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: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of substituted 2-acylpyridine-alpha-(N)-hetarylhydrazones was prepared and studied for their effects on mammalian ribonucleotide reductase activity using a highly purified enzyme preparation from Ehrlich tumor cells and on mouse leukemia L1210 cell growth in culture. Pyridine-2-aldehyde-2-pyridylhydrazone (PH 22), ethyl-2-pyridylketone-I-phthalazinylhydrazone (PH 22-25) and pyridine-2-aldehyde-2'-quinolylhydrazone (PQ 22) inhibited purified ribonucleotide reductase activity and inhibited L1210 cell growth in culture. PH 22-25 inhibited [3H]thymidine incorporation into DNA and inhibited ribonucleotide reductase activity in situ (as measured bvy [14C]cytidine metabolism and as a result inhibited DNA synthesis. There was no effect on RNA synthesis. These data indicate that these substituted hydrazones are potent inhibitors of tumor cell growth through the inhibition of ribonucleotide reductase.
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PMID:Substituted 2-acylpyridine-alpha-(N)-hetarylhydrazones as inhibitors of ribonucleotide reductase activity and L1210 cell growth. 807 87

The R2 gene of ribonucleotide reductase is elevated in BALB/c 3T3 fibroblasts treated with the tumor promotor, 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA treatment increased the half-life of the R2 message by 3-fold, showing that TPA regulates R2 gene expression by a post-transcriptional mechanism(s). A 20-nucleotide (nt) TPA-responsive region was found within the R2 mRNA 3'-untranslated region (3'UTR). Ultraviolet cross-linking detected a novel 45-kDa protein-R2 mRNA complex migration band that bound selectively to the 20-nt fragment and did not bind to the 5'UTR or the coding region of the R2 message, or to the 3'UTRs of mRNA from several other genes, or to the homopolymer poly(A) sequence. The-45 kDa protein-R2 mRNA binding activity observed in unstimulated cells was markedly down-regulated after TPA treatment. Deletion of a 201-nt region, containing the 20-nt sequence, from the 3'UTR caused stabilization of hybrid chloramphenicol acetyltransferase mRNA in the absence of TPA treatment. Furthermore, in vitro decay reaction mixtures supplemented with the 20-nt sense RNA transcript resulted in stabilization of R2 message. A model is presented of R2 message regulation in which a cis-element within the 20-nt sequence of the 3'UTR interacts with a cytosolic protein to form a 45-kDa protein-mRNA binding complex. The TPA-induced alteration of R2 message stability is at least in part due to the down-regulation of the 45-kDa protein-mRNA binding activity which is linked to a reduction in the rate of R2 mRNA degradation.
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PMID:Phorbol ester modulation of a novel cytoplasmic protein binding activity at the 3'-untranslated region of mammalian ribonucleotide reductase R2 mRNA and role in message stability. 812 29

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC50) at 5 microM, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 microM. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 microM, a concentration that inhibits cell proliferation by 50% (IC50) or at 100 microM for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7.5 and 50 microM, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC50 values of 12 and 87 microM, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82% in male mice and 112% in female mice). The anti-tumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.
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PMID:Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase. 817 4

The inhibition by different p-alkoxyphenol derivatives of the growth-regulating enzyme ribonucleotide reductase (RR) in purified Escherichia coli and mouse R2 protein preparations was studied by EPR spectroscopy. The inhibitor-induced inactivation of the catalytic subunit protein R2 was measured at 77 degrees K by observing the decrease of the typical EPR signal from the functionally essential protein-linked tyrosyl free radical. p-Methoxy-, p-ethoxy-, p-propoxy-, and p-allyloxyphenol were about 2 orders of magnitude more effective in inhibiting mouse R2, compared with E. coli R2. Among the p-alkoxyphenols studied, p-propoxyphenol was the most effective inhibitor of mouse R2 (IC50, 0.7 microM) and p-methoxyphenol was the least effective (IC50, 11 microM); p-ethoxy- and p-allyloxyphenol were intermediate. The observed half-maximal inhibition values characterized p-alkoxyphenols as a new class of strong inhibitors of the R2 protein of mammalian RR. p-Propoxy-, p-ethoxy-, and p-allyloxyphenol could be considered as new candidates for anticancer drugs. A special cellular inhibition assay of RR in proliferating tumor cells, in which the tyrosyl radical of R2 at natural concentration was monitored by EPR, showed that the four para-substituted alkoxyphenols also inhibited the enzyme with high efficiency in tumor cells (IC50, between 0.5 microM and 5 microM). Our results with inactivation of protein R2 of RR imply that the cytostatic effect of p-alkoxyphenols on melanoma cells, which has been hitherto explained by inhibition of tyrosinase [Melanoma Res. 2:295-304 (1992)], may be caused at least partly by inhibition of RR. Protein R2 of RR may be considered as an additional target that could be used for future cancer chemotherapy.
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PMID:p-Alkoxyphenols, a new class of inhibitors of mammalian R2 ribonucleotide reductase: possible candidates for antimelanotic drugs. 818 56

The present study was designed to determine the mechanism by which orotic acid, a rat liver tumor promoter, inhibits DNA synthesis in normal hepatocytes in primary culture. Our results indicate that orotic acid inhibited the epidermal growth factor induced expression (mRNA) of both M1 and M2 subunits of ribonucleotide reductase while the expression of c-fos, c-myc, c-Ha-ras and beta-actin was not inhibited to any significant extent. These studies suggest that ribonucleotide reductase may be one target for orotic acid-induced mitoinhibition.
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PMID:Ribonucleotide reductase: a possible target for orotic acid induced mitoinhibition in normal hepatocytes in primary culture. 822 27

Polypeptide growth factors are a diverse group of biological regulators. Because they are fundamentally involved in the cellular processes that are important for transformation and progression to malignancy, alterations in growth factor control and in their signal pathways are often observed in tumor cells. In this review, we consider the participation of growth factors and the mechanisms by which they effect tumor progression, using as examples members of the transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families. We explore the hypothesis that although abrogation of TGF-beta negative growth regulation is necessary for transformation, in the later stages of tumor progression, TGF-beta plays a direct role in the enhancement of invasion and metastasis as an autocrine stimulator of these processes. In addition, we present evidence that demonstrates both the potential and the importance of members of the FGF family in transformation and induction of metastasis. Several models of growth factor regulation of malignancy are presented in which we demonstrate (1) a link between TGF-beta 1 mitogenic stimulation of malignant cells and alterations in the expression of ribonucleotide reductase, a key rate-limiting step in the synthesis of DNA and in cell proliferation; (2) autocrine and/or intracrine FGF mitogenic stimulation of malignant cell proliferation and metastasis; and (3) autocrine TGF-beta regulation of malignant cell locomotion and invasion through elevated proteolytic activity and increased synthesis of hyaluronan and RHAMM, a novel hyaluronan cell surface receptor.
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PMID:Transforming growth factor beta and fibroblast growth factor as promoters of tumor progression to malignancy. 824 21

2',2'-Difluorodeoxycytidine (Gemcitabine, dFdCyd) is a cytotoxic agent which is active toward a variety of tumor cells. It has been shown that there are multiple intracellular sites of action which include ribonucleotide reductase and DNA polymerase. In these studies, the effects of dFdCyd on wild-type mouse leukemia L1210 cells and variant L1210 cell lines which had alterations at the ribonucleotide reductase site or at the deoxyribonucleoside kinase site were studied. For cell growth, the IC50 value for dFdCyd in wild-type L1210 cells was 3.1 nM. In the variant cell lines, the IC50 values were: hydroxyurea-resistant (HU), 3.3 nM; deoxyadenosine-resistant (Y8), 1.8 nM; pyrazoloimidazole/deoxyadenosine-resistant (ED2), 1.9 nM; and deoxyguanosine-resistant (dGuo-R), 44.7 nM. The dGuo-R cell line had a relatively specific loss of the deoxyribonucleoside kinase responsible for phosphorylating deoxyguanosine and cytosine arabinoside with little loss of the deoxycytidine kinase activity. DFdCyd had no effect on the total uptake of [14C]cytidine into the cells or incorporation into RNA. DFdCyd inhibited the conversion of [14C]cytidine to deoxycytidine nucleotides and incorporation into DNA. However, the incorporation of cytidine into DNA was inhibited to a greater extent than was the inhibition of in situ ribonucleotide reductase activity. Ribonucleotide reductase activity in cell-free extracts prepared from L1210 cells treated with dFdCyd (20 nM) overnight was reduced by 50%. These results show that cell lines which have increased levels of ribonucleotide reductase activity (HU and ED2) or loss of feedback inhibition by dATP (ED2 and Y8) are still sensitive to dFdCyd. The findings indicate that ribonucleotide reductase is not the primary site of inhibition by dFdCyd.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of 2',2'-difluorodeoxycytidine (Gemcitabine) on wild type and variant mouse leukemia L1210 cells. 836 54

Using ESR spectroscopy, the ability of enzyme inhibitors to quench protein-derived tyrosyl radicals was studied in two different enzymes, prostaglandin H synthase and ribonucleotide reductase. The prostaglandin H synthase inhibitors indomethacin, eugenol, and MK-410 effectively prevent the formation of tyrosyl radicals during the oxidation of arachidonic acid by prostaglandin H synthase from ram seminal vesicles. A direct reaction with preformed tyrosyl radicals was observed only with eugenol. The other prostaglandin H synthase inhibitors were ineffective. The ribonucleotide reductase inhibitors hydroxyurea and 4-hydroxyanisole, which effectively inactivate the tyrosyl radical in the active site of ribonucleotide reductase present in tumor cells, exhibit a different reactivity with tyrosyl radicals formed by prostaglandin H synthase. Hydroxyurea quenches preformed tyrosyl radicals in prostaglandin H synthase weakly, whereas 4-hydroxyanisole does not quench tyrosyl radicals in prostaglandin H synthase at all. Eugenol, which quenches preformed prostaglandin H synthase-derived tyrosyl radicals, also quenches the tyrosyl radical in ribonucleotide reductase. The results suggest that the reactivity of protein-linked tyrosyl radicals in ribonucleotide reductase and those formed during prostaglandin H synthase catalysis are very different and have unrelated roles in enzyme catalysis.
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PMID:ESR studies on reactivity of protein-derived tyrosyl radicals formed by prostaglandin H synthase and ribonucleotide reductase. 838 Sep 61

Time-related changes have been studied in the content of extracellular DNA, Fe(3+)-transferrin (TF), and Cu(2+)-ceruloplasmin (CP) in the blood plasma and the activity of ribonucleotide reductase (RR) in the tumor cells and spleen of mice during the development of acute lympholeukosis P-388 and after ionizing irradiation. At the initial stages of leucosis P-388, the content of extracellular DNA increases, the TF and CP pools in the blood plasma enlarge, and the RR activity in the tumor cells and spleen of tumoral mice markedly increases. A dose-dependent increase in RR activity was also recorded in the spleen of 5-day-old rats within 15-30 min after irradiation. The causes of these changes and the possibility for these indices to be used in estimating leucosis risk are discussed. Radiation-induced increases in RR activity are discussed in relation to the SOS-response to DNA damage; an increased pool of deoxyribonucleotides is necessary for repair of DNA. The mean contents of extracellular DNA, TF and CP in the blood plasma were obtained from children of different ages degrees of radioactive contamination suffering the consequences of the accident at the Chernobyl' Nuclear Power Station (n = 155). Groups of children have been isolated with increased, sharply decreased, and close to normal levels of extracellular DNA, TF, and CP. The lowered TF pool was observed in children with thyroid glands damaged by incorporated radioactive iodine with the degree of suppression determined by the dose. For most children subject to general irradiation, the TF and CP pools in the blood were higher than in the control, suggesting an adaptive response to irradiation.
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PMID:[Markers of the metabolic changes arising as a result of ionizing radiation exposure]. 854 87

Mammalian ribonucleotide reductase is a highly regulated activity essential for DNA synthesis and repair. The 3'-untranslated region (3'-UTR) of mammalian ribonucleotide reductase R2 mRNA has been implicated in the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate-mediated stabilization of mouse BALB/c 3T3 R2 message. We investigated the possibility that the 3'-UTR contains regulatory information for R2 mRNA turnover. Using 3'-end-labeled RNA in gel shift and UV cross-linking analyses, we detected in the 3'-UTR a novel 9-nucleotide cis-element, 5'-UCGUGUGCU-3', which interacted with a widely distributed cellular cytosolic protease-sensitive factor(s) in a sequence-specific manner to form a 45-kDa R2 binding protein complex. The binding activity was redox-sensitive and down-regulated by 12-O-tetradecanoylphorbol-13-acetate and okadaic acid in a dose-dependent manner. Insertion of a 154-base pair fragment containing the cis-element led to markedly reduced accumulation of chloramphenicol acetyltransferase hybrid mRNA relative to the same insert carrying a series of G --> A mutations within this element that eliminated binding. We suggest that the 9-nucleotide region functions as a destabilizing element. These results provide a model for ribonucleotide reductase gene expression through a novel and specific mRNA cis-trans-interaction involving a phosphorylation signal pathway that leads to changes in the stability of R2 message.
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PMID:Defining a novel cis-element in the 3'-untranslated region of mammalian ribonucleotide reductase component R2 mRNA. cis-trans-interactions and message stability. 870 35


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