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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The familial occurrence of head and neck cancers supports the role of heredity in this disease group. The roles of environmental and genetic factors are difficult to separate. There are several well-characterized entities, however, that are associated with risk and prognosis of head and neck cancer, including Lynch-II syndrome, Bloom syndrome, Fanconi's anemia, xeroderma pigmentosum, ataxia telangiectasia, and Li-Fraumeni syndrome. Mutagen-induced chromosomal damage is associated with an increased risk of multiple primary neoplasms and upper aerodigestive tract cancers. A possible reduction of genotoxicity, mediated by micronutrients, was demonstrated in vitro. Sister chromatid exchanges and micronuclei are useful exposure and disease markers. Metabolic changes (acetylation, DBQ phenotype, and the AH locus polymorphism) have been found to be associated with cancer of the upper aerodigestive tract. Most associations between histocompatibility antigens and solid tumors are relatively weak, probably because of the masking effects of environmental factors. Infections by HPV, EBV, and HSV have a causative or predisposing role in several types of head and neck cancer. Amplification and rearrangement of oncogenes may also play a role in carcinogenesis, and oncogene amplification may be associated with aggressive tumor behavior and unfavorable clinical prognosis. Ploidy of tumors seems to be an important determinant of survival and response to therapy.
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PMID:Hereditary and environmental factors associated with risk and progression of head and neck cancer. 140 93

It has long been recognized that exposure to specific chemical and physical agents can result in the appearance of tumours in both man and animals. There is substantial evidence that DNA is the ultimate cellular target of carcinogens and that DNA repair is an important cellular defence against the effects of carcinogen exposure. Some insight into the molecular processes involved in cellular responses to carcinogens is provided by the occurrence of rare human disorders that display complex abnormalities in processing DNA damage or maintaining genomic integrity. These disorders include xeroderma pigmentosum, Cockayne syndrome, ataxia telangiectasia, dysplastic nevus syndrome and Bloom syndrome. Such disorders have provided clues to some of the basic mechanisms involved in carcinogenesis.
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PMID:Carcinogenesis: molecular defences against carcinogens. 186 47

Compared to normal controls from healthy subjects, cells cultured from patients with the autosomal recessive, cancer-prone disorder ataxia telangiectasia (AT) uniformly display impaired clonogenic survival, in concert with decreased inhibition of DNA synthesis, on exposure to ionizing radiation. In this study we have determined the effects of 4-nitroquinoline 1-oxide (4NQO), a partially radiomimetic chemical carcinogen, on colony-forming ability and rate of DNA synthesis in non-transformed skin fibroblasts strains derived from clinically normal volunteers and AT patients. Strain AT3BI, belonging to AT complementation group A, displayed substantial hypersensitivity to the lethal action of 4NQO, whereas the survival response of strain AT5BI (group D) did not differ significantly from that of the three normal controls. The 4NQO-hypersensitive AT3BI cells exhibited normal inhibition of DNA synthesis when treated with the chemical, as manifested by both dose-response and time-course measurements. However, 4NQO treatment decreased the rate of DNA synthesis to a much lesser degree in AT5BI than in normal strains. Hence, our data demonstrate unequivocally that, unlike that universally observed following exposure of AT cells to ionizing radiation, carcinogen-resistant DNA synthesis does not segregate with elevated cytotoxicity when cultured fibroblasts representing at least some genetic forms of AT (i.e. groups A and D) are damaged by 4NQO.
Carcinogenesis 1991 Jan
PMID:Lack of correlation between hypersensitivity to cell killing and impaired inhibition of DNA synthesis in ataxia telangiectasia fibroblasts treated with 4-nitroquinoline 1-oxide. 189 54

The genetic factors involved in the multistep process of carcinogenesis can be divided at least into two major categories: 1. Mutated or lost genes, which may directly represent one step in the sequential process (tumour suppressor genes); inheritance of one tumour suppressor gene causes dominant expression of the carcinogenic phenotype (the dominant inheritance is described in the accompanying paper); 2. Other genes, which lead to conditions that favour the development of cancer and generally are inherited in a recessive fashion; they are the subject of this paper. Autosomal recessively inherited diseases, such as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's anaemia display increased genome instability (chromosomal fragility and/or DNA-repair deficiencies) and are associated in the homozygote and probably also in the heterozygote state with defined malignancies. Neoplasms particularly of the lymphoreticular system frequently occur in patients with genetically determined immunodeficiencies (e.g. severe combined immune deficiency or Wiskott-Aldrich syndrome). People differ due to their individual genetic constitution in their responses to various classes of carcinogens such as physical and chemical agents, to dietary habits, as well as to viruses. Furthermore, tumours are often found in patients displaying premature aging (e.g. Werner's syndrome). In addition, several metabolic abnormalities such as genetic syndromes featuring chronic liver disease, but also many other inherited metabolic conditions have cancer as a regular or frequent complication.
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PMID:Recessively inherited deficiencies predisposing to cancer. 219 May 29

A series of human lymphoblastoid cell lines (LCLs) called Mex- were defined by Sklar and Strauss on the basis of their inability to remove O6-methylguanine from DNA. Instability of Mex- has previously been shown as a population phenotype of LCLs. We examined whether Mex- as a cellular phenotype is spontaneously convertible or not. At the population doubling number (PDN) 23 after recloning, two out of 15 independent subcultures derived from a Mex- LCL, AT1-1, were found to contain a small fraction of Mex+ cells after treatment with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). Three Mex+ subclones were identified without exposure to ACNU among 486 subclones from replica plating of an expanded Mex- clone (PDN30). The rate of spontaneous conversion was estimated to be in the range of 10(-8)-10(-7) per cell per generation by the fluctuation analyses on two Mex- subclones. These results strongly support the hypothesis that Mex- as a cellular phenotype is spontaneously convertible to Mex+.
Carcinogenesis 1990 Oct
PMID:Evidence for spontaneous conversion of Mex- to Mex+ in human lymphoblastoid cells. 220 88

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.
Carcinogenesis 1987 Feb
PMID:Oxygen toxicity and chromosomal breakage in ataxia telangiectasia. 243 71

It has been previously shown that xeroderma pigmentosum (XP) skin biopsies and their established cell lines exhibit a decrease in catalase activity and enhanced formation of photo-produced H2O2. Several in vivo and in vitro thermodynamic results suggest that the energy of H2O2 disproportionation produced by catalase could be sufficient to synthesize ATP with or without the help of intact mitochondria. In this paper, we first studied the properties of H2O2-stimulated ATP production in extracts of normal and pathological XP skin biopsies and cell lines. In acellular extracts of normal skin biopsies and/or cell lines, ATP production can be increased 2- to 3-fold, but only with a narrow range of H2O2 concentration. In contrast, in extracts of pathological skins or cells, ATP production was only observed when using 10- to 1000-fold less H2O2 concentration as defined for normal extracts. Similar results were noted with two cell lines derived from patients afflicted with ataxia telangiectasia (AT), and with simian virus 40 (SV40) transformed lines of normal, XP and AT cells, Although we have no proof that such a process may exist in vivo, we would like to suggest that both H2O2-stimulated ATP production and catalase activity are good indicators of the degree of normality or abnormality of skin biopsies and/or cell lines.
Carcinogenesis 1989 Aug
PMID:Stimulated production of ATP by H2O2 disproportionation in extracts from normal and xeroderma pigmentosum skins, and from normal, xeroderma pigmentosum, ataxia telangiectasia and simian virus 40 transformed cell lines. 254 89

The excision repair of u.v. damage has been supposed to involve an initial action of DNA topoisomerase II, since some pre-incision step is sensitive to novobiocin, a topoisomerase II inhibitor. But novobiocin also affects mitochondrial structure and ATP metabolism, and this may account for its apparent inhibition of energy-dependent excision repair. We have investigated the effects of etoposide, another inhibitor of topoisomerase II, on u.v.-irradiated human cells: it is a more specific agent with no immediate side-effects on mitochondria. But etoposide is without effect on cellular excision repair, at the pre-incision stage or at the later stages of either DNA resynthesis or strand break ligation; nor does it potentiate cell killing after u.v. irradiation. The chromosome decondensation that accompanies incomplete excision repair in mitotic cells is likewise not greatly affected by etoposide. Therefore, if topoisomerase II is involved in excision repair or its regulation, it acts through a process that in whole cells is insensitive to etoposide. In ataxia telangiectasia cells, which are known to be hypersensitive to etoposide, the mitochondrial activities are not abnormally affected.
Carcinogenesis 1987 Nov
PMID:Action of etoposide (VP-16-123) on human cells: no evidence for topoisomerase II involvement in excision repair of u.v.-induced DNA damage, nor for mitochondrial hypersensitivity in ataxia telangiectasia. 282 76

During selection for methotrexate resistance, SV40-transformed human skin fibroblasts from patients with ataxia telangiectasia (A-T) underwent amplification of the dihydrofolate reductase (DHFR) gene, experienced nearly complete loss of the integrated SV40 sequences and showed a 3.6-fold increase in Ki-ras gene copy number. Over a period of months methotrexate-resistant (MTXr) A-T subclones were obtained, which were able to grow in progressively increasing MTX concentrations up to 100 microM. The ED50 values determined as the effective dose of MTX causing 50% growth inhibition in comparison to control cells increased from 3 x 10(-2) microM for MTXs AT5BI-VA cells to 250 microM MTX for the MTXr AX100 subclone. In contrast, human skin fibroblasts of healthy individuals did not show DHFR gene amplification and loss of SV40 sequences under comparable conditions and were unable to grow in MTX concentrations greater than 1 microM. Gene amplification and loss of DNA sequences are features underlying the genomic instability known to be a characteristic property of A-T cells and being probably responsible for the high cancer incidence in these patients.
Carcinogenesis 1987 Dec
PMID:DHFR gene amplification in cultured skin fibroblasts of ataxia telangiectasia patients after methotrexate selection. 282 82

When dermal fibroblast strains derived from ataxia telangiectasia (AT) and clinically normal donors were exposed to 4-nitroquinoline 1-oxide (4NQO) and their DNA subjected to velocity sedimentation analysis in alkaline sucrose gradients, the incidence of single-strand interruptions detected in the AT strains (AT2BE, AT3BI and AT4BI) was 1.4-1.8 times higher than that seen in the seven normal controls. Cellular uptake of exogenous radiolabelled 4NQO occurred at similar rates in AT and control cultures, arguing against increased influx of the chemical as the root cause of the elevated yield of strand breakage in the former cultures. However, sonicates of each AT strain contained an enhanced capacity to catalyze the reduction of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide; the differences in bioreductase activity between AT and normal cell sonicates correlated closely with those for the incidence of DNA strand openings in 4NQO-treated cultures. Our data further indicated that these single-strand scissions, seen under alkaline conditions, are not manifestations of intermediate reactions in the multistep excision repair process operative on 4NQO lesions because: (i) the interruptions were observed at comparable levels in AT2BE and AT3BI cells, the former purportedly deficient and the latter proficient in 4NQO adduct removal; and (ii) cells known to be defective in repairing all types of 4NQO lesions, namely, xeroderma pigmentosum complementation group A fibroblasts, accumulated breaks at normal rates during 4NQO treatment. Consequently, these breaks appear to represent a class of 4NQO lesions which are themselves alkali-labile and therefore become converted to single-strand interruptions in vitro during exposure of DNA to alkali before velocity sedimentation. We conclude that AT strains tend to sustain abnormally high amounts of DNA damage upon 4NQO exposure due to an elevated capacity to bioactivate the inert parent compound into a proximate carcinogen.
Carcinogenesis 1988 Sep
PMID:Enhanced bioreduction of 4-nitroquinoline 1-oxide by cultured ataxia telangiectasia cells. 313 48


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