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)

Using new in vitro techniques developed at the Cancer Research Unit, cell kinetic measurements were obtained in primary and metastatic human colonic tumors, polyps and normal bowel that did not require in vivo 3HTdR and required only single samples of tissue. These techniques included the measurement of the number of cells in DNA synthesis (LI), an estimate of the DNA synthesis time (Ts) and the growth fraction of tissues by means of the primer-available DNA-dependent DNA polymerase assay (PDP). From these data, the potential doubling time and the cell cycle time (Tc) of the tumors were calculated. Early preliminary data on human colonic specimens presented in Tables 1 and 2 indicate that there is an increase in LI from the low polyps to higher adenocarcinomas. There is little difference between primary and metastatic tumor cell kinetics. Growth fraction estimates (PDP) of the various colonic tissue types are also not significantly different and except for villous adenomas, DNA synthesis times are constant. The median 3HTdR labeling indices of 7% primary adenocarcinomas include a number of samples (approximately 20% of all samples) with high labeling indices (in the 10--20% range). These high labeling tumors may be those that show objective response to S-phase active drugs, e.g., 5-FU.
Cancer 1977 Nov
PMID:Human colonic tumor cell kinetics: potential for therapy. 92 8

The nonhistone proteins of Ehrlich ascites tumor chromatin have been separated into a loosely bound and two tightly bound protein fractions by sequential extraction of chromatin with 0.35 M NaCl and 2 M NaCl:5 M urea. The nonhistone proteins thus obtained were examined for their chemical composition and distribution of DNA polymerase, RNA polymerase, and protein kinase activities. In addition, the effect of these nonhistone proteins on transcription of DNA in vitro has been determined. The results indicate that these nonhistone proteins, fractionated on the basis of their extractability, exhibit varied compositional characteristics and play different functional roles in the synthesis of DNA and RNA and in the possible control of gene activity.
Cancer Res 1976 Sep
PMID:A comparison of the loosely bound and tightly bound nonhistone proteins from Ehrlich ascites tumor chromatin. 97 79

2-Aza-1,N6-etheno-adenosine triphosphate (aza-epsilonATP), a fluorescent analog of adenosine triphosphate, significantly inhibits polyadenylate [poly(A)] polymerase of bovine lymphosarcoma and calf thymus, with 50% inhibition at 200 muM (in the presence of an equal concentration of adenosine triphosphate). Calf thymus RNA polymerases II and III are inhibited 32 and 20%, respectively, by a 3.8-fold excess of aza-epsilonATP; DNA polymerase alpha is not inhibited. The inhibition of poly(A) polymerase by aza-epsilonATP appears to be competitive with adenosine triphosphate; incorporation of aza-epsilonATP is not observed. Polymers of 2-aza 1,N6-etheno-adenosine monophosphate are used as primers, but pootly. 1,N-Etheno-adenosine triphosphate and 9-beta-D-arabinofuranosyladenine triphosphate are poor inhibitors of poly(A) polymerase; adenosine diphosphate is ineffective. Deoxyadenosine triphosphate inhibits to the same extent as aza-epsilonATP, while other naturally occurring nucleotides inhibit poly(A) polymerase to varying degrees, with deoxynucleoside triphosphates more potent than ribonucleoside triphosphates. Inhibition of poly(A) polymerase by naturally occurring nucleoside triphosphates suggests that nucleotides may regulate the enzyme in vivo; inhibition by the fluorescent analog aza-epsilonATP suggests that this compound may be useful in elucidating poly(A) metabolism in both normal and neoplastic cells.
Cancer Res 1976 Sep
PMID:Inhibition of mammalian polyadenylate polymerase by 2-aza-1,N6-etheno-adenosine triphosphate. 98 43

The effects of partially thiolated polynucleotides on the DNA polymerase alpha from regenerating rat liver were investigated. The enzyme was isolated from the nuclear fraction essentially according to the method of Baril et al.; it was characterized as the alpha polymerase on the basis of its response to synthetic templates and its inhibition with N-ethylmaleimide. Although polycytidylic acid had no effect on the DNA polymerase alpha either as a template or as an inhibitor, partially thiolated polycytidylic acid (MPC) was found to be a potent inhibitor, its activity being directly related to its extent of thiolation (percentage of 5-mercaptocytidylate units in the polymer). In comparison, the DNA polymerase beta which was purified from normal rat liver nuclear fraction, was much less sensitive to inhibition by MPC. Analysis of the inhibition of the alpha polymerase by the method of Lineweaver and Burk showed that the inhibitory action of MPC was competitively reversible with the DNA template, but the binding of the 7.2%-thiolated MPC to the enzyme was much stronger than that of the template (Ki/Km less than 0.03). Polyuridylic acid as such showed some inhibitory activity which increased on partial thiolation, but the 8.4%-thiolated polyuridylic acid was less active than the 7.2% MPC. When MPC was annealed with polyinosinic acid, it lost 80% of its inhibitory activity in the double-stranded configuration. However, 1 to 2%-thiolated DNA isolates were significantly more potent inhibitors than were comparable (1.2%-thiolated) MPC and showed competitive reversibility with the unmodified (but "activated") DNA template. These results indicate that the inhibitory activities of partially thiolated polynucleotides depend not only on the percentage of 5-mercapto groups but also on the configuration, base composition, and other specific structural properties.
Cancer Res 1976 Dec
PMID:Action of partially thiolated polynucleotides on the DNA polymerase alpha from regenerating rat liver. 100 Apr 98

Adenovirus 12 (Ad12) (Huie) (highly oncogenic group A) readily induces tumors in newborn rodents. Since Ad12 is isolated from human fecal samples, we investigated whether it plays a role in the etiology of human gastrointestinal cancer. If Ad12 is a causal agent of human cancer, then human tumors should contain Ad12 transforming genes, as indicated by studies of cells transformed in vitro and in vivo by oncogenic viruses. Ad12 DNA and the Ad12 transforming restriction fragment (EcoRI-C fragment, left 16% of the viral genome) were labeled in vitro to 10(7) to 4 X 10(8) cpm/mug by the nick translation reaction of DNA polymerase of Escherichia coli. The fidelity and sensitivity of these probes were established by (i) analysis of DNA from Ad12-transformed cells and from hamsters with tumors induced by Ad12, (ii) reconstruction experiments with added Ad12 DNA and EcoRI restriction fragments, and (iii) comparison of annealing characteristics with Ad12 probes labeled in vivo. With Ad12 [3H]DNA as probe, no viral DNA sequences were detected in 18 normal gastrointestinal tissues and 34 gastrointestinal tumors, including cancers of the colon, rectum, small intestine, and stomach, under conditions that would detect 0.1 copy of the Ad12 genome per tumor cell. Similar analyses of Ad12-transformed hamster cells and Ad12 primary hamster tumors indicated 6-18 copies per cell of over 90% of the viral genome. With the Ad12 EcoRI-C transforming fragment as probe, no hybridization was detected with 32 human gastrointestinal tumors and five normal tissues; this result excludes 1-2% of the Ad12 genome per tumor cell. Our date are strong evidence that Ad12 is not a major cause of human gastrointestinal cancer. The Ad12 transforming EcoRI-C fragment hybridized (50-68% efficiency) with other Ad12 isolates and with Ad18 and 31 (members of oncogenic group A), but not at all with 28 other human Ad serotypes (manuscript in preparation). Thus other group A members probably are also not involved in human gastrointestinal cancer. No viral DNA sequences were detected in 12 normal lungs and 22 lung tumors, suggesting that respiratory cancer does not involve an Ad12 etiology.
 ...
PMID:Do highly oncogenic group A human adenoviruses cause human cancer? Analysis of human tumors for adenovirus 12 transforming DNA sequences. 107 16

All 5 thymus-dependent cell (T-cell) lines (Molt-3; Molt-4; RPMI-8402; CCRF-CEM; CCRF-HSB-2) and 7 thymus-independent cell (B-cell) lines (RPMI-8382, RPMI-8392, RPMI-8412, RPMI-8422, RPMI-8432, RPMI-8442, CCRF-SB) established so far from acute lymphoblastic leukemia patients were examined for deoxynucleotide polymerizing enzymes. All T- and B-cells had DNA polymerase gamma, DNA polymerase beta, and terminal deoxynucleotidyl transferase both in the soluble (the latter 2 enzymes only in small amounts) and chromatin fraction, whereas DNA polymerase alpha was found only in the soluble fraction. With respect to their sedimentation and chromatographic behavior, template-primer requirements, Km for deoxythymidine triphosphate or deoxyguanosine triphosphate divalent cation preference, effect of NaCI and inhibitors, the enzymes from T- and B-cells resembled each other and those from other mammalian cells. DNA polymerase alpha, beta, and gamma from T-cells like those from "fresh" acute lymphoblastic leukemia cells, were more thermolabile than those from B-cells or phytohemagglutinin-stimulated normal lymphocytes. In addition, the terminal deoxynucleotidyl transferase from the above cells was completely inactivated in 5 to 6 min at 50 degrees, whereas the DNA polymerase alpha, beta, and gamma retained considerable activity even after heating for 25 min at 50 degrees. DNA polymerase activity of the soluble fraction from T-cells was of the same magnitude as in B-cells when expressed on a DNA basis but twice that of B-cells when expressed on a protein basis. High terminal deoxynucleotidyl transferase activity, equivalent to that observed in acute lymphoblastic leukemia cells, was found in all T-cell lines that, when expressed on a DNA basis, was 30 to 100 times higher than the B-cell lines tested. These results support the suggestion of earlier investigators that T-cell lines examined here may have originated from leukemic cells.
Cancer Res 1976 May
PMID:Deoxynucleotide-polymerizing enzyme activities in T- and B-cells of acute lymphoblastic leukemia origin. 108 65

Rhodium(II) acetate, propionate, and butyrate showed a considerable variation in their antitumor activity against Ehrlich ascites tumor cells in mice, with the butyrate complex being the most active. The three complexes markedly inhibited DNA synthesis of Ehrlich ascites tumor cells in vivo. Rhodium (II) butyrate was the most potent inhibitor followed by the propionate complex. One hour after administration, rhodium(II) propionate and butyrate induce more uridine-5-3H incorporation into RNA than is seen in the controls. Equilibrium dialysis studied showed that rhodium(II) acetate-1-14C binds to single stranded DNA, poly-A, ribonuclease A, and bovine serum albumin but not to highly polymerized native calf thymus DNA, poly-G, or poly-C. In these cases binding occurred at the two axial positions of rhodium(II) acetate to a nitrogen donor in the ligands. The formation constants of the rhodium(II) acetate and propionate complexes with 5'-adenosine monophosphate were determined. The rhodium(II) propionate complex was more stable. Sedimentation and viscosity measurements of poly-A and poly-A/rhodium(II) acetate complexes indicate a high degree of intramolecular crosslinking in the rhodium(II) acetate/poly-A complex. The rhodium(II) carboxylate complexes were also found to be potent inhibitors of purified DNA polymerase I and RNA polymerase from Escherichia coli.
Cancer Chemother Rep
PMID:Interaction of Rhodium(II) carboxylates with molecules of biologic importance. 110 39

Thmidine (TdR) incorporation into DNA increased in the livers and spleens of rats bearing Yoshida sarcoma (solid type) or AH130 (solid type). TdR kinase and DNA polymerase activities increased in the serum, liver, and spleen of these rats, while thymidine monophosphate kinase activity increased appreciably only in the liver and spleen. On diethylaminoethyl cellulose column chromatography, 2 peaks of TdR dinase activity were separated from the serum and tumor tissues of rats bearing Yoshida sarcoma (solid type) while only 1 peak was obtained from the liver. TdR kinase activity in the serum decreased abruptly 7 hr after removal of the Yoshida sarcoma, while that in the liver decreased more slowly.
Cancer Res 1975 Mar
PMID:DNA synthesis in tumor-bearing rats. 111 20

The influence of 9-beta-D-arabinofuranosyladenine (ara-A) and its 5'-triphosphate derivative on programmed synthesis was tested with an intact cell system as well as with isolated enzyme systems. The effect of ara-A was tested in mouse lymphoma cells (L5178Y). The compound reduces cell proliferation in low concentration by cytostasis; under high ara-A concentration of radioactive precursors into DNA, RNA, and protein showed that ara-A selectively inhibits DNA synthesis. Formation of a polysome complex is not affected by ara-A. [3H]ara-A is incorporated into DNA in an intact cell system; 1 molecule of ara-A is incorporated per 8000 molecules of deoxyadenosine. Most of the ara-A molecules appeared to be in internucleotide linkages. Incorporation of ara-A into RNA could not be detected. 9-BETA-D-Arabinofuranosyladenine 5'-triphosphate (ara-ATP) does not reduce the incorporation rate of the following enzymes, isolated from quail oviducts: DNA-dependent RNA polymerases I and II, polyadenylic acid polymerase, and poly(adenosine diphosphate ribose) polymerase. The compound was found to inhibit DNA synthesis catalyzed by DNA polymerases isolated from quail oviducts and from oncogenic RNA viruses (Rous sarcoma viruses). All the enzymes tested were inhibited by ara-ATP in a competitive way with respect to deoxyadenosine 5'-triphosphate. The highest affinity of ara-ATP, i.e., the highest inhibitory potency of the drug, was found in the assays with the eukaryotic low-molecular DNA-dependent DNA polymerase. The influence on the eukaryotic high-molecular DNA-dependent Dna polymerase was a litte less. Compared to the eukaryotic DNA polymerases, the viral enzymes (RNA-directed DNA polymerase and DNA-directed DNA polymerase) are affected to a smaller extent by ara-ATP. No effects of ara-A and ara-ATP are observed in a protein-synthesizing, cell-free system isolated from L5178Y cells.
Cancer Res 1975 Aug
PMID:Mode of action of 9-beta-D-arabinofuranosyladenine on the synthesis of DNA, RNA, and protein in vivo and in vitro. 114 31

With synchronized tissue culture cells (L929), daunomycin had the greatest inhibitory effect on cell growth when the drug was administered during the later stages of cell division (late S, G2, and M). The level of binding of daunomycin to DNA was not found to be influenced by the phase of the cell cycle. The highest level of radioactivity from [eH]-daunomycin was bound to DNA of the heterochromatin fraction. Both RNA and DNA syntheses were inhibited in isolated enzyme systems when daunomycin-treated DNA, from which the unbound drug was removed by passage through Sephadex column, was used. DNA polymerase was reduced to one-fifth of the control activity, while that of RNA polymerase was reduced to one-half. Similar experiments with daunomycin-treated RNA and DNA polymerase preparations showed that the drug had no effect on the activities of the enzymes per se. Hence, the reduction of RNA and DNA polymerase activities could be accounted for by the loss of template activity of the drug-treated DNA. Daunomycin caused by a marked drop in the formation of a complex between RNA polymerase and DNA, indicating that the binding of daunomycin to DNA may give rise to steric hindrance effects that interfere with the association of the template to RNA polymerase enzyme. Sedimentation profile in alkaline sucrose density gradient of DNA that had been treated with daunomycin showed that no change in the molecular weight could be demonstrated.
Cancer Res 1975 Jun
PMID:Binding of daunomycin to DNA and the inhibition of RNA and DNA synthesis. 116 9


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