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)

A very high incidence of cancers (10%) is recorded in patients homozygous for ataxia telangiectasia (AT). From 1970 to 1987, 35 children were investigated in the department of pediatric neurology in Lille. Three developed a malignancy (one hepatic tumor, one Hodgkin's disease and one non Hodgkin's lymphoma). Constitutional chromosome fragility and immune deficiency are the main features of AT. The first one is probably linked to the pathogenesis of malignancies. Moreover, cancer therapy has to take these features into account.
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PMID:[Oncologic complications and cytogenetic features of ataxia telangiectasia]. 234 49

An assay for ataxia-telangiectasia (A-T) heterozygotes, i.e., healthy carriers of the A-T gene(s), requiring only a small sample (3.5 mL) of peripheral blood, is described. Frequencies of chromatid aberrations in phytohemagglutinin-stimulated blood lymphocytes collected by demecolcine from 0.5 hour to 1.5 hours after x irradiation with 58 roentgens were twofold to threefold higher in A-T heterozygotes than in clinically normal controls and twofold to three-fold higher in A-T patients (homozygotes) than in A-T gene carriers. The persistence of chromatid breaks and gaps in lymphocytes following radiation-induced DNA damage during G2 suggests a deficiency or deficiencies in DNA repair that may be the defect at the molecular level that results in the enhanced radiosensitivity and cancer proneness characterizing A-T gene carriers and patients.
J Natl Cancer Inst 1990 Jun 20
PMID:Enhanced chromatid damage in blood lymphocytes after G2 phase x irradiation, a marker of the ataxia-telangiectasia gene. 234 70

The cytotoxic effect of acute X irradiation was studied by a colony formation assay in 114 human skin fibroblast cell strains from 31 apparently normal individuals and 83 patients with a variety of genetic disorders possibly associated with in vitro hypersensitivity to ionizing radiation. The effect of protracted exposure to beta radiation from tritiated water (HTO) was examined in parallel experiments in 65 of these strains. The disorders included neurological diseases and syndromes characterized by an increased susceptibility to spontaneous and radiation-induced cancer. Homozygous ataxia telangiectasia and Nijmegen break syndrome cells were highly sensitive to both types of radiation. However, the response of cells from the other genetic disorders fell within the broad range characteristic of normal cell strains. While HTO may be useful as a quantitative method for determining the cytotoxic response of human diploid cells to ionizing radiation, the present results indicate that it does not offer a more sensitive assay than acute X irradiation for detecting minor degrees of hypersensitivity.
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PMID:Sensitivity of human diploid fibroblast cell strains from various genetic disorders to acute and protracted radiation exposure. 237 84

The chromosomal breakage syndromes--ataxia-telangiectasia, Fanconi's anemia, and Bloom's syndrome--are associated with growth failure, neurologic abnormalities, immunodeficiency, and an increased incidence of malignancy. The relationship between these features is unknown. We recently evaluated a 21-year-old female with more severe chromosomal breakage, immunodeficiency, and growth failure than in any of the mentioned disorders. As of November 1985, the patient remains clinically free of malignancy. At age 18, the patient's weight was 22.6 kg (50th percentile for seven years), height was 129 cm (50th percentile for eight years), and head circumference was 42 cm (50th percentile for six months). Laboratory studies demonstrated a marked decrease in both B and T cell number and function. The peripheral blood contained 400 to 900 lymphocytes/microL with 32% T11 cells, 17% T4 cells, and 21% T8 cells. The proliferative responses to phytohemagglutinin (PHA), pokeweed mitogen, and concanavalin A were less than 10% of control. There were 1% surface IgM positive cells, and serum IgG was 185 mg/dL, IgM 7 mg/dL, IgA 5 mg/dL. In lymphocyte cultures stimulated with the T cell mitogens PHA, phorbol ester, and interleukin 2, 55% of the banded metaphases demonstrated breaks or rearrangements. The majority of the breaks involved four fragile sites on chromosomes 7 and 14, 7p13, 7q35, 14q11, and 14q32. These are the sites of the genes for the T cell-antigen receptor and the immunoglobulin heavy chain and are sites of gene rearrangement in lymphocyte differentiation. Epstein-Barr virus stimulated B cells and fibroblast cultures also demonstrated a high incidence of breaks, but the sites were less selective. These findings suggest that the sites of chromosomal fragility in the chromosomal breakage syndromes may be informative and that factors other than the severity of the immunodeficiency or the high incidence of chromosomal damage may contribute to the occurrence of malignancy in the chromosomal breakage syndromes.
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PMID:A chromosomal breakage syndrome with profound immunodeficiency. 242 4

Fibroblasts from patients with ataxia-telangiectasia (A-T) were found to be hypersensitive to killing by the antineoplastic agent etoposide. The A-T fibroblast strains GM5823, GM367, and GM2052 were twofold to threefold more sensitive to killing by etoposide than fibroblasts from normal controls (AG1521, AG1522, and IMR90). A simian virus 40 (SV40)-transformed, immortal human fibroblast line (GM5849) derived from the A-T cell line GM5823 was also studied. GM5849 retained the unusual sensitivity of nontransformed A-T fibroblast lines to x-irradiation, bleomycin, and neocarzinostatin (zinostatin). GM5849 was also more sensitive to etoposide than were SV40-transformed fibroblasts from normal controls. M1, and SV40-transformed fibroblast line derived from a patient with xeroderma pigmentosum, had the same sensitivity to etoposide as SV40-transformed fibroblasts derived from normal controls.
J Natl Cancer Inst 1986 Jun
PMID:Hypersensitivity of cultured ataxia-telangiectasia cells to etoposide. 242 35

Spleen cells from control and wasted (wst) mice, a putative animal model for the human genetic disease ataxia-telangiectasia, were tested for inhibition of replicative (semiconservative) DNA synthesis after treatments with bleomycin, gamma-irradiation, 4-nitroquinoline 1-oxide, and ultraviolet irradiation. The wasted cells were found to be more resistant than control cells to the first three treatments, but equally sensitive to ultraviolet light. Bleomycin-stimulated repair synthesis in spleen cells was also studied by the CsCl/bromodeoxyuridine method and found to be similar in cells from wasted and control animals. Similarly, no differences in sensitivity to killing by gamma-rays, as manifested by relative cloning efficiencies, were demonstrated between primary lung fibroblasts from mutant and control mice. We concluded that observed defects in DNA repair in wasted cells are not identical to those reported in human cells from ataxia-telangiectasia patients.
Cancer Res 1986 Aug
PMID:Effect of DNA-damaging agents on isolated spleen cells and lung fibroblasts from the mouse mutant "wasted," a putative animal model for ataxia-telangiectasia. 242 37

Cells derived from patients with ataxia telangiectasia (AT) are known to be exceptionally sensitive to ionizing radiation and chemotherapeutic agents such as bleomycin (BLM), neocarzinostatin, and etoposide. This increased sensitivity is manifested by high chromosome aberration frequencies after treatment. In order to probe the underlying basis for this phenomenon, the technique of premature chromosome condensation was used to determine whether the increased chromosome damage observed after bleomycin treatment is due to increased initial chromosome damage or to a decreased capability of these cells to repair chromosome damage. Five AT cell lines were brought to quiescence and treated with BLM, and initial chromosome damage and repair rates were determined in the G1 prematurely condensed chromosomes. AT cells exhibited increased aberration frequencies compared to normal human fibroblasts immediately after BLM treatment. The five AT cell lines were heterogeneous in the fast component of chromosome break repair, varying from a nearly normal fast repair component in one cell line to a nearly defunct fast repair component in two other AT cell lines. Thus, while the AT cell lines were heterogeneous in the basis for their chromosome breakage sensitivity, all AT cell lines tested showed increased residual chromosome damage after BLM treatment while still in the quiescent phase.
Cancer Res 1988 Jan 15
PMID:Heterogeneity in chromosome damage and repair rates after bleomycin in ataxia telangiectasia cells. 244 45

Ataxia-telangiectasia, an inherited disorder characterized by progressive cerebellar ataxia and telangiectasias, is often associated with primary immunodeficiency and high incidence of malignancies, mostly of the lymphoreticular type. Endodermal sinus tumor is a rare germ cell tumor of the ovary characterized by an extremely rapid growth and poor prognosis. Both these diseases are associated with an abnormal production of alpha-fetoprotein. Primary tumors of the ovary in patients with ataxia-telangiectasia are extremely rare and the association of an endodermal sinus tumor and ataxia-telangiectasia has never been reported in the literature. This case report serves to focus on the particular problems encountered in the diagnosis and management of two diseases both characterized by the same serum marker.
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PMID:Ataxia-telangiectasia and endodermal sinus tumor of the ovary: report of a case. 244 92

We have isolated three radiosensitive mutants (V-C4, V-E5, and V-G8) of the Chinese hamster V79 cell line which also show increased sensitivities to killing by bleomycin (approximately 2-5-fold) and ethyl methanesulfonate (approximately 2-fold). Genetic complementation analysis indicates that all three mutants belong to one complementation group. The mutants show a radioresistant DNA synthesis following X-ray irradiation when compared to wild-type V79 cells. Both the level and the rate of repair of DNA single- and double-strand breaks measured by DNA elution were similar to those observed in wild-type V79 cells. The level of spontaneously occurring chromosome aberrations in two of these mutants differs severalfold from the level observed in wild-type V-79 cells and in V-G8, to approximately 2- and 6-fold increase in V-E5 and V-C4, respectively. X-irradiation of the mutants resulted in consistently 3-4-fold higher levels of chromatid gaps, breaks, and exchanges than observed in wild-type V79 cells. In addition, G1 irradiation of the mutant cells yielded both chromosome and chromatid types of aberrations. The level and pattern of chromosomal aberrations induced by X-rays in V-C4, V-E5, and V-G8 are similar to those observed in ataxia-telangiectasia cells. These results indicate that our mutants represent the first rodent cell mutants which show phenotypic characteristics strongly resembling those in cells from ataxia-telangiectasia patients.
Cancer Res 1989 Mar 15
PMID:Ataxia-telangiectasia-like Chinese hamster V79 cell mutants with radioresistant DNA synthesis, chromosomal instability, and normal DNA strand break repair. 246 55

Dermal fibroblast strains from ataxia-telangiectasia (A-T) patients and clinically normal subjects were exposed to 4-nitroquinoline 1-oxide (4NQO) or its 3-methyl derivative (3me4NQO), and their colony-forming abilities and DNA metabolic properties were compared. Three A-T strains, i.e., AT2BE and AT3BI representing genetic complementation group AB and AT4BI belonging to group C, displayed enhanced (2.4- to 2.8-fold) sensitivity to reproductive inactivation by 4NQO, but exhibited normal survival in response to 3me4NQO. The initial induction and subsequent enzymatic repair of alkali-labile lesions (i.e., damaged sites converted to single-strand breaks in alkali) were quantitated by conventional velocity sedimentation analysis of cellular DNA in alkaline sucrose gradients. On exposure to concentrations of each chemical that produced comparable amounts of DNA damage, A-T and normal cells removed alkali-labile lesions at similar rates. However, the three 4NQO-sensitive A-T strains appeared to be defective in acting on alkali-stable adducts (formed by the parent compound but not its derivative), as judged by strand-break accumulation during posttreatment incubation with 1-beta-D-arabinofuranosylcytosine (araC). Specifically, the number of araC-detectable sites repaired in these A-T strains during the critical 2-h period immediately following 4NQO treatment ranged from 40 to 60% of that processed by normal controls. AT5BI, a fourth A-T strain assigned to complementation group D, responded normally to 4NQO-induced cytotoxicity and removed both alkali-labile and alkali-stable (araC-detectable) lesions normally. We thus conclude that the hypersensitivity of AT2BE, AT3BI, and AT4BI strains to 4NQO may be attributed, at least in part, to faulty execution of the excision-repair process operative on alkali-stable 4NQO adducts.
Cancer Res 1989 Oct 15
PMID:Hypersensitivity to cell killing and faulty repair of 1-beta-D-arabinofuranosylcytosine-detectable sites in human (ataxia-telangiectasia) fibroblasts treated with 4-nitroquinoline 1-oxide. 250 29


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