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)

Expression of the multidrug resistance gene MDR1 is reported to be an important determinant of the response to chemotherapy and survival in some cancers. We compared three methods for determining the intrinsic MDR1 expression in soft tissue sarcomas. We studied MDR1 gene expression in 39 samples from 33 cases of soft tissue sarcomas comprising 11 liposarcomas, nine malignant fibrous histiocytomas, six leiomyosarcomas, four malignant schwannomas, three fibrosarcomas, three synovial sarcomas, and three epithelioid sarcomas, and seven cases of benign soft tissue tumors in adult patients. To detect MDR1 mRNA, reverse transcriptase-polymerase chain reaction (RT-PCR) was performed in all samples. Furthermore, RNA dot-blot analysis with digoxigenin-labeled RNA probe and immunohistochemistry with JSB-1 and C-219 antibodies for P-glycoprotein were employed in 34 and 37 samples in soft tissue sarcomas, respectively. We compared these three detection techniques. Of the 39 specimens, 18 (46%) showed MDR1 PCR products. Liposarcomas (six of 11), malignant fibrous histiocytomas (six of nine), leiomyosarcomas (four of six), fibrosarcomas (two of three) revealed high or intermediate MDR1 expression at high frequency. No MDR1 expression was detectable in malignant schwannomas, synovial sarcomas, or epithelioid sarcomas. Of seven benign soft tissue tumors, one ganglioneuroma and one lipomatosis showed low levels of MDR1 expression. By RNA dot-blot analysis, MDR1 transcripts were detectable in 12 of 34 specimens (35%). Four samples were negative by dot blot despite positivity with RT-PCR. Concordance between MDR1 expression by RNA level with RT-PCR and dot blot and at the protein level with immunohistochemistry using C-219 was found in 16 (47%) of the 34 comparable specimens. Eight samples showed positive immunoreactivity for C-219 despite negative results in RT-PCR and dot-blot analysis. The intrinsic MDR1 expression in soft tissue sarcoma seemed to depend on certain tumor types, such as liposarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and fibrosarcoma. For the evaluation of MDR1 expression, RT-PCR is useful because of its relative simplicity and sensitivity. However, the clinical significance of such low levels of MDR1 expression detected only by RT-PCR must be discussed within systematically treated patient groups.
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PMID:Reverse transcriptase-polymerase chain reaction amplification of MDR1 gene expression in adult soft tissue sarcomas. 872 96

1. Multidrug resistance is the major obstacle to successful cancer chemotherapy. Circumventing multidrug resistance therefore represents a high priority for clinical anti-cancer treatment. Among many reversal strategies, antisense oligodeoxynucleotides may offer a molecular targeting tool for overcoming cellular multidrug resistance. 2. Two 17-mer phosphorothioate antisense oligomers, complementary to the 5' end of the ATG initiator codon-containing region and loop-forming site (located at nucleotides 991-1007 from the first ATG codon) in mdr-1 cDNA sequence, were synthesized. The purpose was to study their effects on the function and expression of P-glycoprotein and mdr-1 gene. 3. The results showed that 10 mumol/l antisense oligomers could significantly inhibit the growth of multidrug resistant K562/Adm cells cultured in adriamycin-containing medium. No such effect was observed for parental (sensitive) K562/S cells. Intracellular daunorubicin accumulation increased greatly in the K562/Adm cells after they were treated with oligomers for 48 h and P-glycoprotein synthesis was strikingly reduced. 4. Further investigation with [alpha-32P]dCTP incorporation by the reverse transcriptase-polymerase chain reaction method revealed that antisense oligomers could result in a reduction in the level of mdr-1 mRNA, probably through hindering mdr-1 gene transcription. 5. The high reversal efficiency and specificity of antisense oligomers in regulating mdr-1 gene expression suggest a potential clinical application in gene therapy for drug resistant malignancies.
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PMID:Modulation of multidrug resistance gene (mdr-1) with antisense oligodeoxynucleotides. 877 66

The purpose of the present study is to examine spatial and temporal expression of P-glycoprotein in the brain of congenitally hydrocephalic HTX rats. P-glycoprotein has been reported not only as a drug efflux pump but also one of the factors that restricts brain edema. We examined the rat brain from postnatal day 1 to 60 using light and electron microscopy, immunohistochemistry, Western immunoblot and reverse transcriptase-polymerase chain reaction (RT-PCR) methods with monoclonal antibody specific for P-glycoprotein. Immunohistochemically, the positive anti-P-glycoprotein reactivity was found in capillaries of the normal control rat cerebrum. In the hydrocephalic HTX rat brains, it was also found in the capillaries, but only very weak to no reactivity was found in the capillaries of the spongy changes and cystic wall in the subcortical and lateral periventricular white matter. Immunoelectron microscopically, the reaction product was found exclusively on the luminal surface of the capillary endothelium in control rats. A tracer study with intracardiac perfusion of lanthanum chloride showed that lanthanum penetrated the tight junctions and passed through the intercellular space. In the Western immunoblot analysis, P-glycoprotein of 170 kDa was detected clearly in most normal control rat brains but it was not found in the hydrocephalic HTX rat brains. Moreover, mdr1 P-glycoprotein gene expression in the subcortical white matter was examined by RT-PCR. It was detected in all normal control rat brains, but not found in the hydrocephalic HTX rat brains. The results suggested that the absence of P-glycoprotein expression in the capillaries of deep subcortical and lateral periventricular white matter of hydrocephalic HTX rats led to a deficiency of the blood-brain barrier and might be related to vasogenic edema and to the formation of the spongy changes and cystic cavities.
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PMID:Spatial and temporal expression of P-glycoprotein in the congenitally hydrocephalic HTX rat brain. 883 57

Research into the relative importance of P-glycoprotein (pgp) overexpression, in comparison to other mechanisms of multidrug resistance (mdr) phenotype development, has been hampered by difficulties of measurement in clinical samples. The small size, heterogeneity and often poor quality of clinical specimens renders the quantitation of mdr mRNA species by Northern analysis or RNAse protection difficult. The reverse transcriptase-polymerase chain reaction (RT-PCR) assay has both the sensitivity and specificity to make it suitable for the analysis of mdr mRNA levels in clinical samples. It also has a significant speed advantage over Northern and RNAse protection analysis. Unfortunately the variable nature of the reactions involved have made it difficult to obtain accurate and reproducible quantitative data. To overcome this difficulty we constructed internal RNA standards to each human and rat mdr mRNA species. When included in the RT-PCR reaction these internal standards allow both comparative and absolute quantitation of individual mdr family mRNA levels.
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PMID:Use of internally controlled reverse transcriptase-polymerase chain reaction for absolute quantitation of individual multidrug resistant gene transcripts in tissue samples. 890 50

Prostate carcinomas are in general resistant against virtually all cytotoxic drugs. Up to now it has not been thoroughly evaluated whether specific resistance factors, such as the expression of the MDR1 gene, play a role in this multi-agent resistance and whether there is a link between drug resistance and hormone-independent growth. We investigated the resistance patterns of a hormone-sensitive and four hormone-independent Dunning rat carcinoma sublines against four drugs which are substrates of P-glycoprotein (vinblastine, taxol, doxorubicin, and etoposide) and two agents (methotrexate and cis-platinum) which are not transported by this efflux pump. All hormone-insensitive sublines, AT.1, AT. 3.1., MatLu and Mat LyLu, continuously showed a clearly enhanced resistance (3- to 26-fold) against the P-glycoprotein substrates, compared to the hormone-sensitive subline G. Only two of the androgen-independent sublines displayed enhanced resistance against methotrexate, whereas all of them were more sensitive against cisplatin than the androgen-sensitive G cells. By addition of verapamil the resistance against vinblastine (9- to 10-fold) and taxol (6.7- to 26.7-fold) in the hormone-insensitive cells could be almost totally reversed. Furthermore, the fluorescent P-glycoprotein substrate rhodamine-123 was effectively pumped out of the four tested hormone-independent cell lines, whereas the hormone-sensitive G cells were unable to extrude the dye. By reverse transcriptase polymerase chain reaction (RT-PCR) with primers specific for the rat mdr1b gene, the homologue to the human MDR1 gene, we could easily detect mdr1b expression in the androgen independent cell lines, but not in the G cells. Our results suggest that the product of the rat mdr1b gene is involved in the multidrug resistance of androgen-independent Dunning prostate carcinoma cells.
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PMID:Multidrug resistance in androgen-independent growing rat prostate carcinoma cells is mediated by P-glycoprotein. 907 44

There is considerable variation in the assays used to evaluate the expression of mdr1 in various human malignancies. Current methodology includes reverse transcriptase polymerase chain reaction (RT-PCR) for assay of mdr1 mRNA, and immunohistochemistry or flow cytometry for detection of the multidrug transporter, P-glycoprotein(P-gp). Normal tissues, such as gastrointestinal mucosa, biliary tract and kidney, express high levels of P-gp, which suggests physiologic functions for this transporter. The some evidence suggests that mdr1 expression is a prognostic factor for response to chemotherapy, as well as for subsequent survival in various kind of tumors. We have developed a novel method using flow cytometry for detection of P-gp in gastric carcinomas. A strong correlation was noted between the flow cytometric data and the degree of drug resistance assessed by thymidine incorporation assay (TIA). We believe that this technique may have a significant potential to be utilized in prediction of P-gp related drug resistance in clinical cancer chemotherapy.
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PMID:[Detection of P-glycoprotein and its clinical significance]. 915 54

A 19-year-old:female patient with malignant schwannoma in the right knee was treated by combination chemotherapy including lipophilic anticancer compounds (cyclophosphamide, doxorubicin, vincristine and dacarbazine). The tumor was radically removed after chemotherapy, but metastatic lesions were noted in the right inguinal nodes. The patient died due to the cachexic state six months after surgery. In human neoplasm, P-glycoprotein (P-Gp) encoded by human multidrug resistance gene MDR1 is known to be related with multidrug resistant phenotype. Northern blot analysis revealed apparent MDR1 expression in the metastatic lesion, while the primary lesion showed faint MDR1 expression detected by only reverse transcriptase-polymerase chain reaction. P-Gp positive tumor cells were immunohistochemically detected both in the metastatic lesion and the primary lesion. The P-Gp-positive tumor cells in the metastatic lesion showed anaplastic features with highly atypical nuclei. These results suggest that MDR1 overexpression is related to the multidrug resistance phenomenon in the malignant schwannoma with morphological differences.
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PMID:A case of malignant schwannoma with overexpression of multidrug resistance gene (MDR1) after chemotherapy. 921 1

MDR1 P-glycoprotein (Pgp 170), a member of the adenosine triphosphate (ATP) binding cassette transporters, acts as an efflux pump for various hydrophobic agents, particularly for xenobiotics such as benzo(a)pyrene. It has also been shown to regulate cell-volume activated chloride channels. Pgp 170 could, therefore, be of particular importance in cellular mechanisms of defence in the airways and in the control of mucus layer composition. For these reasons, we evaluated the precise localization of Pgp 170 in human adult airways. Fresh non-neoplastic bronchial specimens were collected from 33 patients (26 smokers, four exsmokers and three nonsmokers) who underwent surgery for lung carcinoma. The presence of MDR1 messenger ribonucleic acid (mRNA) was demonstrated by reverse transcriptase chain reaction (RT-PCR) in bronchial epithelial cells collected by gentle scraping from either smokers, exsmokers or nonsmokers. Immunodetection of Pgp 170 using a panel of monoclonal antibodies (MRK16, JSB1, C219, C494) was performed either on cryostat or paraffin-embedded sections of histologically normal bronchial tissue. Pgp 170 was constantly detected with intense labelling at the apical surface of ciliated epithelial cells from the surface epithelium or ciliated collecting ducts, and on apical and lateral surfaces of serous cells from bronchial glands. No staining of mucus-secreting cells was observed. Pgp 170 was also demonstrated at the luminal surface of endothelial cells of bronchial capillaries. In conclusion, the expression of MDR1 P-glycoprotein in bronchial structures, particularly at the epithelial apical surface, suggests important roles for this transmembrane protein in human airways.
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PMID:MDR1-Pgp 170 expression in human bronchus. 927 28

Human glioma usually shows intrinsic multidrug resistance because of the blood-brain barrier (BBB), in which membrane-associated P-glycoprotein (P-gp), encoded by the human multidrug resistance gene MDR1, plays a role. We studied drug sensitivity to vincristine (VCR), doxorubicin (DOX) and nimustine (ACNU) in both intracerebrally and subcutaneously xenotransplanted human glioma. We examined the levels of MDR1 and murine mdr3 gene expression in the xenografts by reverse transcriptase polymerase chain reaction and the localization of P-gp by immunohistochemistry. Six of seven subcutaneously transplanted xenografts (scX) were sensitive to the above three drugs. In contrast, all three intracerebrally transplanted human glioma xenografts (icX) were resistant to P-gp-mediated drugs VCR and DOX, but were sensitive to the non-P-gp-mediated drug ACNU. Neither icX nor scX showed any MDR1 expression. Intracerebrally transplanted human glioma xenografts showed an increased level of murine mdr3 gene expression, whereas scX showed only faint expression. The localization of P-gp was limited to the stromal vessels in icX by immunohistochemistry, whereas scX expressed no P-gp. Our findings suggest that the P-gp expressed on the stromal vessels in icX is a major contributing factor to multidrug resistance in human glioma in vivo.
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PMID:Murine P-glycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts. 927 20

We have established competitive reverse transcriptase polymerase chain reaction (RT-PCR) assay for the quantification of MDR1 mRNA encoding P-glycoprotein (P-gp) by analyzing leukemia sublines of MOLT-3 with various expression of MDR1. The expression was quantified by simultaneous RT-PCR of cellular RNA with decreasing amounts of heterologous competitor RNA, which shares the MDR1 primer sequences with the cellular MDR1 mRNA, but yields a different-sized PCR product. This allows resolution of the amplified cDNA fragments. The amounts of MDR1 mRNA measured by the assay were accurate and reproducible over wide range, and were determined as 31.6, 100, and 316 amol/microgram total RNA in MOLT-3/TMQ70, MOLT-3/ TMQ800, and MOLT-3/VCR1,000, respectively. The relative ratio of MDR1 mRNA measured by the competitive RT-PCR among three sublines was similar to that of MDR1 transcript determined by Northern analysis (1:4:12) and to that of P-gp measured by flow cytometry (FCM) analysis. In mononuclear cells from patients with leukemia, MDR1 mRNA could be sufficiently quantified by the competitive RT-PCR established, while FCM assay could scarcely detet P-gp. This study demonstrated that the competitive RT-PCR assay using heterologous competitor RNA is a rapid, reliable, and non-radioactive procedure and is acceptable for the evaluation of MDR1 expression in clinical samples.
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PMID:Quantitative analysis of human multidrug resistance 1 (MDR1) gene expression by nonisotopic competitive reverse transcriptase polymerase chain reaction assay. 929 93


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