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:6.5.1.2 (DNA ligase)
2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelium-associated enzyme xanthine oxidase is known to generate reactive oxygen intermediates which may damage the surrounding tissue. We investigated whether reactive oxygen intermediates released by xanthine oxidase exert a toxic effect on isolated rat islet cells. The xanthine oxidase (25 mU/ml)/hypoxanthine (0.5 mmol/l) system released reactive oxygen intermediates in vitro as detected by luminol in a chemiluminescence analysing system. The addition of nicotinamide inhibited the release of reactive oxygen intermediates in a dose-dependent manner (50% inhibition at 20 mmol/l). Exposure of islet cells to enzyme generated reactive oxygen intermediates caused lysis of 39% of the cells within 15 h. Monitoring the mitochondrial function of islet cells by the conversion of tetrazolium bromide to its formazan product revealed a significant reduction of the respiratory activity down to 51% of that of the controls by 30 min after the initiation of the xanthine oxidase reaction. Mitochondrial dysfunction preceded plasma membrane damage. The addition of nicotinamide, a radical scavenger and inhibitor of the DNA repair enzyme poly(ADP-ribose) synthetase protected the islet cells from lysis and partially preserved their mitochondrial activity in the presence of reactive oxygen intermediates. We conclude that activation of the endothelial enzyme xanthine oxidase, known to be induced by mediators of immune cells or by episodes of ischaemia and reperfusion causes islet cell damage with subsequent cell death in early phases of pancreatic islet cell destruction.
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PMID:Oxygen radicals generated by the enzyme xanthine oxidase lyse rat pancreatic islet cells in vitro. 147 12

The DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT) was analysed in the human ovarian-cancer SW626 cell line and in the human promonocytic leukemia U937 cell line following their synchronisation with low non-toxic concentrations of methotrexate. In SW626, AT increased in the early S phase of the cell cycle and then declined during progression of the S phase to levels found in the G1 phase of unsynchronised cells. In contrast, at the G1/S-phase boundary and in the S phase, U937 cells showed a lower AT content than did exponentially growing unsynchronised cells. In addition, AT activity was greatly reduced in resting U937 cells but was not reduced appreciably in resting SW937 cells but was not reduced appreciably in resting SW626 cells. The results of these studies indicate that AT fluctuations do not follow a constant pattern during the cell cycle of different cell lines.
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PMID:O6-Alkylguanine-DNA alkyltransferase content in synchronised human cancer cells. 158 85

Resistance to alkylating agents is partly due to the presence of the DNA repair enzyme, termed O6 alkyltransferase (O6AT). Preclinical evidence of the transient restoration of sensitivity of cells resistant to nitrosoureas by pretreatment with a methylating agent, whose role is to deplete cells of O6AT activity and clinical evidence of such a depletion in patients lymphocytes, led us to test the sequential administration of dacarbazine 3 h prior to fotemustine, a chloroethylnitrosourea derivative. 24 patients with measurable advanced melanoma entered the trial and are evaluable. Toxicity was mainly haematological with early neutropenia and/or thrombocytopenia. Clinical activity (33%) was impressive especially on lung metastases with high complete response rate for that site (7/14). Unfortunately, the occurrence of a rapidly fatal pulmonary toxicity precludes further use of the regimen before a plausible explanation for this unexpected toxicity is obtained. Indeed, similar cases have been reported in other trials using the sequential schedule while no lung toxicity was reported in single agent or alternated administrations. Preclinical studies are ongoing to test the hypothesis of a glutathione depletion and the possibility of a rescue treatment.
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PMID:Sequential administration of dacarbazine and fotemustine in patients with disseminated malignant melanoma--an effective combination with unexpected toxicity. 159 Oct 62

The level of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (MGMT) was examined in benign and malignant skin tumors induced with different initiating and promoting agents and from both SENCAR and Sensitive SENCAR Inbred (SSIN) mice. The MGMT levels in the tumors were approximately one-half the level observed in normal surrounding epidermis and in keratinocytes from untreated controls. In addition, a carcinoma-producing cell line, VT 17DT, derived from papillomas in SENCAR mice had no detectable MGMT activity (Mer- phenotype), whereas in the non-tumor forming line, 3PC, MGMT activity was comparable to that in papillomas. The comparatively low level of MGMT in papillomas may contribute to their ease of conversion to squamous cell carcinomas by N-ethyl-N-nitrosourea or n-methyl-N'-nitro-N-nitrosoguanidine. MGMT activity was also determined in the epidermis of non-exposed mice of various stocks and strains. Epidermal MGMT activity was similar to levels in the corresponding livers and was, in general, parallel with stock/strain susceptibility to tumor formation. This is the first report that examined MGMT activity in skin tumors and normal keratinocytes in the mice of several stocks and strains.
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PMID:O6-alkylguanine-DNA alkyltransferase activity in epidermal tumor and normal epidermal cells of mice of various stocks and strains. 163 96

Treatment of C57Bl or BALB/C mice with human interferon-alpha A/D (HuIFN-alpha A/D) significantly increased hepatic levels of the DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AT). The maximum induction was seen 24 h after a single dose of 50-100 micrograms/kg IFN-alpha A/D. No induction was observed in rat liver hepatocytes cultured in vitro. Liver AT was also induced by poly(I:C), which is a potent IFN inducer. By increasing AT levels, IFN could protect against the potentially mutagenic alkylation at guanine O6 position caused by some carcinogens. Moreover this finding suggests a link between immune response and the DNA repair system, possibly acting in concert to defend the body from potentially toxic compounds.
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PMID:O6-alkylguanine DNA alkyltransferase is induced by human recombinant interferon-alpha A/D in mouse liver. 164 Jan 18

The phage T4 denV gene, coding for the pyrimidine-dimer specific T4 endonuclease V, was transfected into human repair-proficient fibroblasts, repair-deficient xeroderma pigmentosum fibroblasts, and into wild type CHO hamster cells. Transfectants maintained denV DNA and expressed denV mRNA. Purified T4 endonuclease V encapsulated in liposomes was also used to treat repair-proficient and -deficient human cells. The denV transfected clones and liposome-treated cells showed increased unscheduled DNA synthesis and enhanced removal of pyrimidine dimers compared to controls. Both denV gene transfection and endonuclease V liposome treatment enhanced post-UV survival in xeroderma pigmentosum cells but had no effect on survival in repair-proficient human or hamster cells. The results demonstrate that an exogenous DNA repair enzyme can correct the DNA repair defect in xeroderma pigmentosum cells and enhance DNA repair in normal cells.
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PMID:Enhancement of ultraviolet-DNA repair in denV gene transfectants and T4 endonuclease V-liposome recipients. 166 12

Drug resistance is a major problem in cancer chemotherapy. Treatment protocols generally include a number of different cytotoxic drugs given in combination. Therefore, drug resistance in the tumor is likely to result from the coexpression of several cellular activities able to prevent cell killing by any of the drugs used. In this study we have measured several potential drug resistance mechanisms consisting of the multidrug resistance gene product P-glycoprotein, glutathione, glutathione-transferase and -peroxidase, and the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase in samples of colon carcinoma and normal adjacent mucosa from 23 untreated patients. All of these, with the exception of P-glycoprotein, showed significant increases in tumor tissue levels when compared with normal tissue from the same patient. The significance was highest for glutathione peroxidase (P less than or equal to 0.0005). Individual patients, however, showed very different patterns, with none, several, or all monitored resistance mechanisms elevated in the tumor. The implications both in the choice of drugs and in the use of resistance modifying agents to improve therapy for the individual patient are discussed.
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PMID:Assessment of P-glycoprotein, glutathione-based detoxifying enzymes and O6-alkylguanine-DNA alkyltransferase as potential indicators of constitutive drug resistance in human colorectal tumors. 167 23

DNA polymerase beta (beta-pol) and its mRNA are maintained at constitutive levels during the cell cycle and during stages of cell growth in culture. To study biological consequences of variations in the level of this DNA repair enzyme and/or its mRNA, we prepared expression vectors in which cDNA for human beta-pol is inserted under the control of a metallothionein promoter (pMT) in the sense and antisense orientation, respectively, and these vectors then were used for stable transformation of mouse 3T3 cells. Vectors also contained the mouse DHFR gene, such that culture of transformants in medium with increasing concentrations of methotrexate resulted in amplification of inserted DNA. The levels of sense and antisense transcripts are strongly increased by culture of transformants in medium with 65 microM Zn2+, although some expression is detected even without Zn2+ induction. After five days of induction, the beta-pol level was about threefold higher in sense cells and about 10-fold lower in antisense cells than in parallel cultures without induction. The antisense line has a threefold increased cell doubling time in the presence of 65 microM Zn2+ compared with the absence of Zn2+. Zn2+ (65 microM) induction for the sense line results in normal growth for the first three days and, thereafter, a complete cessation of growth. Yet, these blocked cells remain fully viable. The results indicate that sudden deregulation of beta-pol expression alters cell growth in mouse 3T3 cells.
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PMID:Deregulation of DNA polymerase beta by sense and antisense RNA expression in mouse 3T3 cells alters cell growth. 169 88

The phr gene of Escherichia coli K-12 encodes the light-dependent, DNA repair enzyme photolyase, which removes UV light-induced pyrimidine dimers from cellular DNA. From Southern hybridization analysis of several strains containing successively extended phr deletions, we have determined the direction of transcription of the phr gene on the E. coli K-12 chromosome. Northern (RNA) hybridization analysis suggests that the phr gene is cotranscribed with a previously identified gene of unknown function (orf169) into two messages of different lengths. S1 nuclease mapping analysis indicates that the two transcripts share a single termination site but initiate at two different sites. Finally, we have determined that the presence of orf169 is not necessary for phr gene activity in vivo.
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PMID:Physical analysis of phr gene transcription in Escherichia coli K-12. 169 32

The specificities of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase from brain and liver cells of the chick embryo and of DNase I were demonstrated in vitro by their response to substrate DNA pretreated with monofunctional alkylating agents of different O6-guanine alkylating ability and some antineoplastic agents. Treatment of DNA with ethidium bromide, Hoechst 33258, doxorubicin, Fe2+/bleomycin, and suramin resulted in a dose-dependent diminution of alkyltransferase activity (DE50 approximately 5 micrograms/ml, 15 micrograms/ml, 5 micrograms/ml, 5 micrograms/ml, 100 micrograms/ml, respectively). Apart from bleomycin, comparable results were obtained with DNase I. Thermal denaturation of the substrate DNA reduced both alkyltransferase and DNase I activity. No effect was seen with X-irradiation. Cisplatin decreased only DNase I activity. Some topoisomerase II and/or gyrase inhibitors remained without significant effects on the alkyltransferase reaction whereas DNA catabolism by DNase I was diminished in a dose-dependent manner (DE50 between 6.5 and 19 micrograms/ml).
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PMID:Inhibition of O6-alkylguanine-DNA alkyltransferase and DNase I activities in vitro by some alkylating substances and antineoplastic agents. 172 Jul 84


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