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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The risk of cancer was examined among family members of 9 patients with Fanconi's anemia. Seven cancers of diverse types were observed, as compared with the 10.4 expected (P greater than 0.05). In addition, the study of relatives of 60 patients with acquired aplastic anemia showed no unusual distribution of cancers by site and age at diagnosis. In particular, no relative in either series had acute leukemia. Methodologic issues complicate the interpretation of several published reports of excess cancers among heterozygotes of Fanconi's anemia, ataxia-telangiectasia, and xeroderma pigmentosum.
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PMID:Cancer in relatives of patients with aplastic anemia. 683 7

The ability of the DNA intercalator m-AMSA to produce protein-associated DNA-strand breaks in normal, xeroderma pigmentosum and ataxia-telangiectasia fibroblasts was compared with m-AMSA uptake and cytotoxicity. No differences were detected between the cytotoxicity and DNA breakage produced by this antineoplastic acridine derivative among these three human cell lines. Uptake studies confirmed that no actual increased sensitivity was being masked by decreased intracellular drug. m-AMSA appears to be unique in its ability to produce breaks in cellular DNA that are not associated with an enhanced sensitivity in repair-deficient cells. Intercalator-induced, protein-associated DNA breaks are probably the result of a novel cellular response which differs from that which is abnormal in xeroderma pigmentosum or ataxia-telangiectasia cells.
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PMID:DNA-repair deficiencies do not affect intercalator-induced cytotoxicity or DNA scission in human cells. 689 37

A number of disparate clinical syndromes have been loosely grouped together under the leading of diseases of DNA repair. More logically they should perhaps be termed diseases of diminished capacity to cope with DNA damage, since in only three has defective DNA repair been established as a basis so far. These are xeroderma pigmentosum, ataxia telangiectasia and Fanconi's anaemia. Increased sensitivity may be to radiation, to particular types of chemical mutagens, or to both. This sensitivity may be reflected in an increased liability to chromosome aberrations, decreased cell survival in culture and, in some cases only, increased mutagenesis. In many cases there is an associated increased liability to develop malignant tumours. These syndromes are genetically autosomal recessive so that it is the relatively rare homozygotes which display the full clinical picture. In some cases, however, the heterozygotes share the increased liability to cancer: since these are of relatively high frequency, they may be quantitatively important in the genetics of some human cancers including leukaemias. Immunological abnormalities are common and frequently are selective. This suggests the possibility that the repair systems whose defects are monitored by decreased capacity to cope with DNA damage may also perform functions essential to differentiation during embryonic development. At a molecular level knowledge of the fundamental defects in each of these groups of human mutants is still rudimentary. There is sufficient evidence, however, to conclude that each group is genetically heterogeneous, involving more than one gene locus, so that the total number of genes involved is probably large.
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PMID:Diseases of DNA repair. 698 33

Comparison of the strikingly different distributions of types of cancer that occur in the genetic disorders that feature chromosome instability raises several interesting points. (a) Bloom's syndrome: the distribution suggests that many of the cancers that occur with regularity in the general population just occur more commonly and at an earlier age. (b) Ataxia telangiectasia: cancers of many types are increased in frequency, but lymphoreticular cancers are exceptionally common, the case also in several other genetically determined immunodeficiency disorders. Both Bloom's syndrome and ataxia telangiectasia share defective immunity as a major clinical feature, but the respective roles, if any, of it and of chromosome instability in producing the cancer predispositions are unknown. (c) Fanconi's anemia: cancer apparently has become common only recently. The types and distribution which occur are unusual. Fanconi's anemia cells have been shown to be hypertransformable by oncogenic virus and to be defective in handling certain types of DNA damage (as well as to manifest chromosome instability) so that the recent increase in cancer incidence is both surprising and unexplained. The degree of cancer proneness of Fanconi's anemia per se, untreated by modern methods, must at present be considered unknown. (d) Xeroderma pigmentosum: the cancer predisposition apparently extends only to cells which receive solar damage, i.e., to skin and eye. This would not have been predicted in view of the fact that the cellular mechanism is defective for repairing DNA damage produced not just by sunlight but also by certain classes of chemical carcinogens.
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PMID:Chromosome-breakage syndromes: different genes, different treatments, different cancers. 701 10

The sensitivities of fifteen human fibroblast cell strains to the lethal effects of alkylation damage produced by N-methyl-N-nitrosourea (MNU) and N-ethyl-N-nitrosourea (ENU) have been investigated. Nine cell strains were also investigated for their sensitivities to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Included in our survey are representative strains derived from donors with the repair defective syndromes xeroderma pigmentosum (XP) and ataxia-telangiectasia (A-T), as well as strains derived from patients with Cockayne's syndrome, Bloom's syndrome, Huntington's disease and strains derived from individuals with unclassified syndromes. On the basis of our survival data we report that hypersensitivity to MNU is shown by two A-T strains (AT3BI and AT5BI), an XP strain (XP3BR), and strain 46BR derived from a patient with hypogammaglobulinaemia. This sensitivity to methylating agents is also shown by strains 46BR and XP3BR when treated with MNNG, but not for strain AT5BI. Sensitivity to ENU is shown by strain 11961 (derived from a sun-sensitive individual), XP3BR and a single Cockayne's syndrome strain CS697CTO. Of the strains studied only XP3BR was sensitive to both ethylating and methylating agents and only 46BR showed a greater than two-fold increase in sensitivity compared to normal.
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PMID:The response of a variety of human fibroblast cell strains to the lethal effects of alkylating agents. 706 35

Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439). There were four microcephalic XP blood relatives and none in the FA or A-T families. In the A-T families, idiopathic scoliosis and vertebral anomalies were in excess, while genitourinary and distal limb malformations were found in the FA families. A-T, FA, or XP heterozygotes may constitute an important proportion of individuals at risk for specific malformations or developmental abnormalities.
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PMID:Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families. 712 32

The comparative photosensitizing effects to near-UV irradiation (UVA) of several naturally occurring furocoumarins, 5-methoxypsoralen (5MOP), psoralen, 8-methoxypsoralen (8MOP) and angelicin in producing chromosome damage in vitro in cells derived from hamster, normal human, ataxia telangiectasia (AT) and xeroderma pigmentosum (XP) patients were studied. In Chinese hamster cells, lethality was greatest with psoralen and least with angelicin; 8MOP and 5MOP were intermediate. 8MOP and 5MOP produced sister-chromatid exchanges with almost equal efficiency and to a larger extent by far than angelicin. In all human cell lines studied, 8MOP and 5MOP were similarly effective in the production of sister-chromatid exchanges and chromosomal aberrations. AT and XP cells responded with higher frequencies of sister-chromatid exchanges as well as chromosomal aberrations than normal human cells to 5MOP, 8MOP and angelicin. Evidence is presented which suggests that cell death in Chinese hamster cells following angelicin photosensitization is not clearly related to the production of sister-chromatid exchanges. AT cells were unexpectedly more sensitive to angelicin than normal cells. The presence of 5MOP in some sun-tan preparations is not acceptable in view of the present evidence of its biological activity.
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PMID:Chromosomal damage induced by furocoumarins and UVA in hamster and human cells including cells from patients with ataxia telangiectasia and xeroderma pigmentosum. 719 14

The rate of DNA synthesis was studied in normal cell strains and in strains from patients suffering from the inherited disorder ataxia telangiectasia (AT). After exposure to relatively low doses of oxic X-rays (0-4 krad) DNA synthesis was depressed in AT cell strains to a significantly lesser extent than in normal cells. This response was observed in both an "excision-deficient" and an "excision-proficient" strain. In contrast, there was no difference in DNA-synthesis inhibition between AT and normal cells after UV exposure. After X-irradiation of cells from patients with xeroderma pigmentosum, both complementation group A and XP variants, the observed rate of DNA synthesis was equal to that in normal cells. An exception was the strain XP3BR which has been shown to be X-ray-sensitive. This strain exhibited diminished DNA synthesis inhibition after X-ray doses below 1 krad. These data suggest a relationship between hypersensitivity to X-rays and diminished depression of DNA synthesis.
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PMID:The rate of DNA synthesis in normal human and ataxia telangiectasia cells after exposure to X-irradiation. 720 84

Organ cultures of chick and rabbit embryonic skin were used to assess the tumorigenicity of cultured human cell lines. Cell lines were from patients with (1) specific chromosomal abnormalities and an increased risk of cancer (Down's syndrome, Klinefelter's syndrome, Partial D Trisomy, Bloom's syndrome, Franconi's anemia, ataxia telangiectasia and xeroderma pigmentosum); (2) a specific chromosomal abnormality but no increased risk for cancer (Cri du chat), and (3) a biochemical defect (galactosemia). In addition, tumor cell lines and cell lines of normal origin were used as positive and negative standards. Mitotic ability was quantified by dividing the total number of mitoses in the cell inoculum seen in histologic sections by the number of sections examined to give a computed mean number of mitoses per section (MMS). Neoplastic cell lines showed MMS values greater than 1.0 while cell lines of normal origin were less than 0.25. The cell lines derived from patients with chromosomal abnormalities and the patient with a biochemical defect, whether the individuals were at an increased risk for cancer or not, gave the same range of MMS values as obtained for cells of normal origin. These results that chromosomal aberrations per se do not enhance the cell's capability for proliferation on a xenogenic substrate.
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PMID:Tumorigenicity of chromosomally abnormal human cultured cells in two xenogenic organ culture assays. 720 52

DNA-damaging agents are widely used as therapeutic tools for a variety of disease states. Many such agents are considered to produce detrimental side effects. Thus, it is important to evaluate both therapeutic efficacy and potential risk. DNA-damaging agents can be so evaluated by comparison to agents whose therapeutic benefit and potential hazards are better known. We propose a framework for such comparison, demonstrating that a simple transformation of cytotoxicity-dose response patterns permits a facile comparison of variation between cells exposed to a single DNA-damaging agent or to different cytotoxic agents. Further, by transforming data from experiments which compare responses of 2 cell populations to an effects ratio, different patterns for the changes in cytotoxicity produced by epigenetic and genetic factors were compared. Using these transformations, we found that there is a wide variation (a factor of 4) between laboratories for a single agent (UVC) and only a slightly larger variation (factor of 6) between normal cell response for different types of DNA-damaging agents (x-ray, UVC, alkylating agents, crosslinking agents). Epigenetic factors such as repair and recovery appear to be a factor only at higher dose levels. Comparison in the cytotoxic effect of a spectrum of DNA-damaging agents in xeroderma pigmentosum, ataxia telangiectasia, and Fanconi's anemia cells indicates significantly different patterns, implying that the effect, and perhaps the nature, of these genetic conditions are quite different.
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PMID:Epigenetic and genetic factors in the cellular response to radiations and DNA-damaging chemicals. 725 44


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