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We have provided experimental evidence in favour of the hypothesis that carcinogenesis is triggered by at least two chromosomal events, which must occur in a single diploid somatic cell in a specific time sequence: (i) specific recessive mutational or epigenetic chromosomal change(s) resulting in a heterozygous (m/+), latently premalignant state (initiation); this must be followed by (ii) a chromosomal rearrangement involving the affected locus, and leading to homozygosity (m/m) or hemizygosity (m/o), and subsequent expression of the recessive malignant character (promotion). The complete carcinogen, MNNG, induced mutations (6-thioguanine-resistance), chromosomal rearrangements and SCEs in V79 Chinese hamster cells. TPA, a potent tumour promoter, induced only SCEs and specific chromosomal effects. Antipain, a protease inhibitor and a known inhibitor of both carcinogenesis and tumour promotion, inhibited only the MMNG-induced chromosomal rearrangements (but not mutagenesis and SCEs) and the TPA-induced chromosomal events. These results suggest that (1) both TPA-induced and MNNG-induced chromosomal rearrangements are caused by the activation or induction of mitotic recombination and hence appear to be preventable; (2) chromosomal rearrangement is a rate-limiting step in carcinogenesis; and (3) if mutagenesis is involved in carcinogenesis, it is probably not sufficient. The existence of the human cancer-prone syndromes, Bloom's, Fanconi's anaemia and ataxia telangiectasia, which involve spontaneous chromosomal rearrangements analogous to those induced by carcinogens in normal cells, strongly supports our hypothesis that carcinogenesis involves two chromosomal events. We discuss the implications of this work to carcinogenicity testing and cancer prevention strategies.
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PMID:Chromosomal events in carcinogenic initiation and promotion: implications for carcinogenicity testing and cancer prevention strategies. 700 84

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

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

It has been reported that the p53 gene mediates an ionizing radiation-induced G1 arrest in mammalian cells. To further characterize this important phenomenon, a panel of seven human diploid fibroblast cell strains and 14 human tumor cell lines from a variety of sources with both wild-type and mutant p53 status were assayed for their susceptibility to G1 arrest after gamma-ray irradiation by a continuous labeling [3H]thymidine incorporation technique. An irreversible G1-block involving 20-70% of the cell population was observed in diploid fibroblasts irradiated with 4 Gy. The block was abolished by transfection with the Human Papilloma Virus E6 gene and in an ataxia telangiectasia (AT) cell line, indicating a role for the AT and p53 genes respectively in this process. In contrast to wild-type normal fibroblast cell strains, the G1-block in all tumor cell lines was significantly reduced, irrespective of their p53 status. None of the nine human tumor cell lines with mutant p53 genes showed a significant G1-block following irradiation with 4 Gy. Among the five tumor cell lines expressing wild-type p53, two showed no apparent G1-block. The remaining three showed a G1-block involving only 8-15% of the cell population, a block much smaller in magnitude than that seen in diploid fibroblasts. Finally, a diploid fibroblast cell strain and a tumor cell line, both showing a normal p53 and p21/WAF1 expression pattern, were examined for pRb phosphorylation before and after irradiation. The diploid fibroblast cell strain showed a significant G1-arrest and a clear inhibition of pRb phosphorylation by irradiation whereas the tumor cells showed no G1-arrest and no inhibition of pRb phosphorylation. These results suggest that (1) multiple genetic factors may modulate the occurrence and magnitude of the G1-arrest induced by exposure to ionizing radiation, (2) the capacity for p53 to mediate a radiation-induced G1 arrest is significantly reduced in tumor cells, (3) the disruption of G1-block modulating factor(s) other than p53 may be an important step in carcinogenesis.
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PMID:Diminished capacity for p53 in mediating a radiation-induced G1 arrest in established human tumor cell lines. 747 18

The demonstrations of frequent allelic deletions in lung and colon cancers have reemphasized the importance of clastogenesis in carcinogenesis. We have investigated the mechanisms of induction of chromosome aberrations in ultraviolet-irradiated diploid human fibroblasts. Cells were irradiated with UV at various times during a parasynchronous wave of cell proliferation and then harvested during the first mitosis that followed irradiation. Metaphase spreads were stained with Geimsa and the yields of chromosome aberrations were quantified. Ultraviolet irradiation induced primarily chromatid-type chromosome aberrations which included chromatid breaks and exchanges. Frequencies of aberrations displayed significant differences according to the phase of the cell cycle in which irradiation occurred and the time after irradiation when metaphases were harvested. Fibroblasts that were irradiated when in G0 and then immediately replated to stimulate cell division and cells that were at the S/G2 border when irradiated displayed the fewest numbers of aberrations. For G0-irradiated cells, the first entering mitosis carried a higher frequency of aberrations than those collected 2-4 h later. In contrast, for S/G2-irradiated cells the first into mitosis displayed fewer aberrations than subsequent fractions. Cells that were irradiated when at the G1/S border displayed the greatest numbers of aberrations with the frequencies of chromatic exchanges being significantly increased over all other times of irradiation. These studies confirm that UV is an S-phase-dependent clastogen and point to the G1/S border as a time of maximal sensitivity to clastogenesis. Irradiation of G1 cells was shown to produce a fluence-dependent reduction in the rate of entry of cells into the S-phase. There appeared to be a point late in G1 beyond which cells were resistant to irradiation and experienced less delay in S phase entry. Ataxia telangiectasia fibroblasts failed to delay entry to S phase following UV-irradiation in G1 and displayed hypersensitivity to UV-induced chromosomal aberrations. The delay in entry of damaged cells into the S phase may have the beneficial effect of providing more time for repair of potentially clastogenic DNA damage before the onset of DNA replication.
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PMID:G1 arrest and cell-cycle-dependent clastogenesis in UV-irradiated human fibroblasts. 750 93

Chemical carcinogenesis in the regenerating rat liver is cell-cycle-dependent. Proliferating hepatocytes were maximally susceptible to initiation by a single dose of benzo[a]pyrene diolepoxide I when at the G1/S border. Hepatocytes in early G1 or late S/G2/M were less susceptible and non-proliferating G0 hepatocytes were resistant to initiation. Radiation clastogenesis in proliferating human fibroblasts also is cell-cycle-dependent. Ultraviolet radiation (UV) induced maximal frequencies of chromosomal aberrations in synchronized cells that were at the G1/S border. Cells in early G1 or G2 were significantly less sensitive. For both initiation of chemical carcinogenesis and UV-clastogenesis, it appears that replication of damaged DNA is required and DNA repair before replication reduces cellular risk. If DNA repair is protective, cell cycle checkpoints which delay DNA replication and mitosis should augment this protective influence by providing more time for repair. The contribution of cell cycle checkpoint function to DNA repair during cell cycle-dependent clastogenesis was studied using ataxia telangiectasia (AT) fibroblasts. The AT cells displayed a defect in the coupling of DNA damage to checkpoints which control the G1/S and G2/M transitions and the rate of replicon initiation in S phase cells. UV-clastogenesis in AT cells was cell-cycle-dependent with irradiation at the G1/S boundary inducing 3-times more aberrations than treatment in G0 at the time of release into the cell cycle. Thus, DNA excision repair during the pre-replicative G1 phase was protective even in cells with defective checkpoint function. However, following irradiation at the G1/S border, AT cells displayed about 6-fold increased levels of UV-induced chromosome aberrations in comparison to normal human fibroblasts that were treated at this time. These observations indicate that secondary and tertiary DNA lesions that are produced during replication of UV-damaged DNA (replicative gaps and double-strand breaks) also depend on checkpoint function for repair. The replicon initiation and G2-delay checkpoints that operate after initiation of S phase appear to play a major role in protection against UV-clastogenesis.
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PMID:Cell cycle checkpoints and DNA repair preserve the stability of the human genome. 760 19

Evidence from animal models suggests that 12-O-tetrade-canoylphorbol-13-acetate (TPA) is capable of inducing genetic damage within a tissue, although the mechanism underlying this response is unknown. A favoured hypothesis is that the TPA is acting either by stimulating cells in the tissue directly to generate DNA damaging agents or by recruiting inflammatory cells to the tissue and stimulating them to release such agents. These agents include reactive oxygen species, such as hydrogen peroxide and superoxide anion, as well as products generated during lipid peroxidation and arachidonic acid metabolism. It is not known whether significant alterations occur in the sensitivity of cells to TPA during the process of tumourigenesis. In this paper the capacity of TPA to induce chromosomal breakage (measured by micronuclei induction) was found to be elevated in bladder tumour cell lines compared to two normal cultures, a primary epithelial culture and a fibroblast culture. This effect was observed when cells were exposed to TPA directly or co-cultured with TPA-activated neutrophils isolated from human blood. In addition, we present evidence that loci on chromosome 11 may be involved in altering the response of cells to TPA. When chromosome 11 was inserted into a bladder tumour cell line, a reduction in sensitivity to TPA-activated neutrophils was observed. The chromosome insert did not protect against damage induced by direct treatment with TPA alone. In another scenario, fibroblasts from a patient with ataxia telangiectasia, a syndrome localized to chromosome 11, were shown to have an elevated sensitivity to the chromosome damaging action of TPA-activated neutrophils, but not to TPA alone. These results suggest that some of the alterations occurring in a tissue during tumourigenesis could have a significant impact on the responsiveness of cells to genetic damage by TPA. They also suggest that the damage induced by TPA in a cell may be different if a neutrophil is present.
Carcinogenesis 1994 Dec
PMID:A protective effect of chromosome 11 against DNA damage by TPA-activated neutrophils but not TPA acting alone. 800 Dec 46

Cytosolic activities in liver, stomach, small intestine, colon, lung, kidney, brain and spleen of hamster have been shown to be capable of N-acetylation, O-acetylation and N,O-acetyltransfer utilizing aromatic amine derivatives as substrates. These activities, which have been implicated in the metabolic activation and carcinogenicity of these compounds, were highest in the liver and small intestine. N-Acetylation could be demonstrated with either acetyl CoA or N-hydroxy-N-acetylaminoarenes serving as acetyl donors. Each of these tissues gave two immunoreactive bands (approximately 29 and 31 kDa) on Western blots using anti-rat AT monoclonal antibodies for detection. Single copies of two distinct acetyltransferase genes, designated AT1 and AT2, were detected in hamster DNA by Southern blot analysis using gene-specific hybridization probes for the 3' end of the AT coding regions. A third gene with > 80% sequence similarity to codons 118-158 of AT2 was also detected. Sequence analysis of the two AT genes showed that both had intronless, 0.87 kb coding regions. One was identical with the AT1 reported by Abu-Zeid et al. (Abu-Zeid,M., Nagata, K., Miyata,M., Ozawa,S., Fukuhara,M. and Yamazoe,Y., 1991, An arylamine acetyltransferase (AT-1) from Syrian golden hamster liver: cloning, complete nucleotide sequence, and expression in mammalian cells. Mol. Carcinogen., 4, 81-88). The second, AT2 (GenBank accession number L24912), coded for a 290 amino acid sequence that was 79% homologous with hamster AT1 and had a calculated molecular weight of 33.8 kDa, a theoretical pI of 5.96 and the three cysteines that have been conserved in all known vertebrate ATs at positions 44, 68 and 223. Northern blot hybridization using gene-specific AT probes detected mRNAs for both AT1 and AT2 in each of the eight tissues analyzed. Two AT1 transcripts, approximately 1.7 and 2.3 kb, were found in approximately equal ratios in all eight tissues. Three transcripts for AT2, approximately 1.9, 2.1 and 2.4 kb, were present in approximately equal ratios in the brain, small intestine, lung and colon. The liver, stomach, kidney and spleen had primarily the smaller two AT2 mRNAs. The overall abundance of AT mRNAs was highest in liver, small intestine and colon. The coding sequences of all AT mRNAs analyzed were identical to their corresponding genes, although the lengths of both the 5' and 3' untranslated transcript regions varied.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 Aug
PMID:Biochemical and genetic analysis of two acetyltransferases from hamster tissues that can metabolize aromatic amine derivatives. 805 37

A radioresistant cell clone (1B3) was previously isolated after transfection of an ataxia-telangiectasia (AT) group D cell line with a human cosmid library. A cosmid rescued from the integration site in 1B3 contained human DNA from chromosome position 11q23, the same region shown by both genetic linkage and chromosome transfer to contain the genes for AT complementation groups A/B, C, and D. A gene within the cosmid (ATDC) was found to produce mRNAs of different sizes. A cDNA for one of the most abundant mRNAs (3.0 kb) was isolated from a HeLa cell library. In the present study, we sequenced the 3.0-kb cDNA and the surrounding intron DNA in the cosmids. We used polymerase chain reaction, with primers in the introns, to confirm the number of exons and to analyze DNA from AT group D cells for mutations within this gene. Although no mutations were found, we do not rule out the possibility that mutations may be present within the regulatory sequences or coding sequences found in other mRNAs specific for this gene. From the sequence analysis, we found that the ATDC gene product is one of a group of proteins that share multiple zinc finger motifs and an adjacent leucine zipper motif. These proteins have been proposed to form homo- or heterodimers involved in nucleic acid binding, consistent with the fact that many of these proteins appear to be transcriptional regulatory factors involved in carcinogenesis and/or differentiation. The likelihood that the ATDC gene product is involved in transcriptional regulation could explain the pleiomorphic characteristics of AT, including abnormal cell cycle regulation.
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PMID:Nucleotide sequence analysis of a candidate gene for ataxia-telangiectasia group D (ATDC). 818 13

The mutants irs1, irs2 and irs3 were previously isolated from the Chinese hamster line V79-4 on the basis of their hypersensitivity (2-3-fold) to cell inactivation by X-rays. Here the cross-sensitivities of the irs mutants to an array of chemical mutagens and topoisomerase inhibitors was determined in a differential cytotoxicity assay. Irs2 showed moderate hypersensitivity (2-3-fold) to simple alkylating agents and oxidative mutagens but was most sensitive (8-fold) to the topisomerase I inhibitor camptothecin. In contrast irs2 showed little or no increased sensitivity to four topoisomerase II inhibitors. Irs3 proved to be particularly hypersensitive to DNA crosslinking agents (5-15-fold) such as 1,3-butadiene diepoxide and mitomycin C. Irs1 was hypersensitive (3-fold or greater) to simple alkylating agents, oxidative mutagens and topoisomerase I and II inhibitors and exhibited extreme sensitivity (20-100-fold) to DNA crosslinking agents. The cellular hypersensitivities of irs2 and irs3 were reflected at the level of the chromosome. Camptothecin induced chromosomal aberrations in irs2 consisted almost exclusively of chromatid deletions and exchanges, whilst in irs3 1,3 butadiene diepoxide induced a 50-fold increase in chromatid exchanges compared with V79-4. The nature of irs2's camptothecin hypersensitivity was investigated. Analysis of the protein associated DNA single strand breaks produced by camptothecin indicated that there was no difference between V79-4 and irs2 in either the number of breaks induced or in the rate of their reversal following drug removal. In addition, levels of topoisomerase I activity in V79-4 and irs2 were indistinguishable. The data presented suggest that irs3 is likely to be defective in some aspect of DNA cross-link removal and irs2, whilst showing no gross defect in DNA strand break repair may fail to correctly respond to or repair certain types of strand breaks, possibly those associated with replicating DNA. The phenotypes of irs2 and irs3 respectively show similarities to those of cultured cells from the syndromes ataxia telangiectasia and Fanconi's anaemia.
Carcinogenesis 1993 Dec
PMID:Cellular and chromosomal hypersensitivity to DNA crosslinking agents and topoisomerase inhibitors in the radiosensitive Chinese hamster irs mutants: phenotypic similarities to ataxia telangiectasia and Fanconi's anaemia cells. 826 16


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