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J G Cory

Publications and source records attributed to J G Cory.

At least 91 records · Page 5Linked to original sources
PubMed1982

Noncoordinate changes in the components of ribonucleotide reductase in mammalian cells.

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.

Animals↗
PubMed1982

Effects of combinations of drugs having different modes of action at the ribonucleotide reductase site on growth of L1210 cells in culture.

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.

Adenine↗
PubMed1981

Evaluation of combinations of drugs that inhibit Ehrlich tumor cell ribonucleotide reductase.

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.

Aldehydes↗
PubMed1980

Mode of inhibition of tumor cell ribonucleotide reductase by 2,3-dihydro-1H-pyrazolo[2,3-a]imidazole (NSC 51143).

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.

Adenosine Diphosphate↗
PubMed1979

Specific inhibitors directed at the individual components of ribonucleotide reductase as an approach to combination chemotherapy.

It had been shown previously that the ribonucleotide reductase from mouse tumor consisted of two nonidentical components (Tris and dye fractions, each prepared from the 20 to 40% (NH/)2SO4 protein fraction containing the ribonucleotide reductase activity by blue dextran-Sepharose chromatography). The individual components either separated or present in the intact enzyme can be specifically and independently inhibited by different compounds. The Tris fraction component was inhibited by 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone while the dye fraction component was inactivated by pyridoxal phosphate:BH4- and the dialdehyde derivative of inosine (Inox) and 5'-deoxyinosine prepared by the periodate oxidation of inosine and 5'-deoxyinosine. The intact enzyme could be completely inhibited by any of these compounds. Reductase activity was restored by reconstitution with the exogenous components. The individual components of the reductase in the intact Ehrlich tumor cell could also be specifically inhibited. Activity in the crude cell-free extracts prepared from 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone- or Inox-treated cells was restored by the addition of the appropriate exogenous component. These data suggest that combinations of inhibitors of ribonucleotide reductase which specifically inhibit the components may be useful in the treatment of cancer.

Aldehydes↗
PubMed1979

Effect of 5-fluorouracil on RNA metabolism in Novikoff hepatoma cells.

The resistance of a Novikoff hepatoma cell line (N1-S1/FdUrd) to 5-fluorouracil (FUra) was reversed by the inclusion of inosine in the culture medium. As the concentration of inosine in the medium was increased, there was a marked increase in the uptake of [14C]FUra and conversion to nucleotides with a corresponding increase in the incorporation into RNA. While FUra alone had no effect on this resistant cell line, the combination of FUra plus inosine altered the levels of ribose 1-phosphate but not 5-phosphoribosyl 1-pyrophosphate, altered the maturation of precursor ribosomal RNA by blocking the formation of 18S RNA, altered the methylation of the ribosomal RNA, and caused inhibition of the growth of these cells. No evidence was obtained that fluorodeoxyuridine 5'-monophosphate was formed in the N1-S1/FdUrd cells as a result of treatment with FUra plus inosine. In addition, the metabolism of [3H]deoxycytidine in the presence of FUra plus inosine in the intact N1-S1/FdUrd cells did not indicate significant inhibition of thymidylate synthetase as evidenced by the levels of deoxyuridine 5'-monophosphate or conversion to thymidine 5'-monophosphate.

Animals↗
PubMed1978

Reconstitution of the ribonucleotide reductase enzyme from Ehrlich tumor cells.

Ribonucleotide reductase from Ehrlich tumor cells was separated by chromatography on blue dextran/Sepharose into two protein fractions (Tris and Dye fractions). Neither fraction alone had reductase activity, but when combined, constituted an active enzyme system. Heat treatment of either fraction resulted in an inactive combination. The approximate molecular size of the active component of the Tris and Dye fractions was determined to be 5.7 S and 6.5 S, respectively, compared to 9 S for the intact enzyme. The Tris fraction was inactivated by hydroxylamine while the dye fraction was inactivated by pyridoxal phosphate/BH4-treatment. The inactivation of the Dye fraction was prevented by ATP. These data would indicate that the Tris and Dye fractions were comparable in function to the B2 and B1 proteins, respectively, of the Escherichia coli ribonucleotide reductase.

Animals↗