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)

Combinations of inhibitors directed at the individual components of ribonucleotide reductase were studied for their effects on L1210 cell growth in culture. The combinations included pyrozoloimidazole (IMPY) plus deoxyadenosine and hydroxyurea plus deoxyadenosine. Modulators were utilized to potentiate the effects of hydroxyurea, IMPY, or deoxyadenosine. Desferal was used to modulate the activity of hydroxyurea and IMPY while erythoro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was used as the modulator of deoxyadenosine metabolism. While the combinations of deoxyadenosine-EHNA, hydroxyurea-Desferal, or IMPY-Desferal caused increased growth inhibition of L1210 cells at high drug concentrations, combinations which consisted of deoxyadenosine-EHNA-IMPY-Desferal or deoxyadenosine-EHNA-hydroxyurea-Desferal gave strong synergistic inhibition of L1210 cell growth in culture at concentrations of each of the drugs which alone had minimal inhibitory effects on tumor cell growth. The four-drug combination was clearly more effective than any three-drug combination in terms of inhibition of tumor cell growth. It was also observed that the concentrations of the modulators (Desferal or EHNA) were as critical as the concentrations of hydroxyurea, IMPY, or deoxyadenosine in establishing an effective drug combination.
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PMID:Effects of combinations of drugs having different modes of action at the ribonucleotide reductase site on growth of L1210 cells in culture. 675 22

2,3-Dihydro-1H-pyrazolo[2,3-a]imidazole (NSC 51143; IMPY) inhibits partially purified ribonucleotide reductase from Ehrlich tumor cells. Both cytidine 5'-diphosphate and adenosine 5'-diphosphate reductase activities were inhibited by IMPY, although adenosine 5'-diphosphate reductase activity was inhibited to a greater extent than was cytidine 5'-diphosphate reductase activity at all concentrations of IMPY studied. The inhibition of the intact enzyme by IMPY could be reversed by the addition of the exogenous non-heme iron-containing subunit (tris(hydroxymethyl)aminomethane fraction) but not by the addition of the effector-binding subunit. Further, the inhibition of the intact enzyme or the tris(hydroxymethyl)aminomethane fraction by IMPY could be reversed by the addition of 6 microM Fe(NH4)2(SO4)2, and the inhibition of IMPY could be potentiated by 0.167 mM ethylenediaminetetraacetic acid. These results demonstrate that IMPY inhibits tumor cell nucleotide reductase by interaction with the iron of the non-heme iron-containing subunit.
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PMID:Mode of inhibition of tumor cell ribonucleotide reductase by 2,3-dihydro-1H-pyrazolo[2,3-a]imidazole (NSC 51143). 678 37

The nature of the inhibition of Ehrlich tumor cell ribonucleotide reductase by combinations of agents directed at the non-heme iron-containing component and the effector-binding component was studied with the use of isobolograms. From these studies, it was determined that the combinations of pyrazoloimidazole (IMPY) and dialdehyde of inosine, IMPY and deoxyguanosine triphosphate (dGTP), IMPY and deoxyadenosine triphosphate (dATP), and IMPY and deoxythymidine triphosphate (dTTP) gave synergistic inhibition of cytidine diphosphate reductase. The combination of dATP and dGTP also gave synergistic inhibition. The combinations of hydroxyurea and IMPY, 4-methyl-5-aminoisoquinoline thiosemicarbazone (MAIQ) and IMPY, and dialdehyde of inosine and dialdehyde derivative of 5'-deoxyinosine gave antagonistic inhibition. Other combinations utilizing MAIQ and dATP, MAIQ and dGTP, MAIQ and dTTP, hydroxyurea and dGTP, and hydroxyurea and dTTP gave inhibition which was additive.
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PMID:Evaluation of combinations of drugs that inhibit Ehrlich tumor cell ribonucleotide reductase. 678 98

Ribonucleotide reductase from mammalian cells consists of two nonidentical components which are both required for enzymatic activity. It was found that the addition of the effector-binding component (dye fraction) to cell-free extracts of Ehrlich tumor cells stimulated CDP reductase activity. The decrease in CDP reductase activity which accompanied the decrease in Ehrlich tumor cell proliferation in vivo could be correlated with the decrease in the dye fraction component. In regenerating liver, the reductase activity was increased maximally at 36 h following partial hepatectomy. This activity could be further stimulated by exogenous tumor cell dye fraction. The non-heme iron component (Tris fraction) was isolated and quantitated from the liver extracts of regenerating livers. The maximal increase on the Tris fraction component was observed in the 24-h regenerating liver. These data provide evidence that the components making up the active ribonucleotide reductase species are not coordinately increased at the time of the increase in reductase activity.
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PMID:Noncoordinate changes in the components of ribonucleotide reductase in mammalian cells. 703 47

Ribonucleotide reductase is a highly regulated activity responsible for reducing ribonucleotides to deoxyribonucleotides, which are required for DNA synthesis and DNA repair. We have tested the hypothesis that malignant cell populations contain alterations in signal pathways important in controlling the expression of the two genes that code for ribonucleotide reductase, R1 and R2. A series of radiation and H-ras transformed mouse 10T1/2 cell lines with increasing malignant potential were exposed to stimulators of cAMP synthesis (forskolin and cholera toxin), an inhibitor of cAMP degradation (3-isobutyl-1-methylxanthine) and a biologically stable analogue of cAMP (8-bromo-cAMP). Dramatic elevations in the expression of the R1 and R2 genes at the message and protein levels were observed in malignant metastatic populations, which were not detected in the normal parental cell line or in cells capable of benign tumor formation. These changes in ribonucleotide reductase gene expression occurred without any detectable modifications in the rates of DNA synthesis, showing that they were regulated by a novel mechanism independent of the S phase of the cell cycle. Furthermore, studies with forskolin (a stimulator of the protein kinase A signal pathway) and the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (a stimulator of the protein kinase C signal pathway), alone or in combination, indicated that their effects on R1 and R2 gene expression in a highly malignant cell line were greater than when they were tested individually, suggesting that the two pathways modulating R1 and R2 gene expression can cooperate to regulate ribonucleotide reduction, and interestingly this can occur in a synergistic fashion. Also, a direct relationship between H-ras expression and ribonucleotide reductase gene expression was observed; analysis of forskolin mediated elevations in R1 and R2 message levels closely correlated with the levels of H-ras expression in the various cell lines. In total, these studies demonstrate that ribonucleotide reductase expression is controlled by a complex process, and malignant ras transformed cells contain alterations in the regulation of signal transduction pathways that lead to novel modifications in ribonucleotide reductase gene expression. This signal mechanism, which is aberrantly regulated in malignant cells, may be related to regulatory pathways involved in determining ribonucleotide reductase expression in a S phase independent manner during periods of DNA repair.
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PMID:Alterations in the cyclic AMP signal transduction pathway regulating ribonucleotide reductase gene expression in malignant H-ras transformed cell lines. 750 77

Nitric oxide (NO) synthesized by macrophages inhibits tumor cell replication. NO also inhibits ribonucleotide reductase, an enzyme essential for DNA synthesis, probably by quenching the catalytically active tyrosyl free radical of its R2 subunit. The role of this inhibition in NO-mediated cytostasis was thus evaluated. After a 4-h coculture with macrophages, quenching of the radical was demonstrated by electron paramagnetic resonance spectroscopy in transfected L1210-R2 cells over-expressing the R2 protein. Pronounced cytostasis was simultaneously observed. A NO synthase inhibitor greatly reduced both phenomena. Target cells withdrawn from macrophages partially recovered from cytostasis and radical loss within 90 min. Deoxyribonucleosides added to by-pass ribonucleotide reductase inhibition efficiently reversed cytostasis of K-562 cells. After a 24-h coculture, the quenched tyrosyl radical still reappeared in L1210-R2 cells withdrawn from macrophages, but DNA synthesis did not resume. Moreover, deoxyribonucleosides marginally reversed overnight cytostasis of K-562 cells mediated by macrophages but were efficient against cytostasis induced by hydroxyurea, a ribonucleotide reductase inhibitor. Autocrine cytostasis observed early in TA3-H2 cells committed to produce NO was closely correlated with quenching of the tyrosyl radical but not with formation of dinitrosyl-iron complexes. We thus propose that NO-dependent cytostasis begins with a rapid and reversible inhibition of ribonucleotide reductase, progressively reinforced by other, long-lasting antiproliferative effects.
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PMID:Quenching of the tyrosyl free radical of ribonucleotide reductase by nitric oxide. Relationship to cytostasis induced in tumor cells by cytotoxic macrophages. 752 Apr 45

Mammalian ribonucleotide reductase is a highly regulated activity essential for DNA synthesis and repair. The activity and message levels of the enzyme are elevated in cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, and this appears to be mediated through specific cis elements in the 3'-untranslated region of the R1 and R2 mRNAs that interact with R1 and R2 binding proteins called R1BP and R2BP, respectively. Hydroxyurea-resistant cells with increased R1 and R2 message levels were observed to have increased R1 and R2 message half-lives. This was accompanied by alterations in R1 and R2 3'-untranslated region cis-trans interactions, as judged by band shift and UV cross-linking assays, in which R1BP and R2BP binding was markedly reduced. This first description of mutant mammalian cells altered in message stability regulatory determinants indicates another mechanism for acquiring resistance to an antitumor agent. Furthermore, the present study strongly supports the concept that R1BP and R2BP are important general regulators of ribonucleotide reductase message stability and act as message destabilizing factors.
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PMID:Altered regulation of message stability and tumor promoter-responsive cis-trans interactions of ribonucleotide reductase R1 and R2 messenger RNAs in hydroxyurea-resistant cells. 755 16

Herpes simplex virus (HSV) mutants or recombinant vectors might be useful oncolytic agents. Three general types of HSV vectors can be potentially used for this purpose: (1) mutants in viral transcription factors, such as ICP0 and ICP4; (2) mutants in enzymes involved in nucleic acid metabolism, such as thymidine kinase (TK) and ribonucleotide reductase (RR); and (3) mutants in neurovirulence factors, such as gamma 34.5. We tested the destructive ability of each type against rat 9L gliosarcoma cells in culture. We found that the HSV vectors defective in TK or RR were more efficient at tumor cell lysis in culture than the other types of HSV vectors. This increased efficiency provided the rationale for evaluating the TK and RR mutants in vivo following their stereotactic inoculation into 9L gliosarcomas implanted in rat brains. We employed the X-gal enzymatic histochemical assay to show that HSV-mediated lacZ gene expression was present in cells within the tumor mass in a relatively selective fashion. Immunoreactive HSV capsid and core antigens were present both in cells within the tumor, as well as in cells such as neurons and astrocytes, directly adjacent to the tumor mass. Long-term survival studies revealed that rats treated with either the TK or RR mutant lived significantly longer than control rats (p = 0.014, Kruskal-Wallis one-way analysis of variance). These results indicate that HSV vectors, defective in enzymes needed in nucleic acid metabolism, can preferentially mediate lacZ gene expression in cells within the tumor. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antitumor activity and reporter gene transfer into rat brain neoplasms inoculated with herpes simplex virus vectors defective in thymidine kinase or ribonucleotide reductase. 758 98

Observations during the last several years on the relationships between bone marrow-derived dendritic cells (DC) and the cells which are in direct contact with them led to the idea that DC may have regulatory properties. Such regulatory properties exerted by DC were noted in experimental cancers in murine systems as well as in human cancers. It was noted that patients with the same type of cancer in which DC are present in the tumor survive longer than patients without DC in the tumor. It is not known how DC can abrogate the development of the metastatic tumor cells in the primary tumor, nor how the tumor cells are capable of abrogating the anticancer activity of the DC and allowing the development of tumor metastases. Studies on the anticancer activity of macrophages revealed that these cells have an inducible Nitric Oxide (NO) synthase (NOS) which utilizes arginine to produce NO. Suppressor macrophages release NO, which inhibits the ribonucleotide reductase and mitochondrial oxidation in tumor cells in vitro. It was also reported (4) that Interferon gamma (IFN-gamma), produced by murine T helper 1 cells, induces NOS activity in macrophages, while T helper 2 cells which produce Interleukin-4 (IL-4) inhibit the expression of NOS in macrophages. The hypothesis presented in this paper suggests that DC have a gene for NOS which is inducible by immunomodulators (e.g. IFN gamma, OK432, LPS) and can be suppressed by cytokines produced by tumor cells (e.g. IL-4, IL-10).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Success and failure of dendritic cell (DC) anticancer activity may be modulated by nitric oxide synthetase (NOS) gene expression: a hypothesis. 768 49

We determined the cell cycle-dependent fluctuation of mRNAs that encode different enzymes of the deoxynucleotide metabolism in permanent cell lines of human and murine origin. In normal growing cells, dihydrofolate reductase, thymidine kinase, and both subunits of ribonucleotide reductase all show exactly the same variation. The mRNAs rise near the G1-S boundary, peak in early S phase, and return in G2 to approximately the level of early G1. Deoxycytidine kinase mRNA does not follow this pattern, but remains essentially unchanged. Conversely, in DNA tumor virus-transformed cells, the levels of all these mRNAs remain relatively constant throughout all phases. These data provide evidence that DNA tumor viruses suppress a transcriptional down-regulation common to enzymes responsible for the DNA precursor pathway. The usefulness of analysis of mRNA levels of these genes for the detection of DNA tumor virus transformation is indicated.
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PMID:A common regulation of genes encoding enzymes of the deoxynucleotide metabolism is lost after neoplastic transformation. 769 88


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