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)

1. Pharmacodynamics and pharmacokinetics of antimetabolites. Antimetabolites are administered in the form of a base or its riboside, which is incorporated into the cell and converted to an active or inactive metabolite. The active metabolite remain in the cell inhibiting the enzymes to catalyze nucleotide synthesis for nucleotide triphosphate formation, but the inactive metabolites are rapidly excreted out of the cell. The inhibitory effect of antimetabolites on nucleotide formation is correlated with factors, such as maintenance of drug blood level, incorporation of the drug into the cell, activation and inactivation of the drug, affinity of the active form to the corresponding enzyme, and change in pool size of the intermediate metabolites in nucleotide synthesis. The salvage synthesis occurring at the higher level of the enzymes catalyzing nucleotide synthesis to counteract the inhibition by the drug is also correlated with the nucleotide formation. II. Pyrimidine antagonists 1. Cytosine arabinoside (ara-C) and its derivatives Ara-C is rapidly converted to ara-CTP and ara-U. The former remains in the cell and inhibits DNA polymerase, but the latter is excreted rapidly out of the cell. A small portion of ara-C is incorporated into DNA, which results in the degradation of DNA as demonstrated by reduced sedimentation of bulk DNA in alkaline sucrose gradient centrifugation and the ladder DNA fragmentation with a minimum fragment of approximately 180 base pairs and its conjugates in agarose gel electrophoresis. Behenoyl ara-C (BHAC) is highly lipophilic and highly distributed in the erythrocyte stroma and membrane fraction of leukocytes after iv infusion. The incorporated BHAC is released after the plasma BHAC level decreases, which suggests that erythrocytes can be a drug reservoir after iv infusion. Therefore, severe anemia should be treated before BHAC chemotherapy for longer maintenance of the plasma BHAC level. 2. 5-Fluorouracil (5-FU) and its derivatives Activation of 5-FU in the cells is metabolized by uracil metabolizing enzymes to FUMP and FdUMP. FUMP is further metabolized to FdUMP and is also incorporated to RNA. FdUMP produces a ternary complex with thymidylate synthetase and leucovorin; subsequently, conversion of dUMP to dTMP is strongly inhibited. Thus, FUMP and FdUMP inhibit RNA and DNA metabolism, respectively. Enzyme activity during 5-FU metabolism and consequently the degree of inhibition of DNA and RNA syntheses markedly differ with the tumor cell species. This should be taken into consideration when performing chemotherapy of malignancies.
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PMID:[Clinical pharmacology of anticancer agents (Part 4). Antimetabolites (1)]. 173 42

The correlation between the extent of peritumoral edema and the proliferative potential or the infiltration of mononuclear cells was studied in 17 gliomas. The peritumoral edema was evaluated on contrast enhanced CT scan as the ratio of the low density area around the tumor to the enhanced high density area. The proliferative potential and the infiltration of mononuclear cells into the tumor were investigated immunohistochemically using monoclonal antibody (MAb) against DNA polymerase alpha and anti-Leu MAb's respectively. There was a significant correlation between the extent of the peritumoral edema and the percentage of DNA polymerase alpha positive cells. The degree of the infiltration of mononuclear cells into the tumor tissue also correlated with the extent of peritumoral edema. In gliomas with high proliferative potential and/or severe infiltration of mononuclear cells, the peritumoral edema may be aggravated by disruption of the blood-brain-barrier and increased vascular permeability.
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PMID:[Study on the extent of peritumoral edema in glioma: its correlation with the proliferative potential and tumor-infiltrating mononuclear cells]. 173 25

We studied the expression of three cell proliferation-associated antigens: DNA polymerase alpha, Ki-67 antigen, and transferrin receptor, in 35 T-cell lymphomas of nodal origin (T-NL) and 40 cutaneous T-cell lymphomas (CTCL). Immunohistochemical staining was carried out on frozen tissue sections of these specimens using three monoclonal antibodies, DAKO-PC, CL22-2-42B (DNA polymerase alpha), and OKT9. The proportion of cells positive for CL22-2-42B, DAKO-PC, or OKT9 among all tumor cells was correlated with four histologic subtypes: malignant lymphoma (ML), diffuse, small; mixed; large; and large cell immunoblastic in both T-NL and CTCL. A strong correlation was noted between positivity for CL22-2-42B and that for DAKO-PC or OKT9. On the other hand, no difference in the expression of these three antigens was noted between T-NL and CTCL in the high, intermediate or low grade-malignancy group. In CTCL as well as in T-NL, cells positive for CL22-2-42B, DAKO-PC or OKT9 were significantly more numerous in the high-grade group than the intermediate-grade group, and in the intermediate-grade group than the low-grade group. Furthermore, a significant correlation between survival period and the number of CL22-2-42B-positive cells was noted when the T cell malignancies, CTCL and T-NL were considered (t value = 2.015, p less than 0.05). Thus, the expression of DNA-polymerase alpha, Ki-67 antigen or OKT9 seems to well reflect the biological behavior and/or clinical prognosis of T-cell lymphoma.
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PMID:Expression of three cell proliferation-associated antigens, DNA polymerase alpha, Ki-67 antigen and transferrin receptor in nodal and cutaneous T-cell lymphomas. 175 49

The tumor-inhibiting metal complex trans-imidazolium-bisimidazoletetrachlororuthenate(III) (ICR) reacts with DNA and inhibits template-primer properties for DNA synthesis catalysed by Escherichia coli DNA polymerase I. The reaction with DNA depends on the aging (half-life 6.8 h) of the aqueous solution containing ICR. The kinetics of the reaction with DNA are reminiscent of those for cisplatin.
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PMID:Inhibition of Escherichia coli DNA polymerase I catalysed DNA polymerization by trans-imidazolium-bisimidazoletetrachlororuthenate(III). 179 86

ras proto-oncogenes are activated by point mutation in a wide variety of human and animal tumors, making ras gene analysis a major area of clinical and basic cancer research. Activating point mutations, in each of the three ras genes (Ha-, Ki-, or N-ras), usually occur in one of three specific codons (12, 13, or 61). Thus, an adequate assessment of activating ras gene mutations should include the analysis of at least nine codons. We have developed a rapid method for point mutation analysis of the ras genes, which involves simultaneous (multiplex) PCR amplification of all three homologous ras genes (in the regions surrounding codons 12-13 and codon 61) in a single reaction starting with only 1 microgram of genomic DNA. Although multiplex PCR has been previously used for unrelated sequences, we demonstrate here that multiplex PCR can also be used for highly homologous sequences. Importantly, after coamplification, each of the homologous ras genes can be individually and specifically sequenced even though the other two closely related genes are present in the same template mixture, by using high-stringency conditions permitted by Taq DNA polymerase. An automated multicycle DNA sequencing procedure is used to allow the double-stranded PCR products to be sequenced directly without the need to generate single-stranded templates, further simplifying the protocol. Our multiplex PCR amplification and direct DNA sequencing procedures should greatly facilitate more complete analyses of activating ras gene point mutations, particularly in studies involving many tumor samples.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multiplex polymerase chain reaction amplification and direct sequencing of homologous sequences: point mutation analysis of the ras genes. 180 52

A simple method is described for the construction of subtracted cDNA libraries. The technique was used to create a human pancreatic tumor cDNA library that was screened using either hybridization with cDNA probes or antibodies. cDNA from a well-differentiated tumor cell line (CD-11) was subtracted against RNA from an undifferentiated tumor cell line (Panc-1). The subtracted cDNA was purified from RNA-cDNA hybrids by oligo-dA cellulose affinity chromatography. Single-stranded subtracted cDNA was used as a template for random primed second-strand synthesis using the Klenow's fragment of DNA polymerase. After ligation with Eco R1 adapters, cDNA was inserted into lambda gt11. A library of 140,000 primary pfu was obtained that contained 92% recombinants. A small portion of this library (40,000 pfu) was subjected to probe screening with a mucin cDNA probe known to be differentially expressed by CD-11 cells. The ratio of mucin cDNA clones to actin cDNA clones was increased by greater than 300-fold in the subtracted cDNA library compared to a standard cDNA library from the same cell line. The absolute number of mucin cDNA clones per 40,000 pfu was also increased 32-fold in the subtracted library. Pancreatic tumor mucin cDNAs were also identified in the subtracted library by antibody screening. The subtraction procedure yielded a 50-fold enrichment in differentially expressed cDNA detected by antibodies, compared to a nonsubtracted library from the same cell line.
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PMID:A simple, effective method for the construction of subtracted cDNA libraries. 187 62

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

In a previous report we have characterized cisplatin (CDDP)-resistant sublines (HLac 79-DDP1 to DDP4) of the recloned squamous cell head and neck cancer (SCHNC) line HLac 79-ML revealing significant alterations of glutathione (GSH) metabolism and drug accumulation. In order to overcome CDDP-resistance in HLac 79 cells we now investigated the effect of buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, verapamil (VRP), a calcium channel blocker that has been found to modulate resistance towards a broad spectrum of antineoplastic drugs, cyclosporin A (CSA), an immunosuppressive agent probably affecting drug pharmacokinetics, and aphidicolin (APC), a fungal metabolite interfering with DNA repair through inhibition of DNA polymerase alpha, on HLac 79 CDDP-sensitivity. Using the colorimetric MTT assay, GSH depletion with BSO led to a significant decrease of the 50% inhibitory drug concentration (IC50) in all HLac 79 sublines by dose modifying factors (IC50 CDDP/IC50 BSO + CDDP) ranging from 1.8 to 3.3. VRP, CSA or APC were not effective to overcome CDDP resistance in HLac 79 cells. The potential of BSO to modulate CDDP resistance in vitro was tested in vivo in HLac 79 tumor bearing NMRI nu-nu mice subsequently. Oral administration of BSO 7 days prior and during (days -7 to 8) CDDP treatment (3 mg/kg bw i.p. days 0, 4, 8) produced a significant prolongation of mean survival time mean as compared to chemotherapy alone. This held true for both the maternal line ML in terms of chemosensitization (CDDP: mean = 40.2 +/- 15.9 days vs. CDDP + BSO: mean = 80.3 +/- 30.4 days, p less than 0.001) and the CDDP resistant subline DDP4 in terms of partially overcoming secondary drug resistance (CDDP: mean = 56.5 +/- 13.6 days vs. CDDP + BSO: mean = 72.5 +/- 15.8 days, p less than 0.001). Enhanced toxicity of combined BSO and CDDP treatment manifested by transient 10% reduction of animal mean body weight.
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PMID:Circumvention of drug resistance in cisplatin-resistant sublines of the human squamous carcinoma cell line HLac 79 in vitro and in vivo. 195 May 44

The proliferative capacity of brain-tumor cells was analyzed in vitro and in situ using monoclonal antibody (MAb) against deoxyribonucleic acid (DNA) polymerase alpha. For the in vitro studies, two cultured human glioma cell lines were investigated using MAb against DNA polymerase alpha, the MAb Ki-67, a serum against proliferating cell nuclear antigen (PCNA/cyclin), bromodeoxyuridine (BUdR), and an anti-BUdR MAb. During exponential growth of the cells, the percentage of polymerase alpha-positive cells (the "polymerase alpha score") ranged from 72.0% to 77.1%, the Ki-67-positive cells (the "Ki-67 score") ranged from 43.4% to 59.4%, the PCNA/cyclin-positive cells from 30.9% to 41.4%, and the BUdR labeling index from 28.6% to 39.3%. For the in situ studies, tissue from 60 human brain tumors and from two normal human brains was investigated and the polymerase alpha scores and Ki-67 scores were compared. In normal brain tissue, no immunostaining was found by either method. In brain tumors, both the polymerase alpha scores and the Ki-67 scores correlated with the histological grade of malignancy. Polymerase alpha scores were generally higher than Ki-67 scores in the same specimen, especially in malignant brain tumors. These findings suggest that immunostaining of DNA polymerase alpha is a convenient and important new method by which to estimate the cellular proliferation rate of brain tumors. Polymerase alpha scores may be closer to the growth fraction of the individual tumor than the MAb Ki-67 or other scores.
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PMID:Immunohistochemical demonstration of DNA polymerase alpha in human brain-tumor cells. 196 2

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.
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PMID:In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results. 198 Oct 14


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