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

Rats were subjected to 3,500 r of X-irradiation in a single dose while breathing oxygen at 1 ATM pressure. Comparison was made between the delayed effects of irradiating thoracic, lumbar, and the cauda equina fields. The lumbar field involved the alpha-motoneurons and spinal roots supplying the sciatic nerve, while the cauda equina field involved these spinal roots but spared the alpha-motoneurons in the spinal cord. Thoracic irradiation produced paraplegia after an interval of 127-150 days. In the irradiated zone, the spinal cord was severely damaged, but the thoracic spinal roots were spared. Lumbar irradiation produced paraplegia after an interval of 83-211 days. In the irradiated zone, the alpha-motoneurons were largely spared, the spinal cord showed mild to moderate white matter damage, but the most severe damage was of the lumbosacral spinal roots. The posterior roots were more affected than the anterior. In longer interval cases the degeneration of the roots appeared to be due to focal devitalization. Evidence is advanced that root degeneration had been progressing for at least 4 weeks before the onset of paraplegia. In the cauda equina series the lumbosacral spinal root changes were similar to those in the lumbar series. This study indicates that different levels of the neuraxis have different degrees of susceptibility to X-irradiation. The thoracic cord appears more susceptible than the lumbosacral; the lumbosacral roots appear more susceptible than the thoracic; the posterior roots are more susceptible than the anterior. These findings may have relevance to the study of radiation damage in man, even though the dose schedule used in this experimental study differs greatly from that used for radiotherapy.
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PMID:Delayed myeloradiculopathy produced by spinal X-irradiation in the rat. 83 11

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.
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PMID:Response of fibroblast cultures from ataxia-telangiectasia patients to oxidative stress. 220 88

The basal levels of superoxide dismutase (SOD) activity and chromosome aberration (CA) and sister-chromatid exchange (SCE) frequencies were examined in cultured fibroblasts or Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs). These cells were derived from patients with chromosome instability syndromes (CISs) including Bloom's syndrome (BS), Fanconi's anemia (FA) and ataxia telangiectasia (AT). Embryonal fibroblasts and LCLs from normal subjects served as controls. Although LCLs tended to exhibit a higher SOD level than fibroblasts due to an elevation of Cu/Zn-SOD activity, BS and FA fibroblasts with increased frequencies of CAs and/or SCEs showed abnormally elevated SOD activity due to the manifold increase of Mn-SOD levels compared with control cells. However, BS and AT LCLs with almost control levels of CA and SCE frequencies showed no, or a slightly elevated, SOD activity, suggesting a possible selection of such cells during EBV transformation. The observed parallelism between the SOD activity and the cytogenetic manifestation may imply an involvement of active oxygen species, especially superoxide radicals, in the increased chromosome damage of CIS cells.
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PMID:Superoxide dismutase activity and chromosome damage in cultured chromosome instability syndrome cells. 236 19

Toxic effects of ionizing radiation and elevated O2 levels (hyperoxia) are both thought to be mediated by oxidizing free radicals. In view of the reported hypersensitivity of ataxia telangiectasia (A-T) cells to the clastogenic effect of ionizing radiation, the chromosomal sensitivity of A-T cells to hyperoxic culture conditions was investigated in unirradiated and G0-irradiated A-T lymphocyte cultures. Unlike Fanconi's anaemia lymphocytes, which tend to respond to oxygen, especially after treatment with mitomycin C, both non-irradiated and G0-irradiated A-T lymphocytes failed to show an effect. We conclude that the excessive spontaneous and radiation-induced chromosomal breakage in A-T does not result from a deficiency in the cellular defences against the clastogenic effect of hyperoxia.
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PMID:Oxygen toxicity and chromosomal breakage in ataxia telangiectasia. 243 71

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)
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PMID:Molecular mechanism of novel DNA sugar damage by an antitumour protein antibiotic. 294 68

It has been previously shown that skin biopsies isolated from various xeroderma pigmentosum (XP) patients present a permanent decline in catalase activity from the onset of the disease to the tumor formation. We report here that cultured XP cell strains are also markedly deficient in the catalase activity with about only 25% of the activity measured in normal human cells. No direct correlation between catalatic activity and excision repair ability has been found, since a XP variant line is as deficient as an XP-C strain. The exact cause of the catalase deficiency is still unknown but could be due to the synthesis of a modified enzyme or to an abnormal regulation leading to a limited enzyme synthesis. Furthermore, simian virus 40 transformation of normal and radiosensitive cells (XP, ataxia telangiectasia) provokes a decrease in catalase activity of about 80% compared to the control derivatives. Mathematical analysis performed on our data shows a clearcut distinction between XP and normal cells while some of the XP heterozygote cells exhibit an intermediate behavior. Although most of the XP syndrome could be explained by the impairment in the excision repair ability, the decrease in catalase activity leading to a probable increase in intracellular H2O2 concentration and/or to a higher sensitivity to any oxygen-activated species could represent an additive effect in inducing the carcinogenic process.
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PMID:Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts. 300 May 76

The survival of the wild-type parent and two mutant lines of Chinese hamster cells, known to be defective in DNA repair, has been determined as a function of exposure to gamma rays under aerobic and hypoxic conditions. When compared to the wild-type line, one of the mutants selected for sensitivity to ethyl methyl sulfonate (EMS), and known to be defective in the repair of DNA strand breaks, exhibits a markedly enhanced sensitivity to aerobic irradiation but a reduced enhancement to hypoxic irradiation and thus an enhanced oxygen enhancement ratio (OER). In contrast, the other line, known to be defective in the incision step of excision repair, exhibits the reverse pattern of sensitivity and hence a reduced OER. The results are compared to findings in bacterial mutants and cells obtained from ataxia telangiectasia (AT) patients and heterozygotes.
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PMID:DNA repair-deficient Chinese hamster ovary cells exhibiting differential sensitivity to gamma rays under aerobic and hypoxic conditions. 398 66

An AT1-specific angiotensin II receptor antagonist (GR117289; 1 mg/kg I.V. bolus) was administered daily to ten chronically catheterized, normotensive ewes during late pregnancy (from 126 +/- 1 days) until parturition (139 +/- 1 days); five control animals received an equivalent volume of vehicle solution. Following drug administration, mean maternal blood pressure decreased from 87 +/- 1 mmHg to a minimum of 79 +/- 1 mmHg at 0.5 h (P < 0.05; n = 10) and remained low for 4-6 h without any concomitant change in fetal blood pressure or maternal and fetal heart rates. In animals fitted with flow probes, uterine blood flow decreased from 443 +/- 21 to 363 +/- 27 ml/min at 0.5 h post-drug (P < 0.05; n = 6); this change was positively correlated with the reduction in maternal blood pressure. The mean decrements in uterine and umbilical blood flows measured by steady-state infusion of tritiated water were -611 +/- 171 ml/min at 4-6 h (P < 0.05; n = 5) and -71 +/- 19 ml/min at 0.5-1 h (P < 0.05; n = 5), respectively. Significant reductions (P < 0.05; n = 10) in fetal arterial oxygen tension (-1.6 +/- 0.4 mmHg), saturation (-6.6 +/- 1.6%) and content (-0.3 +/- 0.1 mumol/ml) were evident at 0.5 h post-drug and were maintained for 6-12 h. Umbilical oxygen delivery decreased at 0.5-1 h following drug administration (P < 0.01; n = 5), but was unaccompanied by any significant change in fetal oxygen consumption. Chronic decreases in daily fetal pH and blood oxygen content occurred in GR117289-treated ewes. There were no significant differences in gestational length or neonatal outcome between vehicle- and GR117289-treated groups of ewes with single fetuses.
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PMID:Haemodynamic responses to an angiotensin II receptor antagonist (GR 117289) in maternal and fetal sheep. 778 19

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.
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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.
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PMID:A protective effect of chromosome 11 against DNA damage by TPA-activated neutrophils but not TPA acting alone. 800 Dec 46


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