Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6) are important enzymes involved in protection of the cell from harmful effects of oxidative degradation. The respective substrates for these enzymes, superoxide anion and hydrogen peroxide, can be generated within the cell either by normal metabolism or by ionizing radiation. The hypothesis that the inherent radiosensitivity associated with the human autosomal recessive disease Ataxia telangiectasia is due to decreased levels of SOD and/or catalase was tested. The results suggest that fibroblast cells derived from ataxia patients are normal with respect to these two enzymes.
 ...
PMID:Superoxide dismutase and catalase activities in Ataxia telangiectasia and normal fibroblast cell extracts. 48 42

The object of this study was to determine whether ataxia-telangiectasia (AT) cells are more sensitive than normal cells to reduced oxygen species generated either during normal cell processes or resulting from metabolism of xenoblotics. To test this hypothesis four AT and four normal fibroblast cultures were exposed to hydrogen peroxide (H2O2) and the induction of micronucleated cells was assayed. AT cultures responded to the H2O2 treatment with a greater increase in micronucleus frequencies than that observed in normal cultures (P less than 0.01). At time course study showed that an elevation in micronucleus frequencies occurred earlier in AT cultures (significant increase by 1.5 h after treatment) than in normal cultures, possibly indicating a G2-phase sensitivity of AT cells to H2O2. The addition of an aqueous extract of areca nut to the cultures, as an example of exogenous stress, induced a greater frequency of micronucleated cells in AT cultures than in the normal cultures. These results suggest that the AT syndrome may serve as a model for investigating the role of reduced oxygen species in cancer.
 ...
PMID:Response of fibroblast cultures from ataxia-telangiectasia patients to oxidative stress. 220 88

The effect of hydrogen peroxide on the rate of semi-conservative DNA synthesis in ataxia telangiectasia (AT) and normal human lymphoblastoid cells was investigated. The rate of DNA synthesis in AT cells was not depressed to a lesser extent than in normal cells, as might have been expected since H2O2 is a radiomimetic agent. On the contrary, 4 AT cell lines displayed a higher sensitivity to the inhibitory effect of H2O2 on DNA synthesis than 2 normal cell lines. Comparable levels of cytotoxicity were detected in cell viability studies. Furthermore, neither the level of DNA breakage produced by H2O2, nor the rate of repair of these lesions was significantly different in normal and AT cells. Together, these results indicate that the AT cell lines utilized in this study are not hypersensitive to the oxidant. It is suggested that H2O2 may not induce lethality via the direct action of the hydroxyl radical (OH.).
 ...
PMID:Identification of 4 ataxia telangiectasia cell lines hypersensitive to gamma-irradiation but not to hydrogen peroxide. 277 Jul 63

Neocarzinostatin (NCS) belongs to a family of antitumour protein antibiotics that selectively inhibit DNA synthesis. Replicon initiation in mammalian cells is selectively inhibited by NCS, and cells defective in DNA repair, such as ataxia telangiectasia fibroblasts, are especially sensitive to NCS as they are to X-ray. The holoantibiotic consists of a nonprotein chromophore (Mr = 659), tightly and specifically bound to an apoprotein (Mr = 10,700). The apoprotein protects the highly labile chromophore from degradation in aqueous solution; all the activity resides in the nonprotein chromophore. The latter binds specifically to DNA, especially to regions rich in T and A residues, with a tight binding site consisting of four base pairs. NCS chromophore consists of three main structural subunits: a naphthoic acid derivative, an amino-sugar and a connecting highly unsaturated middle component (C12H5) with a strained ether (probably epoxide) and cyclic carbonate. The authors have proposed that the naphthoic acid subunit intercalates DNA and the positively charged amino sugar binds electrostatically to the negatively charged sugar phosphate backbone of DNA; these two anchors serve to juxtapose the middle piece with the deoxyribose of mainly thymidylate residues in DNA. Upon activation of the drug by a thiol (which forms an adduct with the middle piece) and in the presence of O2, there is a selective oxidation of the 5'-C of deoxyribose to produce a DNA strand break with a phosphate at the 3'-end and a nucleoside 5'-aldehyde at the other. Kinetic analysis shows that one molecule of thiol adds to DNA-bound NCS chromophore even in the absence of oxygen; this is rapidly followed by the consumption of 1 mol of O2 and then another mol of thiol. The oxygen of the 5'-aldehyde is derived from O2, not H2O. Even in the absence of O2 the NCS chromophore abstracts a hydrogen from C-5' of deoxyribose in DNA, presumably generating a carbon-centred radical intermediate in the DNA (other mechanisms have not been eliminated) which can add O2 to form a peroxy derivative. The second molecule of thiol may be involved in the cleavage of this complex to form the 5'-aldehyde at the strand break. There is no evidence for the involvement of metals or a diffusible form of reduced oxygen.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Molecular mechanism of novel DNA sugar damage by an antitumour protein antibiotic. 294 68

A defect in DNA repair coupled to anomalous DNA synthesis after induction of certain radiogenic DNA damage is suspected to underlie the radiosensitivity of cells from patients with ataxia-telangiectasia (A-T). The response of cultured skin fibroblasts from A-T patients and A-T heterozygotes to six agents inducing various levels of DNA strand breakage by different mechanisms was studied to obtain further information on the nature of the 'A-T critical DNA lesion'. The A-T cells showed varying degrees of hypersensitivity to the cytotoxic action of the quinone-containing anti-tumor antibiotics streptonigrin and adriamycin and to hydrogen peroxide. This hypersensitivity was accompanied by reduced inhibition of DNA synthesis compared to normal cells after treatment with these agents. A limited degree of cellular hypersensitivity that was not sufficient to allow for definition of a separate sensitivity range was shown by A-T heterozygous cells. On the other hand, the A-T cells showed a normal response to paraquat, saframycin A and ellipticine. Taken together with previous results showing hypersensitivity of A-T cells to ionizing radiation, bleomycin and neocarzinostatin, these data indicate that the critical DNA lesion in A-T cells is a strand break caused by deoxyribose destruction following the action of free radicals targeted into the DNA.
 ...
PMID:Abnormal response of ataxia-telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism. 661 60

Skin fibroblasts from ataxia telangiectasia and xeroderma pigmentosum (XP) donors and from the XP sib (possible heterozygote), all genetically predisposed to a high risk of cancer, show an increased susceptibility to light-induced chromatid breaks after culture in vitro. Light-induced chromatid breaks were shown previously to result from generation of hydrogen peroxide (H2O2) during light exposure. The level of susceptibility attained is significantly higher than that observed in 13 lines of fibroblasts from normal skin of donors ranging in age from 3 days to 92 years or from fetal skin tested at various population doubling levels. Two lines of normal skin fibroblasts transformed by chemical carcinogens to neoplastic cells also show a significant increase in susceptibility as compared with their untransformed controls. These data indicate for human cells, as reported earlier for mouse cells, an association between enhanced susceptibility to light-induced chromatid damage and neoplastic potential; this association is further supported by the high susceptibility of cells derived from a human adenocarcinoma. Two observations are consistent with the concept that the increased susceptibility does not result from greater initial damage to the DNA of the neoplastic cells. First, activities of the ubiquitous H2O2 scavenging enzyme, glutathione peroxidase, are similar in the paired normal and neoplastic cell populations. Second, cells of the paired lines are equally sensitive to DNA breakage by exogenous H2O2. The enhanced susceptibility associated with neoplastic potential may result from an impaired capacity to repair DNA rather than a greater initial sensitivity of the neoplastic cells to the damaging agent.
 ...
PMID:Light-induced chromatid damage in human skin fibroblasts in culture in relation to their neoplastic potential. 731 76

Cells from patients with ataxia-telangiectasia (AT) are more sensitive than cells from normal individuals to a number of compounds which induce DNA damage via oxygen-derived free radical attack. We tested the hypothesis that AT cells would show a sensitivity to reactive oxygen species (ROS) generated by activated inflammatory cells. AT cells were exposed to neutrophils activated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or to xanthine/xanthine oxidase (X/XO), an enzyme system which generates superoxide and hydrogen peroxide. Induced micronuclei (MN) frequencies (corrected for spontaneous MN frequencies) were significantly higher in AT cell cultures than in cultures from normal individuals (comparison of MN frequencies of AT vs. normal cultures: for treatment with activated neutrophils, P = 0.003; for X/XO, P = 0.05). The comet assay was used to determine whether the elevated chromosomal damage in the treated AT cells was due to a difference in strand breakage or its rejoining. X/XO treatment was used in studies of single-stranded (SS) DNA breakage, and X-ray treatment for double-stranded (DS) DNA damage. AT and normal cells showed no significant differences in the initial levels of SS (P = 0.29) or DS (P = 0.91) DNA damage. Likewise, they exhibited similar rejoining kinetics (rejoining half-time for SS = 10 min, for DS = 30 min). These data support the involvement of the AT loci in determining a cell's ability to deal with oxidative stress, although the mechanism underlying this effect has yet to be resolved. The data also suggest that AT patients are at elevated risk of sustaining DNA damage in tissues undergoing inflammatory reactions.
 ...
PMID:Response of fibroblast cultures from ataxia-telangiectasia patients to reactive oxygen species generated during inflammatory reactions. 792 23

Evidence from animal models suggests that 12-O-tetrade-canoylphorbol-13-acetate (TPA) is capable of inducing genetic damage within a tissue, although the mechanism underlying this response is unknown. A favoured hypothesis is that the TPA is acting either by stimulating cells in the tissue directly to generate DNA damaging agents or by recruiting inflammatory cells to the tissue and stimulating them to release such agents. These agents include reactive oxygen species, such as hydrogen peroxide and superoxide anion, as well as products generated during lipid peroxidation and arachidonic acid metabolism. It is not known whether significant alterations occur in the sensitivity of cells to TPA during the process of tumourigenesis. In this paper the capacity of TPA to induce chromosomal breakage (measured by micronuclei induction) was found to be elevated in bladder tumour cell lines compared to two normal cultures, a primary epithelial culture and a fibroblast culture. This effect was observed when cells were exposed to TPA directly or co-cultured with TPA-activated neutrophils isolated from human blood. In addition, we present evidence that loci on chromosome 11 may be involved in altering the response of cells to TPA. When chromosome 11 was inserted into a bladder tumour cell line, a reduction in sensitivity to TPA-activated neutrophils was observed. The chromosome insert did not protect against damage induced by direct treatment with TPA alone. In another scenario, fibroblasts from a patient with ataxia telangiectasia, a syndrome localized to chromosome 11, were shown to have an elevated sensitivity to the chromosome damaging action of TPA-activated neutrophils, but not to TPA alone. These results suggest that some of the alterations occurring in a tissue during tumourigenesis could have a significant impact on the responsiveness of cells to genetic damage by TPA. They also suggest that the damage induced by TPA in a cell may be different if a neutrophil is present.
 ...
PMID:A protective effect of chromosome 11 against DNA damage by TPA-activated neutrophils but not TPA acting alone. 800 Dec 46

Skin fibroblasts from certain patients with the photosensitivity dermatitis/actinic reticuloid syndrome show enhanced sensitivity to ultraviolet radiation compared to normal fibroblasts. To probe further the link between oxidative damage and this disease, we have obtained a more extensive set of cell lines from patients with a severe form of the disease and examined their sensitivity towards oxidative stress by measuring cell survival following UVA radiation (330-450 nm) or hydrogen peroxide treatment (0.1-2.4 mM). The activation of the stress gene, heme oxygenase, has also been assessed by measuring the accumulation of mRNA after hydrogen peroxide treatment. Our studies have confirmed that a slight ultraviolet sensitivity is a characteristic of photosensitivity dermatitis/actinic reticuloid syndrome cell strains and we further demonstrate that these cell lines are particularly sensitive to hydrogen peroxide with up to a three- to fourfold increased sensitivity as compared to normal controls. We also show that certain ataxia telangiectasia strains that are especially sensitive to hydrogen peroxide are also slightly sensitive to ultraviolet radiation. Hydrogen peroxide induces accumulation of mRNA for the oxidant-inducible stress protein, heme oxygenase, with similar kinetics (maximum mRNA accumulation 2-4 h following treatment) and with a similar range of magnitudes in both normal (6.6-20.6 times mRNA increase over basal levels) and photosensitivity dermatitis/actinic reticuloid (2.9-12.8 times) skin cells. Because cells from photosensitivity dermatitis/actinic reticuloid patients show increased sensitivity towards oxidative stress but show no significant change in oxidant activation of the heme oxygenase gene, we propose that the defect involves a late stage of processing of oxidative damage rather than a compromised free radical scavenging system.
 ...
PMID:Cellular sensitivity to oxidative stress in the photosensitivity dermatitis/actinic reticuloid syndrome. 817 61

A series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones was prepared via several synthetic routes and evaluated as AII receptor antagonists in vitro and in vivo. The preferred compounds contained a [2'-(5-tetrazolyl)biphenyl-4-yl]methyl side chain at N4 and an n-butyl group at C5. A number of these bearing an alkyl or aralkyl substituent at N2 showed in vitro potency in the nanomolar range (rabbit aorta membrane receptor), and several of these, e.g., the 2,2-dimethyl-1-propyl analogue (54, IC50 = 2.1 nM), effectively blocked the AII pressor response in conscious rats with significant duration (2.5 h at 1 mg/kg orally for 54). Among analogues possessing aryl substituents at N2, ortho substitution on the phenyl moiety resulted in several derivatives with in vitro potency in the low nanomolar range. One of these, featuring a 2-(trifluoromethyl)phenyl substituent at N2 (25, IC50 = 1.2 nM), was effective at 1 mg/kg orally in the rat model, with a duration of > 6 h. Implications for hydrophobic and hydrogen-bonding interactions with the AT1 receptor are discussed.
 ...
PMID:Triazolinones as nonpeptide angiotensin II antagonists. 1. Synthesis and evaluation of potent 2,4,5-trisubstituted triazolinones. 835 55


1 2 3 4 5 6 7 8 9 10 Next >>