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

The survival of cells in density-inhibited, confluent cultures maintained at 37 degrees C was examined following exposure to 137Cs gamma rays at low dose rates (0.023 or 0.153 Gy/h) or to 60Co gamma rays at a single high dose rate (0.70-0.75 Gy/min). Cells from an ataxia telangiectasia (AT) homozygote showed no dose-rate effect, whereas a three- to fivefold increase in D0 was observed for all other cell strains exposed at low dose rates. The magnitude of the dose-rate effect did not differ significantly among cells from persons with hereditary retinoblastoma, basal cell nevus syndrome, or AT-heterozygote compared with normal cell strains, and was not related to the size of the shoulder (extrapolation number) of the survival curve. Furthermore, no differences in the capacity for the repair of potentially lethal damage during confluent holding were observed among these latter cell strains.
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PMID:Effect of dose rate on the survival of irradiated human skin fibroblasts. 147 61

The frequencies of chromatid breaks and gaps in metaphase cells fixed 2 h after G2 phase X-irradiation (1 Gy) were in almost all cases at least two- to three-fold higher in skin fibroblasts from individuals with genetic conditions predisposing to cancer than in comparable cells from clinically normal controls. Previously, we reported this response in all cancer-prone genetic disorders tested including ataxia telangiectasia, Bloom's syndrome, Fanconi's anemia, xeroderma pigmentosum (XP), familial polyposis, Gardner's syndrome, hereditary malignant melanoma, dysplastic nevus syndrome and cancer family members. One exception was XP-A. In this report we add information on skin fibroblasts from retinoblastoma, Wilms' tumor and XP-C patients, 13 clinically normal controls and six cell lines from fetal or infant cells. Factors affecting the response are identified and include pH, temperature, cell density, culture medium or serum, microbial contamination and visible light exposure (effective wavelength 405 nm). Because of experimental variability, known normal controls should be used in each group of assays. With adequate control of the above factors this response could provide the basis of a test for detecting individuals carrying genes that predispose to a high risk of cancer.
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PMID:Factors affecting and significance of G2 chromatin radiosensitivity in predisposition to cancer. 256 34

We have developed a host cell reactivation assay of DNA repair utilizing UV-treated plasmid vectors. The assay primarily reflects cellular repair of transcriptional activity of damaged DNA measured indirectly as enzyme activity of the transfected genes. We studied three plasmids (pSV2cat, 5020 base pairs; pSV2catSVgpt, 7268 base pairs; and pRSVcat, 5027 base pairs) with different sizes and promoters carrying the bacterial cat gene (CAT, chloramphenicol acetyltransferase) in a construction that permits cat expression in human cells. All human simian virus 40-transformed cells studied expressed high levels of the transfected cat gene. UV treatment of the plasmids prior to transfection resulted in differential decrease in CAT activity in different cell lines. With pSV2catSVgpt, UV inactivation of CAT expression was greater in the xeroderma pigmentosum group A and D lines (D0 = 56 J X m-2) than in the other human cell lines tested (normal, ataxia-telangiectasia, Lesch-Nyhan, retinoblastoma)(D0 = 680 J X m-2)(D0 is the dose that reduces the percentage of CAT activity by 63% along the exponential portion of the dose-response curve). The D0 of the CAT inactivation curve was 50 J X m-2 for pSV2cat and for pRSVcat in the xeroderma pigmentosum group A cells. The similarity of the D0 data in the xeroderma pigmentosum group A cells for three plasmids of different size and promoters implies they all have similar UV-inactivation target size. UV-induced pyrimidine dimer formation in the plasmids was quantified by assay of the number of UV-induced T4 endonuclease V-sensitive sites. In the most sensitive xeroderma pigmentosum cells, with all three plasmids, one UV-induced pyrimidine dimer inactivates a target of about 2 kilobases, close to the size of the putative CAT mRNA.
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PMID:One pyrimidine dimer inactivates expression of a transfected gene in xeroderma pigmentosum cells. 299 75

A statistical analysis of the radiosensitivity of 204 different survival curves of nontransformed human fibroblast cell strains of different genetic origins was made using three criteria: the multi-target one-hit model (characterized by parameters n and D0), the surviving fraction for a 2 Gy dose (S2) and the mean inactivation dose (D). D is found to be the best parameter for characterization of anomalous radiosensitivity linked to a genetic disorder and for discrimination between groups of cell strains of differing radiosensitivity. Its use allows the description of a range of 'normal' radiosensitivity for control fibroblasts and the classification of the various genetic disorders as a function of their mean radiosensitivity expressed in terms of D. Nine groups of cell strains appear to exhibit radiosensitivity which differs significantly from that of the controls: seven groups are hypersensitive (ataxia-telangiectasia homozygotes and heterozygotes, Cockayne's syndrome, Gardner's syndrome, 5-oxoprolinuria homozygotes and heterozygotes, Fanconi's anaemia) and two groups are more radioresistant (fibroblasts from retinoblastoma patients and from individuals with chromosome 13 anomalies). Since the coupled parameter n and D0 failed to discriminate between the radiosensitivity of the different genetic groups, we recommend the use of D to make an intercomparison of intrinsic radiosensitivity of nontransformed human fibroblasts.
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PMID:Re-evaluation of in vitro radiosensitivity of human fibroblasts of different genetic origins. 348 86

Diseases associated with DNA and chromosomal instability, along with their underlying etiopathologic mechanisms, are among the most complex and poorly understood of any group of disorders known. Their pathogenesis is almost certainly intimately related to the most fundamental processes of life itself: the maintenance, replication, and expression of the genome. Include is a discussion of xeroderma pigmentosum, ataxia-telangiectasia. Cockayne's syndrome, Fanconi's anemia, retinoblastoma, and neurodegenerative diseases.
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PMID:Genetic diseases associated with DNA and chromosomal instability. 354 81

The effects of confluent holding recovery on survival, chromosomal aberrations, and progression through the life cycle after subculture of human diploid fibroblasts X-irradiated during density inhibition of growth have been examined. The responses of three normal strains were determined and compared with those of four ataxia-telangiectasia (AT), an AT heterozygote, and two hereditary retinoblastoma strains. The capacity for potentially lethal damage repair (PLDR) was slightly reduced in retinoblastoma cells and almost absent in AT cells, but normal in an AT heterozygote. The decline in chromosomal aberrations seen in normal cells during confluent holding was absent in AT cells, consistent with the lack of PLDR. Following subculture, all irradiated AT fibroblasts progressed through the cell cycle to the first mitosis with no delay. AT heterozygotic and retinoblastoma cells showed both an enhanced delay in the initiation of DNA synthesis and a large fraction of cells irreversibly blocked in G1 as compared with normal cells. Both the delayed entry into S and the G1 block were reduced by confluent holding. These results indicate that AT homozygotic and heterozygotic cells respond quite differently to X irradiation.
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PMID:Effect of confluent holding on potentially lethal damage repair, cell cycle progression, and chromosomal aberrations in human normal and ataxia-telangiectasia fibroblasts. 396 44

A possible causal association between chromosome structural change and neoplastic transformation has long been mooted, particularly since chromosomal changes occur frequently in the cells of a variety of malignancies. Only in recent years, however, has the evidence in support of this contention begun to appear convincing, and this has followed from the application of developments in cytogenetic techniques. The advent of methods for revealing specific bands in the human metaphase complement has enabled all the chromosomes and many chromosomal regions to be unambiguously identified, and the recent application of prophase banding methods gives further improvements in resolution. With these techniques, specific constitutional chromosomal deletions or translocations have been discovered in inherited cases of retinoblastoma (del.13q14), Wilms' tumour with aniridia (del.11p13) and renal-cell carcinoma (t(3:8) (p21:q24)), in which each of the chromosomal changes appears to be a dominant factor in inheriting a predisposition to a tissue-specific tumour. A heritability for cancer predisposition is also associated with the inherited chromosomal instability syndromes of Bloom's, Fanconi's anaemia and ataxia telangiectasia, although specific chromosomal changes have not been reported to be associated with the neoplasms in such individuals, except in some cases of lymphoma and leukaemia in ataxia telangiectasia. Specific chromosomal translocations have, however, been recorded in a variety of malignancies, with a particular involvement of chromosomes 22, 14, 8, 15, 17 and 21. However, although many hundreds of patients with the specific 9/22 rearrangement seen in chronic myeloid leukaemia and also those with the 14/8 rearrangement in Burkitt's, and other, lymphomas have been described, no single case in which these rearrangements were present as constitutional changes has been reported. The possible nature of the changes seen at the cytogenetic level in terms of gene content of the chromosomes involved is discussed.
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PMID:Cytogenetics of heritability in cancer. 629 35

Survival, cumulative labeling indices and chromosomal aberrations were studied in normal, ataxia telangiectasia (AT) and hereditary retinoblastoma fibroblasts after X-irradiation during density-inhibition of growth and immediate release by subculture to low density. The D0 of the survival curves were: normal strains, 150-160 rad; Retinoblastoma strains AG 1880, 95 rad; AG 1978, 40-50 rad (sensitive fraction); AT5BI, 45 rad. Mainly chromosome-type Aberrations were induced in normal and retinoblastoma cells. The frequency of X-ray-induced chromosomal aberrations was much higher in AT5BI cells, and 33-45% were of the chromatid type. Normal and retinoblastoma cells showed a measureable X-ray induced G1 delay before entering S. In addition, a fraction of the cells showed an apparently irreversible G1 block; these cells did not initiate DNA synthesis up to 120 h post-irradiation and subculture. The G1 block was much more marked in retinoblastoma cells; after 400 rad about 70% of retinoblastoma cells did not enter S as compared with only 20% of normal cells. Neither a G1 delay nor a G1 block was observed in AT cells irradiated with up to 400 rad despite their hypersensitivity to cell killing by X-rays and evidence of severe chromosome damage. These results suggest different mechanisms for the X-ray hypersensitivity of AT and retinoblastoma cells.
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PMID:Comparison of kinetics of X-ray-induced cell killing in normal, ataxia telangiectasia and hereditary retinoblastoma fibroblasts. 684 73

We recently showed (Scott and Zampetti-Bosseler 1980) that X-ray sensitive mouse lymphoma cells sustain more chromosome damage, mitotic delay and spindle defects than X-ray resistant cells. We proposed that (a) chromosome aberrations contribute much more to lethality than spindle defects, and (b) that DNA lesions are less effectively repaired in the sensitive cells and give rise to more G2 mitotic delay and chromosome aberrations. Our present results on human fibroblasts with reported differential sensitivity to ionizing radiation (i.e. normal donors and patients with ataxia telangiectasia and retinoblastoma) support the first hypothesis since we observed a positive correlation between chromosome aberration frequencies and cell killing and no induced spindle defects. Our second hypothesis is however not substantiated since X-ray sensitive fibroblasts from the ataxia patient suffered less mitotic delay than cells from normal donors. A common lesion for mitotic delay and chromosome aberrations can still be assumed by adopting the hypothesis of Painter and Young (1981) that the defect in ataxia cells is not in repair but in a failure of DNA damage to initiate mitotic delay. In contrast to other reports, we found the retinoblastoma cells to be of normal radiation sensitivity (cell killing and aberration).
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PMID:Cell death, chromosome damage and mitotic delay in normal human, ataxia telangiectasia and retinoblastoma fibroblasts after x-irradiation. 697 65

Diploid fibroblast cell strains derived from 14 patients with various forms of retinoblastoma (RB) and 5 non-RB patients with constitutional chromosome anomalies involving chromosome 13 were assayed for their clonogenic survival after X-irradiation. Cells from a patient with ataxia telangiectasia (AT) was used as a radiosensitive reference strain. When compared with cell strains from 7 healthy persons as normal controls, a marked radiosensitivity was observed in strain from an AT patient. However, none of the cell strains derived from RB patients or patients with inborn anomalies in chromosome 13 showed pronounced deviation from the normal range of radiosensitivity. The findings thus did not warrant either the RB as radiosensitive genetic disease or the presence of repair locus on chromosome 13, deletion or triplication of which was previously suggested to link to radiosensitivity.
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PMID:Radiosensitivity of fibroblasts from patients with retinoblastoma and chromosome-13 anomalies. 705 93


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