Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.
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PMID:Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells. 150 1

Purine and pyrimidine adducts of alpha-methylene-gamma-lactone demonstrated potent cytotoxicity against murine L1210 lymphoid leukemia growth as well as a variety of human tissue cultured tumors. The most potent compound, 9-[(2-methyl-4-methylene-5-oxotetrahydrofuran-2-yl)-methyl 1] adenine 1 demonstrated significant inhibition of DNA synthesis in L1210 leukemic cells with moderate inhibition of protein synthesis. The major enzyme activities inhibited by 1 were DNA polymerase alpha, ribonucleoside reductase and t-RNA polymerase with marginal inhibition of thymidine kinase, TMP kinase, PRPP amidotransferase and IMP dehydrogenase. The inhibition of DNA polymerase alpha activity by 1 was evident at the lowest concentration 25 microM and was evident within 15 min incubation at 100 microM. The magnitude of enzyme inhibition was consistent with the observed DNA synthesis inhibition by 1. The only deoxyribonucleotide level reduced by 1 was the dATP pool level. U.V. absorption of DNA after interacting with 1 demonstrated a hyperchromic effect and L1210 DNA strand scission was observed after 24 hr incubation with 1 suggesting some type of interference with the DNA template by the drug.
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PMID:The effects of alpha-methylene-gamma-lactone purines and pyrimidines on L1210 lymphoid leukemia nucleic acid metabolism. 201 69

A series of analogues related to helenalin demonstrated moderate capability for inhibiting the growth of murine P-388 lymphocytic leukemia cells in vivo and in vitro. The growth inhibition correlated with suppression of both DNA and protein synthesis in P-388 cells. The inhibition of protein synthesis occurred at a relatively low concentration and appeared to occur at the level of initiation. The suppression of DNA synthesis in P-388 cells correlated positively with inhibition of inosine 5'-monophosphate dehydrogenase activity. Although nuclear and alpha DNA polymerase activities were suppressed by certain analogues, the inhibition of the polymerases did not correlate positively with DNA synthesis inhibition and, furthermore, the magnitude of suppression of DNA polymerase activity did not appear to be sufficient to account for the observed suppression of DNA synthesis in P-388 cells.
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PMID:Antitumor agents 68: effects of a series of helenalin derivatives on P-388 lymphocytic leukemia nucleic acid and protein synthesis. 286 Dec 71

Helenalin and bis (helenalinyl) malonate, sesquiterpene lactones, were shown to be cytotoxic against the growth of P-388 lymphocytic leukemia cells in culture. DNA and protein synthesis were reduced by these agents preferentially, with RNA synthesis being affected only marginally. This study focused on the identification of the enzyme target(s) responsible for the inhibition of DNA synthesis by the sesquiterpene lactones. Purine synthesis was strongly inhibited at the IMP dehydrogenase step. Suppression of IMP dehydrogenase activity and purine synthesis paralleled the DNA synthesis inhibition with respect to both dose dependence and time of incubation with drug. Deoxyribonucleoside triphosphate pools in the P-388 cells were significantly reduced by both drugs and the DNA polymerase alpha activity was only moderately inhibited by both drugs in cytoplasmic preparation. However, inhibition of a partially purified DNA polymerase alpha was of a much greater magnitude. Activity of the ribonucleotide reductase complex was reduced by more than 50% at 100 microM concentration of either drug. The drugs appeared to affect the hydrogen donor system of the reductase complex, since the activity of the ribonucleotide reductase enzyme itself was not affected but both thioredoxin and glutaredoxin were markedly inactivated by the sesquiterpene lactones. Thymidylate synthetase activity was not affected by the sesquiterpene lactones in P-388 cells. These data suggest that the inhibition of IMP dehydrogenase and the ribonucleotide reductase complex activities by helenalin and bis (helenalinyl) melonate was the primary reason for the observed inhibition of DNA synthesis, but that inhibition of DNA polymerase alpha may also play a role. The inhibition of the sensitive enzymes is likely to be related to drug alkylation of thiol active groups of the enzymes in a manner similar to the action of N-ethylmaleimide. The mode of action of helenalin and bis (helenalinyl) malonate does not appear to be similar to that of the parthenolide-type sesquiterpene lactones which contain an epoxide moiety.
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PMID:Inhibition of nucleic acid synthesis in P-388 lymphocytic leukemia cells in culture by sesquiterpene lactones. 289 92

Helenalin and bis(helenalinyl)malonate were shown to be cytotoxic against the growth of human KB carcinoma cells. DNA synthesis was inhibited significantly. This inhibition was afforded because of the drugs' effects on a number of enzyme activities. The inhibition of IMP dehydrogenase and ribonucleotide reductase complex activities correlated positively with the inhibition of DNA synthesis of the KB cells. DNA polymerase activity was inhibited by the drugs to a lesser degree. The deoxyribonucleotide pools were markedly reduced in the presence of the drug, which would be consistent with a blockage of the enzyme ribonucleotide reductase as well as suppression of DNA synthesis. XMP levels were also reduced, which is consistent with suppression of IMP dehydrogenase activity by the drugs. Ribonucleoside phosphate pools, particularly CDP and GDP, were elevated after drug treatment, which would be expected with a blockage at ribonucleotide reductase. Thus DNA alkylation is not the mechanism of action of the antineoplastic sesquiterpene lactones; rather, the cell-killing effect is related to DNA synthesis inhibition by the drug.
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PMID:Effect of helenalin and bis(helenalinyl)malonate on nucleic acid and protein synthesis in human KB carcinoma cells. 290 84

Molephantinin, a germacranolide, has previously been shown to possess antineoplastic activity in rodents. The principle effect of molephantinin on Ehrlich ascites carcinoma cells was to depress DNA and protein synthesis both in vivo and in vitro. DNA synthesis was inhibited at the following sites: DNA polymerase, purine synthesis specifically at inosinic acid dehydrogenase and to a lesser degree at dihydrofolate reductase, pyrimidine synthesis at orotidine monophosphate decarboxylase, thymidine kinase, histone phosphorylation, and oxidative phosphorylation processes. The protein synthesis inhibition pattern resembled more an initiation inhibitor as opposed to an elongation inhibitor.
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PMID:Antitumor agents LII: The effects of molephantinin on nucleic acid and protein synthesis of Ehrlich ascites cells. 709 35

The diterpene esters, genkwadaphnin and yuanhuacine, have been shown to possess significant antileukemic activity in the P-388 screen. The major metabolic effects of the diterpene esters were on DNA and protein synthesis. The effects on DNA synthesis in vitro were evoked at a lower concentration than that required for protein synthesis inhibition. The sites in DNA synthesis which were inhibited were DNA polymerase and purine synthesis. In the latter pathway the enzyme activities inhibited were phosphoribosyl aminotransferase, inosinic acid dehydrogenase, and dihydrofolate reductase. In vivo administration of the diterpene esters at 0.8 mg/kg afforded identical types of effects on purine and DNA synthesis and in addition suppressed histone phosphorylation and reduced the number of surviving tumor cells. The in vivo effects on purine and DNA synthesis were evident as early as 6 and 24 hr after administration of a single dose of the diterpene esters.
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PMID:Antitumor agents LV: Effects of genkwadaphnin and yuanhuacine on nucleic acid synthesis of P-388 lymphocytic leukemia cells. 717 20

Inhibitors of IMP dehydrogenase (EC 1.2.1.14), including mizoribine (Bredinin) and mycophenolic acid, have significant antitumor and immunosuppressive activities. Studies were aimed at determining the mechanism by which intracellular GTP depletion induced by these agents results in inhibition of DNA synthesis. Incubation of human CEM leukemia cells for 2 hr with IC50 concentrations of either mizoribine (4 microM) or mycophenolic acid (0.5 microM) reduced cellular GTP levels an average of 68% or 58%, respectively, compared with the levels in control cells. Under similar conditions, mizoribine and mycophenolic acid decreased the amount of [3H]adenosine incorporated into primer RNA by 75% and 70%, respectively, relative to the untreated controls, but had no significant effect on total RNA synthesis. Repletion of the guanine nucleotide pools by coincubation of CEM cells with guanosine plus 8-aminoguanosine prevented both the inhibition of primer RNA synthesis and the inhibition of tumor cell growth induced by these agents. Additional studies demonstrated that GTP depletion alone was capable of directly inducing inhibition of primer RNA synthesis. Primer RNA synthesis was inhibited an average of 84% in whole-cell lysates that lacked GTP but contained all remaining ribo- and deoxyribonucleoside triphosphates. On an M13 DNA template, RNA-primed DNA synthesis catalyzed by the purified complex of DNA primase (EC 2.7.7.6) and DNA polymerase alpha (EC 2.7.7.7) was decreased an average of 70% in the absence of GTP, compared with synthesis in the presence of 0.5 mM GTP. These results provide evidence that mizoribine and mycophenolic acid inhibit DNA replication by inducing GTP depletion, which suppresses the synthesis of RNA-primed DNA intermediates.
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PMID:GTP depletion induced by IMP dehydrogenase inhibitors blocks RNA-primed DNA synthesis. 774 81

N-Substituted indan-1.3-diones have proven to be potent cytotoxic agents effective against the growth of single cell leukemia tumors and cell lines derived from solid tumors. A number of the derivatives were active against growth of solid tumors e.g. colon, lung bronchogenic and osteosarcoma for which few effective agents are available to inhibit their growth. These agents inhibited DNA and RNA synthesis of L1210 cells. The de novo purine synthetic pathway was inhibited at PRPP amido transferase and IMP dehydrogenase. The pyrimidine synthetic pathway was inhibited at aspartate transcarbamylase. Other sites which demonstrate minor inhibition were DNA polymerase alpha, r- and t-RNA polymerase, ribonucleoside reductase, dihydrofolate reductase, nucleoside kinases and thymidylate synthetase. In addition d(NTP) pool levels were reduced by the drugs. L1210 DNA strand scission was evident after exposure to drugs for 24 hr. at 100 microM.
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PMID:Cytotoxicity and mode of action of substituted indan-1, 3-diones in murine and human tissue cultured cells. 784 49

N-substituted diphenimides and 6,7-dihydro-5H-dibenz[c,e]azepines demonstrated significant cytotoxic activity against the growth of murine and human cells. These derivatives were active against leukemias, carcinomas and sarcomas. Different derivatives with N-substitutions showed specific activity against the growth of several tumor types. These agents inhibited L1210 leukemia IMP dehydrogenase and PRPP amido transferase activities; this was reflected in the inhibition of purine and DNA synthesis. Other sites inhibited to a minor degree by these agents included DNA polymerase alpha, r- and tRNA polymerases, ribonucleoside reductase, dihydrofolate reductase, pyrimidine synthesis, and nucleoside kinase. d(NTP) pool levels were reduced after 24 h incubation with these derivatives. L1210 DNA strand scission was evident after drug treatment.
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PMID:The cytotoxicity of N-substituted diphenimides and 6,7-dihydro-5H-dibenz[c,e]azepines. 829 66


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