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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Carcinogenesis 1982
PMID:The response of a variety of human fibroblast cell strains to the lethal effects of alkylating agents. 706 35

DNA rearrangement rather than point mutation is an emerging hypothesis for human carcinogenesis. Although there is no direct evidence for this hypothesis, indirect evidence is provided by cancer cytogenetics and genetics. It has been suggested that patients with Bloom's syndrome, a disorder of spontaneous chromosomal rearrangement, develop the common fatal internal cancers and thus that genetic rearrangements, rather than chemical mutagens, cause most internal human cancers. To test this observation, we have derived age- and sex-adjusted cancer incidence rate ratios for specific organ sites in patients with three chromosomal instability disorders (Bloom's syndrome, xeroderma pigmentosum, and dyskeratosis congenita) and have found that the increased incidence of cancer in all three disorders is limited to specific and often uncommon organ sites. We conclude that chromosomal instability disorders do not predispose patients to the common fatal internal cancers. Although DNA rearrangement remains a promising concept in human carcinogenesis, the organ site specificity of cancers associated with Bloom's syndrome, xeroderma pigmentosum, and dyskeratosis congenita cannot be used as evidence to implicate this mechanism.
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PMID:Organ site specificity for cancer in chromosomal instability disorders. 709 64

The response of cultured human cells to treatment with 1'-acetoxysafrole (1'-AcO-S) and 1'-acetoxyestragole (1'-AcO-E), which are electrophilic and mutagenic, has been examined. Fifty percent survival of T98G cells followed exposure to 0.2 mM 1'-AcO-E. Fifty percent inhibition of DNA synthesis rate occurred after exposure to 0.3-0.5 mM of either compound. DNA repair replication in treated cells was measured by the combined 5-bromodeoxyuridine density and radioisotope labelling method. Detectable levels of repair over a 4 h time period appeared following exposure to 0.1 mM or higher concentrations of either compound. However, the maximum level of repair in 1'-AcO-S-treated cells was only 15% of the value seen after a saturating dose of u.v. (254 nm), and that for 1'-AcO-E was only 10% of the u.v. maximum. The time course for repair was similar for u.v. and 1'-AcO-S up to at least 11 h after treatment. Normal human fibroblasts (GM38) exhibited a similar ability to that of T98G cells for repair of 1'-AcO-S-induced damage. Even SV40-transformed fibroblasts from a xeroderma pigmentosum patient (complementation group A) exhibited a low but significant amount of repair after treatment with 0.5 mM 1'-AcO-S. The repair patch size distribution in T98G cells treated wih 1'-AcO-S or 1'-AcO-E was 19-23 nucleotides, -70% of the value obtained by the density-labelling method in u.v.-irradiated human cells.
Carcinogenesis 1982
PMID:Repair replication characteristics of human cells exposed to 1'-acetoxysafrole or 1'-acetoxyestragole. 712 73

The formation and repair of alkali-labile sites in the DNA of human cells treated with 254 nm u.v. light, 1'-acetoxyestragole (1'-AcO-E) or 1'-acetoxysafrole (1'-AcO-S) have been studied. DNA was analysed by sedimentation in alkaline sucrose gradients after the cells had been layered on the gradients in lysis solution for 15 h (long lysis) or for only 0.75 h (short lysis). With the long lysis technique, a dose of 20 J/m2 resulted in 0.2-0.4 strand breaks/10(8) daltons while treatment of cells with 0.5 mM 1'-AcO-E or 1'-AcO-S caused 0.1-0.3 strand breaks/10(8) daltons. In excision repair proficient T98G cells, one third to two thirds of these strand breaks disappeared upon 4 h incubation after exposure to each of the three agents. In excision repair deficient xeroderma pigmentosum fibroblasts (XPA), the alkali-labile sites produced by 1'-AcO-E or 1'-AcO-S were still repaired, although those resulting from u.v.-irradiation were not. Similar characteristics were observed after the short lysis period. The sedimentation velocities of nucleoids, prepared from treated XPA cells, in neutral sucrose gradients containing ethidium bromide, did not reveal the presence of overt strand breaks in the DNA, suggesting that the lesions were of a type in which the sugar-phosphate backbone was intact but sensitive to hydrolysis by alkali. The contribution of this type of damage to the total DNA damage produced by the agents was estimated to be less than 1% for u.v., and less than 2.5% for 1'-AcO-E and 1'-AcO-S.
Carcinogenesis 1982
PMID:Alkali-sensitive sites in DNA from human cells treated with ultraviolet light, 1'-acetoxysafrole or 1'-acetoxyestragole. 712 74

It was shown previously that following treatment with ethylnitrosourea (ENU) SV40-transformed cells from xeroderma pigmentosum patient XP12RO, complementation group A remove O6-ethylguanine from their DNA 2 to 3 times more slowly than do such cells from a normal individual (GM637), but that each of the several other DNA adducts studied are removed at the same rate by both cell lines. If O6-ethylguanine contributes significantly to the cytotoxic effect of ENU, a population which can excise this lesion more rapidly than another during the posttreatment period should exhibit a higher survival. We compared these two cell lines for survival of colony-forming ability following exposure to ENU. XP12RO-SV40 cells proved approximately 3.5-fold more sensitive than GM637. To extend this study to non-transformed diploid human fibroblasts, we compared the survival of cells derived from normal individuals (NF) with that of fibroblasts from several XP patients: XP12BE (group A), XP7BE (group D), and XP4BE (an XP variant). The survival curve of NF, XP7BE, and XP4BE cells, but not XP12BE cells, exhibited a distinct shoulder. The slope of the survival curve for XP12BE cells was 3-fold steeper than that of the exponential part of the curve for NF; the slope of the curve for XP7BE cells, 2-fold steeper; and that of XP4BE cells, 1.7-fold steeper. This enhanced cytotoxicity was not observed in XP12BE cells treated with methylating agents such as methylnitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine. We compared NF and XP12BE cells for sensitivity to the mutagenic action of ENU and found approximately 3-fold higher frequencies of 6-thioguanine resistant mutants in the XP cells. This result is expected if the XP cells are slower than normal in excising O6-ethylguanine and if this adduct is mutagenic. When we compared the frequency of mutations induced by ENU and u.v. radiation at doses which caused equal cell killing, ENU was 4-fold more efficient a mutagen than u.v.
Carcinogenesis 1981
PMID:Enhanced cell killing and mutagenesis by ethylnitrosourea in xeroderma pigmentosum cells. 727 35

Postreplication repair has been studied in ultraviolet light (UV)-irradiated fibroblast strains derived from eight apparently normal control donors and seven xeroderma pigmentosum patients. One control donor strain had an intermediate defect in postreplication repair similar to that in excision-deficient xeroderma pigmentosum fibroblasts. However, unlike the xeroderma pigmentosum strains, this control donor strain had normal UV-induced unscheduled DNA synthesis and normal survival after irradiation with UV. This unique fibroblast strain should after irradiation with UV. This unique fibroblast strain should be useful in studies designed to elucidate the possible role of postreplication repair in UV-induced carcinogenesis and mutagenesis.
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PMID:Human fibroblast strain with normal survival but abnormal postreplication repair after ultraviolet light irradiation. 738 23

Lymphoblastoid cell lines (LCLs) established from chromosomal breakage syndromes or related genetic disorders have been used to study the effects of mutagens on human lymphoid cells. The disorders studied include xeroderma pigmentosum, ataxia telangiectasia, Fanconi's anemia, Bloom's syndrome and Cockayne's syndrome. Three approaches were used to assess the cells' ability to cope with a particular mutagen: (1) assaying recovery of DNA synthetic capabilities as measured by [3H]thymidine (dT) incorporation; (2) measurements of classical excision DNA repair by isopyknic sedimentation of DNA density labeled with 5-bromo-2-deoxyuridine (BrdU); (3) determining cell survival by colony formation in microtiter plates. LCLs established from xeroderma pigmentosum showed increased sensitivities to ultraviolet (354 nm) light and N-acetoxy-2-acetylaminofluorene (AAAF) as determined by DNA synthesis or colony formation and had diminished levels of excision-repair. Cockayne's syndrome LCLs, on the other hand, had increased sensitivities to ultraviolet (UV) light, AAAF and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) while showing near normal levels of DNA-repair after treatment with each agent. An LCL established from ataxia telangiectasia had decreased DNA repair synthesis and defective colony-forming ability following treatment with MNNG. LCLs, in addition to ease of establishment, appear likely to provide useful material for the study of DNA repair replication and its relationship to carcinogenesis.
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PMID:DNA repair in lymphoblastoid cell lines established from human genetic disorders. 743 93

Hyperthermia specifically inhibits the repair of UV-induced DNA photolesions in transcriptionally active genes. To define more precisely which mechanisms underlie the heat-induced inhibition of repair of active genes, removal of cyclobutane pyrimidine dimers (CPDs) was studied in human fibroblasts with different repair capacities and different transcriptional status of the adenosine deaminase gene, i.e. normal human cells, human cells carrying an inactive copy of the adenosine deaminase gene and xeroderma pigmentosum complementation group C fibroblasts. The results indicate that repair of active genes is impaired by inhibition of two repair pathways: (i) a global repair system involved in the repair of CPDs in potentially active genes; and (ii) the transcription-coupled repair pathway responsible for the accelerated repair of the transcribed strand. Since X-ray-induced DNA damage is also preferentially removed from the transcribed strand of active genes, selective inhibition of repair of radiation-induced DNA damage in active genes may play a key role in radiosensitization due to hyperthermia.
Carcinogenesis 1995 Apr
PMID:Selective inhibition of repair of active genes by hyperthermia is due to inhibition of global and transcription coupled repair pathways. 753 81

Mutagenicity and carcinogenicity of the ubiquitous environmental pollutant benzo[a]pyrene is mediated via its reactive diol epoxide metabolite, anti-BPDE, with the predominant formation of N(2)-deoxyguanine adducts in genomic DNA. Polyclonal and monoclonal antibodies specific for (+/-)-anti-BPDE DNA adducts were used for the quantitative detection of genotoxic damage in DNA treated in vitro and in vivo with ( +/- )-anti-BPDE. In non-competitive enzyme-linked immunosorbent assay the polyclonal antiserum (BP1) exhibited higher affinity, avidity and sensitivity than the monoclonal antibody (5D2). A linear antibody binding response was observed over a wide carcinogen dose range with a detection limit of < 0.1 fmol adducts in immobilized DNA. Non-competitive immuno-slot blot assay could detect 0.2 adducts/10(6) nucleotides induced by < 1 nM ( +/- )-anti-BPDE. The high sensitivity and mono-adduct specificity of non-competitive immunoassays allowed the detailed study of ( +/- )-anti-BPDE-DNA adduct processing human cells exposed to very low levels of the genotoxin. Analysis of polyclonal antiserum binding sites in DNA from repair-proficient human fibroblasts revealed adduct removal rates directly proportional to the initial genotoxic insult. Despite efficient repair, substantial damage persisted in repair-proficient cells exposed to high doses of carcinogen. At low levels of initial damage (0.882 and 3.44 +/- 0.17 adducts/ 10(6) nucleotides) approximately 50% repair was observed after 4 and 8 h respectively. Cells removed approximately 40% of the lesions in 8 h at an intermediate level of damage (20.7 +/- 1.5 adducts/10(6) nucleotides). At higher DNA damage levels (105 +/- 8 and 177 +/- 1 adduct/10(6) nucleotides) 33 and 19% of the lesions respectively were repaired in 24 h. Repair-deficient xeroderma pigmentosum group A fibroblast cells did not show any significant loss of antibody binding sites at high or low initial modification levels. These data suggest that the level of initial DNA damage has a significant impact on the overall efficiency of cellular repair, with potential implications for the biological consequences of deleterious DNA lesions in mammalian cells.
Carcinogenesis 1995 Sep
PMID:DNA repair in human cells: quantitative assessment of bulky anti-BPDE-DNA adducts by non-competitive immunoassays. 755 50

A host cell reactivation (HCR) assay was employed to study the capacity of a normal and three repair-deficient human lymphoblastoid cell lines to repair DNA damage induced by UV irradiation and the aromatic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-acetyl-2-aminofluorene (AAF) respectively. The cell line belonging to xeroderma pigmentosum complementation group C (XP-C) removed all three types of damage less efficiently than the normal cell line, but more efficiently than the cell line belonging to xeroderma pigmentosum complementation group D (XP-D). The cell line belonging to complementation group B of Cockayne's syndrome (CS-B) showed reduced host cell reactivation. Fibroblasts from CS-B patients have reduced gene-specific DNA repair, but normal total genomic DNA repair, thus our data suggest that the HCR assay measures the capacity for gene-specific DNA repair. In the XP-D cell line, which had practically no DNA repair capacity, AAF adducts had a more potent inhibitory effect on gene expression than UV and PhIP adducts. When corrected for this inhibitory effect, the wild-type, XP-C and CS-B cell lines repaired low levels of AAF and UV adducts with similar efficiencies, however, PhIP adducts were repaired less efficiently.
Carcinogenesis 1995 Nov
PMID:Repair of DNA lesions induced by ultraviolet irradiation and aromatic amines in normal and repair-deficient human lymphoblastoid cell lines. 758 9


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