Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate was shown to inhibit development of Rausher's leukosis and growth of spleen. Activity of DNA-dependent RNA polymerases A and B was distinctly altered. The activity of RNA polymerase B was increased two-fold within the first days of the leukosis development; RNA polymerase A was activated five-fold in the course of subsequent progression of the impairment. Methotrexate inhibited the RNA polymerase activity in leukemic spleens. As suggested by correlation between weight of the spleen and the activity of RNA polymerases A and B, the enzymatic activity may be considered as a marker of the leukosis development.
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PMID:[Effect of methotrexate on the activity of DNA-dependent RNA polymerases (A and B) in the spleen of mice infected with Rauscher leukemia virus and on the development of virus-induced leukemia]. 44 90

Methotrexate (MTX) transport was examined in 27 patients with untreated acute lymphocytic leukemia (ALL) and 31 patients with relapsed ALL using a previously described fluorescent MTX analog (PT430) displacement assay (Blood 80:1158, 1992). Only 13% of untreated patients were considered to have impaired MTX transport, whereas more than 70% of relapsed patients had evidence of impaired MTX transport. To further characterize the basis for this defect, Northern analyses for the reduced folate carrier (RFC) were performed on the RNA available from the leukemic blasts of 24 patients in whom MTX transport had been measured. Six of nine samples with impaired MTX transport had decreased RFC expression (one had no detectable RFC expression), while three had no decrease in RFC expression. None of 15 samples with normal MTX transport had decreased RFC expression. A reverse-transcriptase polymerase chain reaction (RT-PCR) assay was developed to quantitate RFC mRNA expression more accurately. Decreased RFC expression was demonstrated in six of the nine samples with impaired MTX transport, confirming the results obtained by Northern blot. These data indicate decreased RFC expression associated with impaired MTX transport is observed in relapsed ALL following treatment with MTX-containing therapy.
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PMID:Defective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression. 902 33

The DNA topoisomerase I (topo1) inhibitor topotecan (TPT) and topo2 inhibitors doxorubicin, etoposide and mitoxantrone (MXT) are widely used antitumor drugs. They stabilize otherwise transient ("cleavable") complexes of topo1 or topo2 with DNA, respectively. Collisions of DNA replication forks (during replication) or progressing RNA polymerase molecules (during transcription) with these complexes convert them into double-strand DNA breaks (DSBs). Formation of DSBs triggers activation of ATM and phosphorylation of histone H2AX, the markers that have been used to correlate DNA damage with cell cycle phase or induction of apoptosis. In the present study we explored a relationship between H2AX phosphorylation and activation of checkpoint kinase 2 (Chk2) in human lung carcinoma A549 cells treated with TPT or with MXT. Activation of Chk2 was detected immunocytochemically using a phospho-specific (Thr68) Ab and measuring Chk2-Thr68(P)immunofluorescence (IF), concurrently with DNA content, by laser scanning cytometry. In the untreated cells, activated Chk2 was present predominantly in centrosomes. Upon treatment with TPT or MTX, the activated Chk2 presented itself in form of either minute or large IF foci in the cell's nucleoplasm. H2AX phosphorylation whether induced by TPT or MXT was rapid, with the maximal rate occurring during the initial 2 h and peaking at 2 h of treatment. TPT or MXT induced Chk2 activation occurred at a distinctly slower pace, peaking at 4 h. While TPT-induced H2AX phosphorylation and Chk2 activation were maximal in S-phase cells, Chk2 activation was also much pronounced in G(2)M cells; the least affected by TPT were G(1) cells. MTX-induced H2AX phosphorylation was maximal in G(1) cells while Chk2 activation was maximal in G(2)M and minimal in G(1) cells. The pattern of cell-cycle phase specific response to TPT or MXT by H2AX phosphorylation and Chk2 activation was different when measured either as integrated or maximal pixel of gammaH2AX or Chk2-Thr68(P) IF, the former reflecting total IF per nucleus the latter stressing the punctate (foci) character of expression of these phospho-modified proteins.
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PMID:Kinetics of histone H2AX phosphorylation and Chk2 activation in A549 cells treated with topotecan and mitoxantrone in relation to the cell cycle phase. 1845 60

Mucins are a family of large glycoproteins that represent the major structural components of the mucus and are encoded by 20 different mucin genes. Mucin expression can be modulated by different stimuli. In this study, we analyzed four mucins (MUC2, MUC3, MUC13, and MUC17) in coculture of Caco-2/HT29-MTX cells to demonstrate the variation in gene expression in the presence of antioxidant compounds like chlorogenic acid, epicatechin gallate, and quercetin (apple, tea, and coffee polyphenols, respectively). coculture of Caco-2/HT29-MTX cells was treated with polyphenols, and the expression of four mucins was determined by reverse-transcriptase PCR. In addition, the secretion levels of MUC2 were established by enzyme-linked immunoassay (ELISA) analysis. The results showed that each polyphenol compound induces different expression patterns of the mucin genes. Statistically significant up-regulation of MUC17 was observed following incubation with epicatechin gallate and quercetin. ELISA results did not prove any significant differences in protein levels of MUC2 after treatment by the polyphenol compounds. The polyphenols considered in this study may influence mucin secretion and act on diverse salivary substrates to change the barrier properties of mucins for mucus secretion in different ways.
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PMID:Effects of chlorogenic acid, epicatechin gallate, and quercetin on mucin expression and secretion in the Caco-2/HT29-MTX cell model. 3084 27