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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Associations between hematopoietic cells and their microenvironment are central to the development and maintenance of a functional hematopoietic system. It is important, therefore, to identify the surface receptors that mediate adhesive interactions among hematopoietic cells, stromal cells, and extracellular matrix components. In this study, we examined the expression of mRNA transcripts encoding a number of cell adhesion molecules and surface antigens in primitive hematopoietic cells isolated from murine bone marrow and fetal liver. Using a panel of probes, we hybridized a library of globally amplified cDNA prepared by reverse transcriptase-polymerase chain reaction of poly(A)+ mRNA from individual precursors and mature cell populations, representing precisely defined positions within the hematopoietic developmental hierarchy. The panel included probes specific for the CD45, CD34, P-glycoprotein (mdr1), Ly-6A/E (Sca-1), heat stable antigen (CD24), Fc receptor for IgG FcgammaRII (CD32), CD44, CD22, and ICAM-1 (CD54) genes, as well as alphaL (CD11a), alphaM (CD11b), beta2 (CD18), alpha4 (CD49d), alpha5 (CD49e), beta1 (CD29), and beta7 integrin subunit sequences. The data, which revealed stage- and lineage-specific expression patterns, should prove useful in designing future mechanistic studies aimed at elucidating the role played by adhesion receptors in normal and abnormal hematopoiesis.
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PMID:Expression mapping of adhesion receptor genes during differentiation of individual hematopoietic precursors. 932 54

Renal cell carcinoma (RCC) displays strong resistance against many chemotherapeutic drugs. Overexpression of P-glycoprotein (Pgp) appears to be part of this resistance. The involvement of another resistance mechanism, involving the decreased activity of DNA topoisomerase II (topoII), remains uncertain. By culturing the human RCC lines RC2 and RC21 in the presence of increasing concentrations of etoposide, we derived the variant sublines RC2E, RC21A and RC21E, that had acquired approximately 30-, 60- and 90-fold resistance to this drug respectively. RC2E, RC21A and RC21E were approximately 50-, 5- and 400-fold cross-resistant to doxorubicin respectively. RC2E and RC21E also showed cross-resistance (approximately 200- and 3500-fold respectively) to vinblastine. Quantitative differences in MDR1 and Pgp expression (elevated in RC2E and RC21E) and topoII alpha (reduced in RC21E and RC21A) were demonstrated using Western blotting and the reverse transcriptase/polymerase chain reaction. Decreased amounts of topoII alpha were reflected in a reduced activity of RC21A and RC21E as measured by unknotting phage P4 DNA. Qualitative changes of the topoII alpha gene, such as point mutations in the motif B/DNBS and DNA-binding regions, or differences in methylation status of the promoter gene of RC21E, were not found. These cell lines represent a model of a solid tumor in which overexpression of Pgp, a combination of increased Pgp and decreased topoII alpha, and a decrease of topoII alpha are represented.
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PMID:Decreased levels of topoisomerase II alpha in human renal cell carcinoma lines resistant to etoposide. 939 88

Before the prognostic significance of P-glycoprotein (P-gp) expression can be properly evaluated in prospective clinical trials of P-gp modulators, standard techniques for the measurement of P-gp must be widely accepted. Several multicenter trials have demonstrated large discrepancies in the observed levels of P-gp expression in the same clinical samples evaluated at different centers. The greatest discrepancies occurred with samples that expressed low levels of P-gp. Although standardized procedures have dramatically increased the interlaboratory reproducibility of flow cytometry and polymerase chain reaction assays, data from immunocytochemistry remain difficult to interpret. Consensus recommendations are presented for improving data reproducibility. These recommendations emphasize the importance of using calibrated batches of antibodies and two different antibodies for immunocytochemistry, the need for an internal standard for reverse transcriptase-polymerase chain reaction (RT-PCR) assays, the need for the presentation of data as a continuous variable, and the need for setting standard parameters for flow cytometry. It is also extremely important for the success of clinical trials that multiple techniques be employed to insure accurate measurement of P-gp expression.
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PMID:Measuring multidrug resistance expression in human malignancies: elaboration of consensus recommendations. 940 62

The effect of substituted phenothiazines was studied in three different systems; bacteria and cancer cells and reverse transcriptase enzyme of Moloney leukemia virus. F'lac and hemolysin plasmids were eliminated by some substituted phenothiazines from E. coli at a very low frequency. The same phenothiazine derivatives also were synergistic with tetracycline in bacteria and shown antimutagenic effect in Ames test. No mutagenic effects were observed in TA 98 strain of Salmonella typhimunium. Chloroethyl-substituted phenothiazines showed antimutagenicity equivalent to the parent compounds; however, phthalimido-substituted phenothiazines had higher antimutagenicity of 50%. P-glycoprotein responsible for multidrug resistance was also inhibited in tumor cells. The accumulation of the fluorescent rhodamine 123 in the phenothiazine treated multi-drug resistant tumor cells was measured by flow cytometry. Some of the substituted phenothiazines were effective P-glycoprotein blockers, while some compounds had moderate activity, but others were without effect as compared to 5 microM verapamil. On the basis of computer analysis there are some correlations between the biological activities and the dipole moments, and entropy of the studied molecules. Our results suggest that the inhibition of Hly+ plasmid replication and P-glycoprotein function may depend partly on similar electronic properties of the studied phenothiazine derivatives. The activity of Moloney leukemia virus reverse transcriptase was inhibited by the substituted phenothiazines, however, no basic differences were found in the activities of phthalimido- and chloroethyl substituted phenothiazines.
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PMID:Drug resistance reversal, anti-mutagenicity and antiretroviral effect of phthalimido- and chloroethyl-phenothiazines. 941 99

We have demonstrated that low-level expression of P-glycoprotein (PGP), detectable by reverse transcriptase polymerase chain reaction (RT-PCR) assay and flow cytometric assay, is an important factor in multidrug resistance (MDR) in ACHN cancer cells. In this study, we established a subline highly resistant to adriamycin (ACHN/ADM) from ACHN cells, and determined the correlation between PGP levels and MDR levels using ACHN/ADM cells and their parent ACHN cells. The ACHN/ADM cells showed overexpression of PGP, and sensitivity to antitumor agents was lower than that found in ACHN cells. Intracellular accumulation of ADM in ACHN/ADM cells was approximately half the amount of its accumulation in ACHN cells. Sensitivity to ADM in ACHN/ADM cells was enhanced by chemosensitizers with an increase in intracellular ADM accumulation. These results indicate that PGP levels correlate with MDR levels and suggest that chemotherapy using chemosensitizers might be effective in the treatment of renal cancers with overexpression of PGP.
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PMID:Correlation of expression levels of P-glycoprotein with resistance to adriamycin in a renal adenocarcinoma cell line. 944 50

We examined the expression levels of P-glycoprotein (P-Gp)/the human multidrug resistance gene (MDR1) and in vivo chemosensitivity in the 7 osteosarcoma xenografts. Three of seven (43%) osteosarcoma xenografts expressed MDR1 by reverse transcriptase-polymerase chain reaction (RT-PCR). The OSS-516R xenograft selected with vincristine (VCR) from the MDR1-negative xenograft OSS-516, which was sensitive to VCR and doxorubicin (DOX), acquired cross-resistance to DOX. In the OSS-516R, RT-PCR assay showed definite MDR1 expression and immunohistochemical analysis demonstrated P-Gp-positive tumor cells. These results suggest that P-Gp/MDR1 overexpression is related to multidrug resistance in human osteosarcoma in vivo.
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PMID:Multidrug resistance mediated by overexpression of P-glycoprotein in human osteosarcoma in vivo. 945 50

To combat infection and inhibit viral replication of HIV in the brain, antiretroviral agents must cross the blood-brain barrier (BBB). An in vitro BBB model consisting of bovine brain microvessel endothelial cells grown on porous filters was used to study and compare the transport of nevirapine, a potent and selective nonnucleoside reverse transcriptase inhibitor, with other HIV antiretroviral agents currently in use for the treatment of HIV infection. These included nucleoside reverse transcriptase inhibitors (didanosine, stavudine, zalcitabine, zidovudine), a nonnucleoside reverse transcriptase (delaviridine), and protease inhibitors (indinavir, saquinavir, VX-478). Nevirapine was the most permeable antiretroviral agent studied in the BBB model. The order of in vitro BBB permeability was nevirapine >> VX-478 > didanosine, stavudine, zalcitabine, zidovudine > indinavir > saquinavir. There was an apparent bell-shaped relationship between in vitro BBB permeability and octanol/phosphate-buffered saline distribution coefficient (D) where all lipophilic (log D > 2.5) as well as hydrophilic (log D < -0.5) antiretrovirals were less permeable than nevirapine (log D = 1.8). There were no significant effects on the in vitro BBB permeability of nevirapine in combination with other antiretroviral agents. Saquinavir was the only drug shown to have an affinity for the P-glycoprotein efflux pump, which may have contributed to its very low permeability. The apparent ability of nevirapine to readily permeate the BBB and enter the brain, where it may inhibit replication of HIV, potentially increases its therapeutic value.
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PMID:In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. 952 83

Expression of multidrug resistance (mdr) genes encoding the P-glycoprotein (P-gp) drug efflux pump was analysed in cultured rat liver epithelial cells acutely treated by the DNA-damaging agent methyl methanesulfonate (MMS). Exposure to this alkylating agent used at 30 microg/ml for 12 or 24 h was shown to enhance mdr mRNA levels in rat liver cells without alteration of cell viability. Induction of mdr transcripts occurred through increased expression of the mdr1b gene as indicated by reverse transcriptase-polymerase chain reaction analysis using rat mdr gene-specific primers and was not associated with up-regulation of cytochrome P-450 1A1, thereby suggesting that this detoxifying enzyme and P-gp were not coordinately regulated by MMS. In addition, the DNA-damaging agent was found to enhance in a dose-dependent manner cellular efflux of the P-gp substrate rhodamine 123, which was inhibited by the P-gp inhibitor verapamil, thus providing evidence that exposure to MMS led to increased P-gp-related drug transport in rat liver cells. The up-regulation of functional P-gp expression occurring in MMS-treated liver cells may be interpreted as a part of the cellular response to DNA damage.
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PMID:Induction of multidrug resistance gene expression in rat liver cells in response to acute treatment by the DNA-damaging agent methyl methanesulfonate. 953 88

To evaluate the clinical significance of drug resistance mechanisms in breast cancer, we examined the expression of MDR1 and MRP in primary breast carcinoma and normal adjacent tissue using a highly quantitative and reproducible reverse transcription-PCR assay. Expression of both genes was observed in all specimens examined, both tumor (n = 74) and normal adjacent tissue (n = 55). The expression of MDR1, however, was low, with the level of expression being 25 times less than the drug-resistant control cell line KB 8-5. Immunohistochemical analysis of P-glycoprotein corroborated the PCR results; only 6% (2 of 31) were positive for JSB1 staining, and 0 of 32 were positive for for UIC2. MRP expression did not exceed control cell line levels, and immunohistochemistry detected moderate levels of expression. MDR1 expression was independent of grade, stage, tumor size, nodal status, metastasis, and estrogen receptor and progesterone receptor status. There was, however, a significant correlation of MDR1 expression with age and histology. Approximately twice the expression of MDR1 was observed in the < 50 age group compared to the > 50 age group, and lobular carcinoma had 4 times the expression of MDR1 of other histological types. MRP expression was independent of all other clinical parameters. Thus, these results show that although MDR1 expression is detectable in primary breast carcinoma by PCR, this expression as measured by quantitative reverse transcriptase-PCR is extremely low. The significance of these low levels is yet to be determined. MDR1 expression was higher in < 50 age group and lobular carcinoma, which may contribute to poor prognosis associated with young age and lobular histology.
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PMID:Quantitative reverse transcriptase-polymerase chain reaction measured expression of MDR1 and MRP in primary breast carcinoma. 962 74

The resistance of tumor cells to chemotherapeutic drugs is a major obstacle to successful cancer chemotherapy. Expression of the MDR 1 gene, which encodes for a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of anticancer drugs. Recently, one mutant p 53 form was shown to stimulate the MDR 1 gene promoter in vitro, whereas wild-type p 53 repressed this activity. We examined the relationship between p 53 gene mutation and MDR 1 gene expression in specimens from non-small cell lung cancer patients. Tumor samples were obtained from 21 patients during surgery. Mutations of exon 5 through exon 8 of the p 53 gene were detected by the polymerase chain reaction single strand conformation polymorphism method. MDR 1 expression was semi-quantified by the reverse transcriptase polymerase chain reaction method. We identified p 53 gene mutation in samples from 7 patients. MDR 1 gene expression was observed in samples from 20 patients. The expressivity of the MDR 1 gene tended to be higher in patients with adenocarcinoma. No significant relationship between p 53 mutation and MDR 1 expressivity was observed in our study.
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PMID:[Relationship between p 53 gene mutation and MDR 1 gene expression in surgically resected non-small cell lung cancer]. 1070 35


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