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

Because the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and the multitargeted antifolate pemetrexed are registered in the treatment of second-line non-small-cell lung cancer (NSCLC), empirical combinations of these drugs are being tested. This study investigated molecular mechanisms underlying their combination in six NSCLC cell lines. Cells were characterized by heterogeneous expression of pemetrexed determinants, including thymidylate synthase (TS) and dihydrofolate reductase (DHFR), and mutations potentially affecting chemosensitivity. Pharmacological interaction was studied using the combination index (CI) method, whereas cell cycle, apoptosis induction, and EGFR, extracellular signal-regulated kinases 1 and 2, and Akt phosphorylation were studied by flow cytometry, fluorescence microscopy, and enzyme-linked immunosorbent assays. Reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, and activity assays were performed to assess whether erlotinib influenced TS. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays demonstrated that EGFR and k-Ras mutations were related to erlotinib sensitivity, whereas TS and DHFR expression were related to pemetrexed sensitivity. Synergistic cytotoxicity was found in all cells, most pronounced with pemetrexed + erlotinib (24 h) --> erlotinib (48 h) sequence (CI, 0.09-0.40), which was associated with a significant induction of apoptosis. Pemetrexed increased EGFR phosphorylation and reduced Akt phosphorylation, which was additionally reduced by drug combination (-70.6% in H1650). Erlotinib significantly reduced TS expression and activity, possibly via E2F-1 reduction, as detected by RT-PCR and Western blot, and the combination decreased TS in situ activity in all cells. Erlotinib and pemetrexed showed a strong synergism in NSCLC cells, regardless of their genetic characteristics. Induction of apoptosis, modulation of EGFR and Akt phosphorylation, and changes in the expression of critical genes involved in pemetrexed activity contribute to this synergistic interaction and support the clinical investigation of these markers.
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PMID:Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. 1818 83

A novel virulent bacteriophage, vB_VspP_pVa5, infecting a strain of Vibrio splendidus was isolated from a sea-cage aquaculture farm in Greece, and characterized using microbiological methods and genomic analysis. Bacteriophage vB_VspP_pVa5 is a N4-like podovirus with an icosahedral head measuring 85 nm in length and a short non-contractile tail. The phage had a narrow host range infecting only the bacterial host, a latent period of 30 min and a burst size of 24 virions per infected bacterium. Its genome size was 78,145 bp and genomic analysis identified 107 densely-packed genes, 40 of which could be annotated. In addition to the very large virion encapsulated DNA-dependent RNA polymerase which is the signature of the N4-like genus, an interesting feature of the novel phage is the presence of a self-splicing group I intron in the thymidylate synthase gene. A tRNAStop interrupted by a ~2.5kb open reading frame-containing area was also identified. The absence of genes related to lysogeny along with the high efficacy observed during in vitro cell lysis trials, indicate that the vB_VspP_pVa5 is a potential candidate component in a bacteriophage cocktail suitable for the biological control of V. splendidus in aquaculture.
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PMID:Isolation and characterization of a N4-like lytic bacteriophage infecting Vibrio splendidus, a pathogen of fish and bivalves. 2928 14


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