cytometric analyses. The relationship between Pgp and p53 protein accumulation and clinicopathological parameters as well as prognosis was determined. Expression of Pgp was observed in 81% of oral squamous cell carcinomas (SCCs) and 71% of pre-malignant lesions. Sixty-five of 75 p53-positive oral SCCs and 21/24 p53-positive pre-malignant lesions showed expression of Pgp. Significant correlation between Pgp and p53 expression was found not only in oral SCCs but also in pre-malignant lesions. Co-expression of Pgp and p53 proteins was indicative of poor prognosis. Follow-up studies of 35 patients showed that 7 of 10 oral SCCs with accumulation of Pgp and p53 proteins also exhibited shorter disease-free survival (recurrence/metastases). Our findings provide clinical evidence for a significant association between Pgp and p53 protein expression in oral tumorigenesis and may account for the aggressive nature of the tumour and poor prognosis.
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PMID:P-glycoprotein is positively correlated with p53 in human oral pre-malignant and malignant lesions and is associated with poor prognosis. 998 37


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