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: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A fibroblast-like cell culture was established from a stomach biopsy of a patient with metastatic adenocarcinoma. One of the cultures, at the 6th passage level, left unattended for a month at 37 degrees, produced numerous foci of epithelioid cells. Upon subculturing, an epithelioid cell line, designated HCCL (human carcinoma cell line), was established. The HCCL cells released particles possessing the characteristics of oncornaviruses: density 1.175 g/ml, cores with a density of 1.22-1.26 g/ml, high-molecular-weight RNA (60-70S) and RNA-instructed DNA polymerase activity (deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 2.7.7.7). Inoculation of particles released from HCCL cells into cultures of human embryo muscle fibroblasts resulted in the appearance of foci of transformed cells.
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PMID:Transformation of cultured human embryonic fibroblasts by oncornavirus-like particles released from a human carcinoma cell line. 5 57

Cell renewal in the large intestine mucosa is normally tied to a rigidly compartmentalized model. Immunohistochemical identification of cells in S phase through uptake of bromodeoxyuridine is the method of choice for detailed compartmental mapping of proliferation, while immunohistochemical detection of proliferation-associated antigens (Ki-67, PCNA, DNA polymerase alpha) provides information in advanced tumor cases. Mucosal hyperproliferation due to inflammation may be transient (self-limited colitis, Crohn's disease, acute radiation damage) or lasting (ulcerative colitis). Progressive shifting of the proliferation zone to the crypt surface (Stage II abnormality) is a late feature of irradiated rectal mucosa and subgroups of ulcerative colitis patients at high risk for cancer. Hyperproliferation and Stage II abnormality coexist in the mucosa of patients with colorectal neoplasia, but are mutually independent and correlated to different clinical and pathological features of the disease. These cytokinetic abnormalities are highly predictive markers of the adenoma-carcinoma sequence, but are not associated with de novo adenocarcinoma. Proliferation increases progressively in the subsequent steps of this sequence, except in early cancer.
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PMID:Cell proliferation in colorectal tumor progression: an immunohistochemical approach to intermediate biomarkers. 146 8

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

Naturally occurring sesquiterpene lactones and their semisynthetic derivatives, such as the O = C-C = CH-bearing helenalin and its esters, have been shown to demonstrate potent cytotoxicity against the growth of murine L1210 lymphoid leukemia and human Tmolt3 leukemia, colon adenocarcinoma, HeLaS3, lung bronchogenic, KB, osteosarcoma, and glioma cells. The modes of action of helenalin in L1210 cells are the inhibition of DNA, RNA, and protein syntheses. This study confirms that thiol bearing enzymes of nucleic acid metabolism were significantly inhibited, e.g. DNA polymerase alpha, IMP hydrogenase, and ribonucleoside reductase. The addition of GSH to the reaction medium demonstrated total recovery of L1210 ribonucleoside reductase activity. Helenalin reduced cellular GSH levels in L1210 cells. Helenalin also reduced all four pool levels of d(NTP)s which would account for part of the observed inhibition of DNA synthesis. Reductions in the ribonucleotide pool levels were also generally evident after drug treatment. Thus, the sesquiterpene lactones appear to have more than one mode of action in L1210 cells. All of the modes of actions of helenalin are feasible mechanisms to lower nucleic acid synthesis and cause cell death of the L1210 leukemia cells.
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PMID:The cytotoxicity of helenalin, its mono and difunctional esters, and related sesquiterpene lactones in murine and human tumor cells. 152 2

Fifty cases of colorectal adenocarcinoma were immunohistochemically examined for the relationship between distribution of plasminogen activators (PAs) and the degree of differentiation of cancer cells as reflected by carcinoembryonic antigen (CEA) expression as well as tumor cell kinetics. The A chain of urokinase-type PA (u-PA-A) was mainly observed in the apical portions of highly differentiated cancer cells. Increased expression and change in localization to the cytoplasm were found with progressive dedifferentiation. The numbers of DNA polymerase alpha (pol. alpha) positive cancer cells also increased in line with u-PA-A expression. The B chain of u-PA (u-PA-B), and the A and B chains of tissue-type PA (t-PA-A and -B) did not show similar alteration. The present findings suggest that the distribution of u-PA-A in colorectal carcinoma tissues, the degree of tumor differentiation, and the proliferation kinetics of cancer cells are closely related.
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PMID:Immunohistochemical analysis of plasminogen activator expression in human colorectal carcinomas: correlation with CEA distribution and tumor cell kinetics. 190 Nov 19

The activities of orotate phosphoribosyltransferase (OPRT), cytidine triphosphate (CTP) synthetase, deoxycytidine monophosphate (dCMP) deaminase, thymidine monophosphate (dTMP) kinase, uridine (Urd) kinase, thymidine (dThd) kinase, Urd and dThd phosphorylases, and DNA polymerase were examined in the eight human lung squamous cell carcinomas and five lung adenocarcinomas, and five tumor-adjacent normal lung tissues. All of these enzymes are involved in pyrimidine nucleotide synthesis. The metabolism of 5-fluorouracil (5-FU) was determined. The levels of these enzymes, except for OPRT, were high in tumor tissues and almost the same between lung squamous cell carcinomas and adenocarcinomas, with no statistical difference. The activities for phosphorylation and degradation of 5-FU were similar in each tissue type of tumor. As 5-FU is incorporated into tumor cells and is metabolized actively to 5-FU nucleotides in squamous cell carcinoma tissues, at almost the same level seen in adenocarcinoma tissues, this drug should have a wide clinical application.
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PMID:Comparison of pyrimidine nucleotide synthetic enzymes involved in 5-fluorouracil metabolism between human adenocarcinomas and squamous cell carcinomas. 216 41

To test the utility of the polymerase chain reaction in identifying single base mutations in a gene known to give rise to an altered enzyme and drug resistance phenotype, a human colon adenocarcinoma cell line resistant to methotrexate, with a known single base mutation (Srimatkandada et al., J. Biol. Chem. 264:3524, 1989) was examined. Poly A+ RNA was used for cDNA synthesis with reverse transcriptase, deoxynucleoside triphosphates, and 5 microM 3' primer that anneals outside the coding region of the human dihydrofolate reductase. The RNA:DNA hybrid was used as a template for the polymerase chain reaction with the addition of a 5' primer and Thermus aquaticus (Taq)I DNA polymerase. These primers flank the coding region of the human dihydrofolate reductase and define a region of 650 bases. The polymerase chain reaction was carried out for 40 cycles resulting in full length transcripts in microgram amounts clearly visible by ethidium bromide staining on agarose gels. DNA was isolated by standard methods, and double-stranded DNA was sequenced by the chain-termination method using TaqI DNA polymerase. A single point mutation was discovered at position 91 (T----C) resulting in a substitution of serine for phenylalanine at codon 31, as determined previously by classical cDNA cloning and sequencing. Sequence analysis indicated that this base transition resulted in the loss of Eco RI and Xmn I sites and the gain of a HinfI site in the cDNA, which were confirmed by restriction digests.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detection of a single base mutation in the human dihydrofolate reductase gene from a methotrexate-resistant cell line using the polymerase chain reaction. 264 Jan 57

The effect of alpha-1-antichymotrypsin (ACT), which is known as an efficient serum protease inhibitor and is detected in tumor cell nuclei, on DNA synthesis was studied. ACT inhibited the activity of DNA polymerase alpha purified from human stomach adenocarcinoma. Other human serum proteins including serum albumin, alpha-1-acidglycoprotein, alpha-1-antitrypsin, and immunoglobulin G, as well as other protease inhibitors, such as leupeptin, pepstatin, PMSF and chymostatin, did not affect the activity of DNA polymerase alpha. It was therefore concluded that the inhibitory action of ACT on DNA polymerase alpha was direct phenomenon unrelated to its protease inhibitory activity. Furthermore, the effect of ACT on DNA synthesis was also studied using lysolecithin-permeabilized cultured human stomach carcinoma cells. ACT added in the medium inhibited DNA synthesis and the degree of inhibition depended on incubation time. It was proportional to ACT concentration and the concentration of ACT required for 50% inhibition was 0.8 mg/ml.
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PMID:Inhibition of DNA synthesis by alpha-1-antichymotrypsin. 327 75

alpha 1-Antichymotrypsin (ACT), which is known as an efficient serum protease inhibitor and is detected in tumor cell nuclei, was found to inhibit the activity of DNA polymerase alpha purified from human stomach adenocarcinoma. The concentration of ACT required for 50% inhibition was 1.0 mg/ml and the manner of its inhibition showed the partially competitive relationship between ACT and DNA in the assay system. Furthermore the removal of ACT by anti-ACT antibody lost its antichymotryptic and anti-DNA polymerase activities in parallel. On the other hand, it did not inhibit the activity of human DNA polymerase beta. Other human serum proteins including serum albumin, alpha 1-acid glycoprotein, alpha 1-antitrypsin, and immunoglobulin G as well as other protease inhibitors such as leupeptin, pepstatin, phenylmethylsulfonyl fluoride, and chymostatin did not affect the activity of DNA polymerase alpha. Furthermore ACT heated at 60 degrees C did not inhibit DNA polymerase alpha, although it could still bind to DNA as well as native ACT. It was therefore concluded that the inhibitory action of ACT on DNA polymerase alpha was a direct phenomenon unrelated to its protease inhibitory or DNA binding activities.
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PMID:Inhibition of human DNA polymerase alpha by alpha 1-antichymotrypsin. 349 Sep 7

Human lung cancers of distinct histology exhibit different responses to radiation therapy in vivo. For examination of the basis of this phenomenon, the radiation survival curves and levels of relevant enzymes were determined in 16 lung cancer cell lines derived from tumors of different histology. These included lines from 5 adenocarcinomas, 7 small cell tumors, 3 variant small cell tumors, and 1 large cell tumor. These findings were compared to those obtained with the use of a normal skin fibroblast cell line. Whether cloned in liquid culture or soft agarose, cell lines had similar radiation survival curves. These curves were consistent with the apparent in vivo radiation responsiveness of the tumors. Although considerable heterogeneity in radiation survival curves was observed among the cell lines, cells from large cell lines and small variant lines had pronounced shoulders and extrapolation numbers (n) from 5.6 to 14. In contrast, cells from small cell lines and adenocarcinoma cell lines were more "sensitive" (-n values of 1-3.3). In these cell lines, levels of DNA polymerase beta, glutathione (GSH), GSH transferase, GSH reductase (NAD(P)H), gamma-glutamyltransferase did not correlate with radiation parameters of sensitivity. DNA polymerase beta and GSH levels were, however, higher than those in a line of normal skin fibroblasts. These cell lines may be useful in identifying the basis of the variable responsiveness of human lung cancer cells to ionizing radiation.
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PMID:Heterogeneity in the radiation survival curves and biochemical properties of human lung cancer cell lines. 614 44


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