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Showing papers on "Sister chromatid exchange published in 1987"


Journal Article
TL;DR: Results show that common fragile sites are hot spots not only for chromosomal lesions such as gaps but also for SCE formation, as measured by sister chromatid exchanges.
Abstract: Experiments were performed to gain further insight into chromosome structure and behavior at common fragile sites by testing the hypothesis that gaps at these sites predispose to intrachromosomal recombination as measured by sister chromatid exchanges (SCEs). Human lymphocytes were concurrently treated with aphidicolin, for determination of fragile site expression, and with 5-bromodeoxy-uridine, for SCE analysis. Aphidicolin induced chromosome gaps nonrandomly, with the great majority of gaps occurring at common fragile sites. On average, 66% of gaps were accompanied by an SCE at the site of the lesion. Analysis of two specific common fragile sites at 3p14 and 16q23 showed the same pattern; that is, on average 70% of gaps at these sites were accompanied by an SCE. These results show that common fragile sites are hot spots not only for chromosomal lesions such as gaps but also for SCE formation.

158 citations


Journal ArticleDOI
22 Jan 1987-Nature
TL;DR: Evidence is presented here, as in the accompanying paper from a different laboratory12, for the existence in Bloom's syndrome of an abnormality of the DNA ligase involved in semi-conservative DNA replication.
Abstract: Cells from patients with Bloom's syndrome, a rare disease associated with increased cancer frequency, exhibit cytological abnormalities1–3. These include increased numbers of homologous chromatid interchange figures and sister-chromatid exchanges, together with abnormally slow replicon-fork progression4–6 and retarded rate of DNA-chain maturation7,8, and suggest that the primary defect in this recessive disorder affects S-phase DNA replication. DNA ligases and DNA polymerases have long been prime candidates for abnormality in Bloom's syndrome, but various studies of DNA polymerases in Bloom's syndrome cells have disclosed no abnormalities9–11. Evidence is presented here, as in the accompanying paper from a different laboratory12, for the existence in Bloom's syndrome of an abnormality of the DNA ligase involved in semi-conservative DNA replication.

146 citations


Journal ArticleDOI
TL;DR: The data on cell growth inhibition suggest that this is the result of increased incorporation of bromodeoxyuridine per cell due to decreased numbers of growing cells, although other mechanisms cannot be ruled out.
Abstract: Substantial increases in chromosome aberrations were induced in Chinese hamster ovary cells by medium made hyperosmotic with NaCl, KCl, sucrose, sorbitol or dimethyl methylphosphonate. The increases were associated with cytotoxicity but occurred in the range (e.g., 70% survival) commonly included in in vitro tests for 'genotoxicity'. The relation between increased osmotic pressure and chromosome aberrations is compound-dependent, e.g., some compounds may have a direct effect in addition to an effect mediated by osmotic pressure/ionic strength. Also, glycerol at high osmolality was not toxic and did not induce aberrations, probably because rapid equilibration across the cell membrane precluded severe osmotic stress to the cells. Weak increases in DNA single-strand breaks (NaCl and KCl) and double-strand breaks (NaCl) were also detectable, at higher concentrations and more toxic levels than those required to produce aberrations. Slight elevations in sister-chromatid exchange frequencies caused by hyperosmotic medium were found in the presence of toxicity and severe cell cycle delay. Our data on cell growth inhibition suggest that this is the result of increased incorporation of bromodeoxyuridine per cell due to decreased numbers of growing cells, although other mechanisms cannot be ruled out. The observations on chromosome aberrations demonstrate the need for keeping in vitro test conditions in the physiological range, and provide a means for investigation of indirect DNA damage.

138 citations


Journal ArticleDOI
TL;DR: The results of this study point to major differences between the bacterial and mammalian assays in terms of the relative potency of these food-related compounds.
Abstract: A series of compounds isolated on the basis of their mutagenicity in the Ames/Salmonella reversion assay were previously identified in fried beef and chemically synthesized for further evaluation. In this study three of these compounds were tested for genotoxic effects in the UV5 line of Chinese hamster ovary (CHO) cells, which is deficient in nucleotide excision repair. Both 2-amino-3,4-dimethyl-imidazo]4,5-f]quinoline (MeIQ) and 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) gave very weak responses for cell killing, hprt mutation induction and sister chromatid exchange. These effects occurred at doses in the range of 100-800 micrograms/ml (approximately solubility limit), and dose-dependent increases were not observed. Induction of chromosomal aberrations did not occur with either compound. Nor did either of these compounds produce differential cytotoxicity in normal CHO cells versus UV5 cells, indicating that potentially repairable DNA damage was not responsible for the observed cell killing. In contrast to these results, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), which constitutes greater than 90% of the mass of bacterial mutagens in beef, was strongly positive for all endpoints at doses in the range 1-3 micrograms/ml. PhIP also gave marked differential cytotoxicity (ratio of 6) and cell survival curves that were strongly dependent on repair capacity. Because PhIP is 50- to 300-fold less mutagenic than MeIQ and MeIQx in Salmonella TA1538, these results point to major differences between the bacterial and mammalian assays in terms of the relative potency of these food-related compounds.

135 citations


Journal ArticleDOI
TL;DR: The results support the need for batteries of markers to detect and to quantify the carcinogenic dose to humans resulting from both specific and "background" environmental exposures.
Abstract: In order to validate markers of internal dose and biologically effective dose of carcinogens, a battery of measurements was made on blood samples from 22 smokers and 24 nonsmokers. The markers included immunoreactivity in an enzyme-linked immunosorbent assay (ELISA) quantified in white blood cells with the use of a polyclonal anti-benzo[a]pyrene diol epoxide-I-DNA antibody, 4-aminobiphenyl hemoglobin (4-ABP-Hb) adducts measured by negative chemical ionization mass spectrometry, sister chromatid exchange (SCE) in cultured lymphocytes, and cotinine in plasma measured by radioimmunoassay. Several blood samples were drawn from each subject. In blood samples 1 and 3 having detectable levels of DNA adducts, mean femtomole-per-microgram levels were consistently higher among smokers compared to nonsmokers. The borderline significance of this difference may be attributable to the small numbers of subjects. Consistently higher adduct levels were seen in females compared to males. In sample 3, adduct levels were significantly correlated with measurements of active smoking in smokers and with passive smoking in nonsmokers. By contrast to the ELISA data, which may reflect cumulative exposure from multiple background sources, the 4-ABP-Hb assay was able to distinguish clearly between smokers and nonsmokers. SCEs were significantly elevated in the smokers compared to nonsmokers. Also observed were significant correlations between 4-ABP-Hb and both cotinine and SCEs, as well as a positive correlation between the 4-ABP-Hb and DNA adduct levels (sample 3) that was highly significant. The correlation between DNA and 4-ABP-Hb adducts was significant in smokers but not nonsmokers (sample 3). These results support the need for batteries of markers to detect and to quantify the carcinogenic dose to humans resulting from both specific and "background" environmental exposures.

123 citations


Journal ArticleDOI
TL;DR: A group A xeroderma pigmentosum revertant with normal sensitivity was created by chemical mutagenesis that repaired (6-4) photoproducts normally but not pyrimidine dimers and had near normal levels of repair replication, sister chromatid exchange, andmutagenesis from UV light.
Abstract: A group A xeroderma pigmentosum revertant with normal sensitivity was created by chemical mutagenesis. It repaired (6-4) photoproducts normally but not pyrimidine dimers and had near normal levels of repair replication, sister chromatid exchange, and mutagenesis from UV light. The rate of UV-induced mutation in a shuttle vector, however, was as high as the rate in the parental xeroderma pigmentosum cell line.

114 citations


Journal Article
TL;DR: The results suggest that chromosomal DNA of peripheral blood lymphocytes is sensitive to cigarette smoking, and these cells provide an index of the mutagenic damage caused by these exogenous agents in individual patients and the ability of individuals to repair that damage, and might predict susceptibility to malignant events.
Abstract: Cigarette smoking is considered to be the single most important acquired cause of cancer mortality. Studies of chromosome aberrations, sister chromatid exchanges, and fragile sites in peripheral blood or bone marrow are useful methods to detect the effects of the environmental mutagens or carcinogens found in cigarette smoke. The effects of smoking on the immature cells in the bone marrow have not been studied. Here, we examine the peripheral blood and bone marrow in 18 smokers (15 females and 3 males) with a median age of 25 years (range, 21-40) and an average cigarette use corresponding to 6 pack years. In both bone marrow cells and peripheral blood lymphocytes, we were able to show a significantly increased frequency of sister chromatid exchanges in smokers with a 5 or more cigarette pack year history, but not in those who smoked less than 5 pack years. We also found a higher frequency of sister chromatid exchanges in peripheral blood lymphocytes than in bone marrow cells. In addition, the peripheral lymphocytes of smokers demonstrated (a) a significantly higher frequency of fragile sites, (b) an increased number of metaphases with extensive breakage; and (c) elevated expression of fragile sites at the cancer breakpoints 3p14.2, 11q13.3, 22q12.2, and 11p13-p14.2 and at the oncogene sites bcl 1, erb B, erb A, and sis. Our results suggest that chromosomal DNA of peripheral blood lymphocytes is sensitive to cigarette smoking. Studies of the chromosomal changes in these cells provide an index of the mutagenic damage caused by these exogenous agents in individual patients and the ability of individuals to repair that damage, and might predict susceptibility to malignant events.

86 citations


Journal ArticleDOI
TL;DR: It is premature to conclude that O6mG is not a lesion lethal to certain cultured cells, but data linking O 6mG to causation are inconclusive, and a model invoking a mismatch and excision response to O6MG proposed by Sklar & Strauss (1980).
Abstract: SUMMARY O 6 -methylguanine ( O 6 mG) produced in DNA by such SN1 methylating agents as N -methyl- N -nitrososurea and N -methyl- N ′-nitro- N -nitrosoguanidine (MNNG) has been suggested by some to be the lesion that leads to certain biological endpoints in mammalian cells: cell killing, sister chromatid exchange (SCE) production, mutagenesis and cellular transformation. Other evidence is interpreted as inconsistent with this point of view. The finding of Karran & Williams (1985) that O 6 mG delivered to cells in culture resulted in the depletion of the activity of the protein responsible for repair of O 6 mG in DNA ( O 6 mG-DNA methyltransferase, O 6 MT) provided a tool for the assessment of the role of O 6 mG in producing biological endpoints. In this paper we review much of the literature on human cells pertinent to this question. In addition we present our survival data obtained using the depletion technique of Karran & Williams as well as data supporting a model invoking a mismatch and excision response to O 6 mG proposed by Sklar & Strauss (1980). Although data linking O 6 mG to causation are inconclusive, it is premature to conclude that O 6 mG is not a lesion lethal to certain cultured cells.

78 citations


Journal ArticleDOI
TL;DR: Findings are similar to the reported observations with the synthetic estrogen, diethylstilbestrol, and support the hypothesis that aneuploidy induction is important in cell transformation and possibly carcinogenesis induced by estrogens.
Abstract: The ability of 17 beta-estradiol to induce morphological transformation of Syrian hamster embryo cells was examined and dose-dependent increases were observed over the concentration range of 1-10 micrograms/ml. However, treatment of the cells with 17 beta-estradiol failed to induce any detectable increases in gene mutations, chromosome aberrations, sister chromatid exchanges or unscheduled DNA synthesis. In contrast, over the dose range that was effective in inducing cell transformation, 17 beta-estradiol induced numerical chromosome changes (both chromosome gains and losses). These findings are similar to the reported observations with the synthetic estrogen, diethylstilbestrol, and support the hypothesis that aneuploidy induction is important in cell transformation and possibly carcinogenesis induced by estrogens.

71 citations


Journal ArticleDOI
TL;DR: Immunofluorescent detection of SCE formation in dermal fibroblasts was employed over a wide range of 5-bromodeoxyuridine (BrdU) substitution into template DNA to show that this SCE elevation reflects both an increased baseline SCE frequency and an exaggerated increment in S CE formation as BrdU substitution increases.

62 citations


Journal ArticleDOI
TL;DR: Elevation of extracellular magnesium levels prevented the effects of nickel on heterochromatin and inhibited cell transformation, but did not substantially reduce the DNA damage induced by nickel in euchromatic regions.
Abstract: Raising the extracellular level of magnesium ions inhibited nickel-induced DNA strand breaks, DNA-protein crosslinks, sister chromatid exchanges, chromosomal aberrations and cell transformation. Carcinogenic nickel ions preferentially damaged centromeres and other heterochromatic regions of Chinese hamster ovary cell chromosomes. Elevation of extracellular magnesium levels prevented the effects of nickel on heterochromatin and inhibited cell transformation, but did not substantially reduce the DNA damage induced by nickel in euchromatic regions. This study suggests that heterochromatic DNA damage may be important to the nickel-induced neoplastic transformation process.

Journal ArticleDOI
TL;DR: The frequency of cells with chromosome aberrations was significantly decreased by the post-treatment with vanillin at G2 phase, suggesting that the effect of vanillin was S-phase-dependent.
Abstract: Effects of vanillin on the induction of sister-chromatid exchanges (SCEs) and structural chromosome aberrations by mitomycin C (MMC) were investigated in cultured Chinese hamster ovary cells. Vanillin induced neither SCEs nor chromosome aberrations by itself. However, an obvious increase in the frequency of SCEs was observed when MMC-treated cells were cultured in the presence of vanillin. The effect of vanillin was S-phase-dependent. On the contrary, the frequency of cells with chromosome aberrations was significantly decreased by the post-treatment with vanillin at G2 phase.


Journal ArticleDOI
TL;DR: The techniques described yield more than sufficient numbers of mitotic cells for analyzing sister chromatid exchange, chromosome aberrations, and micronuclei following in vitro or in vivo exposure to chemicals or radiation.
Abstract: A detailed methodology is presented for culturing mouse peripheral blood lymphocytes isolated on density gradients and stimulated to divide using either phytohemagglutinin, concanavalin A, or lipopolysaccharide. The techniques described yield more than sufficient numbers of mitotic cells for analyzing sister chromatid exchange, chromosome aberrations, and micronuclei following in vitro or in vivo exposure to chemicals or radiation.

Journal ArticleDOI
TL;DR: No correlations between the number of aberrations, micronuclei or SCEs on one hand and the extent or duration of exposure to styrene on the other could be detected and no increase was detected in the frequency of any of the cytogenetic endpoints studied.
Abstract: Chromosome aberrations, micronuclei and sister-chromatid exchanges were analysed in blood lymphocytes of 21 reinforced plastic workers, exposed to styrene from 1 to 25 years, and 21 control persons. Occupational hygienic measurements showed personal exposure to styrene to range from 34 to 263 mg/m3 air, the average was 98 mg/m3. Urinary mandelic acid levels of the workers varied from below detection limit to 7 mM/1 l urine. No increase was detected in the frequency of any of the cytogenetic endpoints studied. No correlations between the number of aberrations, micronuclei or SCEs on one hand and the extent or duration of exposure to styrene on the other could be detected.

Journal ArticleDOI
TL;DR: The increased background SCE levels observed appears to reflect the sensitivity of hepatocytes to SCE-inducing DNA damage resulting from the dietary intake of mutagenic/carcinogenic compounds.
Abstract: Primary cultures of adult rat hepatocytes were tested for their suitability to assess sister chromatid exchange (SCE)-inducing DNA damage produced by both directly and indirectly acting mutagens/carcinogens. Compared to other genotoxicity assay systems which utilize the metabolizing activity of liver microsomes, this system is at least 1-2 orders of magnitude more sensitive. The approximate drug concentrations leading to a doubling of control SCE levels were 2.5 X 10(-4) M for cyclophosphamide, 4.5 X 10(-5) M for dimethylnitrosamine, 2.5 X 10(-6) M for N-methyl-N-nitro-N-nitrosoguanidine, 2 X 10(-10) M for aflatoxin B1 (AFB1) and 30 mJ for u.v. The most potent inducer of SCE proved to be AFB1, leading to a significantly elevated level of exchanges at a concentration of 10(-12) M. The increased background SCE levels observed (0.75 SCE/chromosome) appears to reflect the sensitivity of hepatocytes to SCE-inducing DNA damage resulting from the dietary intake of mutagenic/carcinogenic compounds. In view of the high sensitivity and versatility of this genotoxicity assay system, it will be of use for the detection of the low levels of mutagenic/carcinogenic compounds found in the environment.

Journal ArticleDOI
TL;DR: The defect of the mutant which renders it slow in DNA strand break rejoining and high in sister chromatid exchange induction reduces its ability to recombine foreign DNA molecules.
Abstract: Transformation frequencies were measured in CHO mutant EM9 after transfection with intact or modified plasmid pSV2-gpt. The mutant and wild-type strain behaved similarly under all conditions except when homologous recombination was required to produce an intact plasmid. Therefore, the defect of the mutant which renders it slow in DNA strand break rejoining and high in sister chromatid exchange induction reduces its ability to recombine foreign DNA molecules.

Journal Article
TL;DR: Results indicate that the cleavable complex may be important in 4'-(9-acridinylamino)methansulfon-m-anisidide-induced SCE, and discourage the use of novobiocin, an inhibitor which prevents formation of the clevable complex.
Abstract: The cell cycle dependence of sister chromatid exchange (SCE) induced by topoisomerase II inhibitors was studied in Chinese hamster V79 cells. 4′-(9-Acridinylamino)methansulfon- m -anisidide, which increases the concentration of covalently linked DNA-topoisomerase II complexes (cleavable complexes), induces SCE strongly in only a short period of the cell cycle. The sensitive period was identified as occurring in early to mid-S phase through the use of labeled thymidine incorporation and flow cytometry. Novobiocin, an inhibitor which prevents formation of the cleavable complex, did not induce SCEs in any part of the cell cycle. However, novobiocin did decrease the level of 4′-(9-acridinylamino)methansulfon- m -anisidide-induced SCEs. These results indicate that the cleavable complex may be important in 4′-(9-acridinylamino)methansulfon- m -anisidide-induced SCE.

Journal Article
TL;DR: It is concluded that the cellular capacity to repair O6-chloroethylguanine adducts in DNA, which is reflected in the methyl repair process, is an important factor in determining cytotoxic response, and that increased repair of O 6-chlorOethylguAnine decreases cytotoxicity and causes fewer sister chromatid exchanges and DNA interstrand cross-links to form in cells treated with chloroethylnitrosoureas.
Abstract: We investigated the cytotoxic and cytogenetic effects of 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-1-nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea on five cell lines established from human glioma biopsy specimens. Compared to the sensitive cell line SF-126, SF-188 cells are 3- to 6.5-fold more resistant to the cytotoxic effects and 8- to 14-fold more resistant to the induction of sister chromatid exchanges. Cytotoxic effects and induction of sister chromatid exchanges are intermediate for SF-210 and SF-295 cell lines compared with SF-126 and SF-188. There is a good correlation between susceptibility to the cytotoxic effects and formation of DNA interstrand cross-links for cells treated with 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-1-nitrosourea . We quantitated the extent of repair of O6-methylguanine after treatment of these cell lines with [3H]methylnitrosourea. SF-126 cells showed no detectable repair of O6-methylguanine, SF-210 and SF-295 had intermediate levels of repair, and SF-188 had very high levels of repair. We conclude that the cellular capacity to repair O6-chloroethylguanine adducts in DNA, which is reflected in the methyl repair process, is an important factor in determining cytotoxic response, and that increased repair of O6-chloroethylguanine decreases cytotoxicity and causes fewer sister chromatid exchanges and DNA interstrand cross-links to form in cells treated with chloroethylnitrosoureas. We studied the effects of cis-diamminedichloroplatinum(II) and nitrogen mustard in these cell lines. cis-Diamminedichloroplatinum(II) was equally cytotoxic and induced the same number of sister chromatid exchanges and DNA interstrand cross-links in all five cell lines. In contrast to the results obtained by treatment with chloroethylnitrosoureas, SF-126 cells treated with nitrogen mustard are 7.6-fold more resistant to the cytotoxic effects, 2-fold more resistant to the induction of sister chromatid exchanges, and 3-fold more resistant to the induction of DNA interstrand cross-links than are SF-188 cells. The results of this investigation with five human glial-derived cell lines clearly indicate that the molecular mechanisms of cellular resistance to alkylating chemotherapeutic agents are highly specific. Cellular resistance to chloroethylnitrosoureas does not result in cross-resistance to nitrogen mustard or cis-diamminedichloroplatinum(II).

Journal ArticleDOI
TL;DR: The genotoxic effects of methyl isocyanate were investigated using four short-term tests: the Salmonella reversion assay (Ames test), the Drosophila sex-linked recessive lethal assay, and the sister chromatid exchange (SCE) and chromosomal aberration assays in cultured Chinese hamster ovary (CHO) cells.
Abstract: The genotoxic effects of methyl isocyanate (MIC) were investigated using four short-term tests: the Salmonella reversion assay (Ames test), the Drosophila sex-linked recessive lethal assay, and the sister chromatid exchange (SCE) and chromosomal aberration assays in cultured Chinese hamster ovary (CHO) cells. No evidence was found for the induction of mutations in either Salmonella or Drosophila. MIC did, however, induce SCEs and chromosomal aberrations in CHO cells both in the presence and absence of Aroclor-induced rat liver S-9.

Journal ArticleDOI
TL;DR: Chinese hamster ovary cells were exposed for 2 hr with and without mitomycin C (MMC) (1 X 10(-8)M) to pulsed wave radiofrequency radiation (RFR) at 2450 MHz and there was no significant increase in sister chromatid exchange in the RFR-exposed or TC groups over that of the 37 degrees C control.
Abstract: Chinese hamster ovary (CHO) cells were exposed for 2 hr with and without mitomycin C (MMC) (1 X 10(-8)M) to pulsed wave radiofrequency radiation (RFR) at 2450 MHz. The repetition rate of 25,000 pulses per sec (pps), pulse width of 10 microseconds, and exposure geometry used, resulted in a specific absorption rate (SAR) of 33.8 W/kg. The following exposure regimens were used: a 37 degrees C water bath control; a water bath temperature control (TC) in which the continuously monitored medium temperature closely followed the temperature rise in the RFR-exposed flasks; and the RFR-exposed cells in a water bath set at 37 degrees C prior to exposure. RFR exposure resulted in a maximum cell culture medium temperature of 39.2 degrees C. In the absence of MMC, there was no significant increase in sister chromatid exchange (SCE) in the RFR-exposed or TC groups over that of the 37 degrees C control. When a simultaneous treatment of RFR and MMC occurred there was no statistical difference in SCE frequency from that caused by chemical treatment alone.

Journal ArticleDOI
TL;DR: In cultured PBLs, MIC had a stimulatory effect on cell cycling rates as measured by the replicative index, and it caused a significant reduction in mononuclear leucocyte counts and the mitotic indices.
Abstract: Mice were exposed to 1, 3, or 6 ppm methyl isocyanate (MIC) for 6 hr/day for four consecutive days. Lung cells and peripheral blood lymphocytes (PBLs) were removed and cultured for analysis of sister chromatid exchange (SCE) and cell cycle kinetics. MIC caused a small but significant increase in SCE frequency of cultured lung cells from mice exposed to 1, 3, or 6 ppm MIC. MIC did not significantly increase SCE levels in PBLs of mice exposed to concentrations as high as 6 ppm. In cultured PBLs, MIC had a stimulatory effect on cell cycling rates as measured by the replicative index, and it caused a significant reduction in mononuclear leucocyte counts and the mitotic indices.

Journal ArticleDOI
TL;DR: It is found that the methyltransferase deficiency correlates with increased levels of mutation and sister chromatid exchange, but does not correlate with increased killing of Mer- HeLa cells by alkylating agents, and it is shown that HeLa Mer- cells repair N-3-methylguanine and N- 3-methyladenine just as efficiently as He La Mer+ cells.
Abstract: Mer- human cells, which lack O6-methylguanine DNA methyltransferase activity, are extremely sensitive to alkylation induced killing, mutation and sister chromatid exchange. We have analyzed a Mer+, a Mer-, and a Mer- revertant HeLa cell line and found that the methyltransferase deficiency correlates with increased levels of mutation and sister chromatid exchange, but does not correlate with increased killing of Mer- HeLa cells by alkylating agents. Furthermore, we show that HeLa Mer- cells repair N-3-methylguanine and N-3-methyladenine just as efficiently as HeLa Mer+ cells.

Journal ArticleDOI
TL;DR: The correlation between cytotoxicity and the induction of S CEs suggests that measurement of SCEs may be useful for determining the cellular response of normal and tumor cells to in vivo treatment with combinations of chemotherapeutic agents.
Abstract: SF-188 is a human glioma-derived cell line resistant to the cytotoxic effects of and the induction of sister chromatid exchanges (SCEs) by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Pretreatment of SF-188 cells with N-methyl-N-nitrosourea (MNU) for 1 h increased the cytotoxicity of a 1-h treatment with BCNU 2- to 10-fold and doubled the number of SCEs; the magnitude of these effects was dependent on the dose of both agents. Treatment of SF-188 cells with MNU resulted in a dose-dependent inhibition of O6-alkylguanine-DNA-alkyltransferase (O6-AT) activity. Low doses of MNU, which did not significantly inhibit O6-AT, did not potentiate SCE induction. Higher doses of MNU inhibited O6-AT and potentiated cytotoxicity and the induction of SCEs. These results are consistent with the hypothesis that in resistant cells treated with BCNU, O6-AT repairs O6-chloroethylguanine before it can form a DNA interstrand cross-link. Inhibition of this enzyme allows for the formation of BCNU-induced DNA interstrand cross-links resulting in increases in cytotoxicity and induction of SCEs. The correlation between cytotoxicity and the induction of SCEs suggests that measurement of SCEs may be useful for determining the cellular response of normal and tumor cells to in vivo treatment with combinations of chemotherapeutic agents.

Journal ArticleDOI
TL;DR: The low level of K1 in the fetus may in fact confer some biological advantage by reducing the risk of mutagenic events during a period of rapid cell proliferation.
Abstract: Vitamin K 1 Increases Sister Chromatid Exchange in Vitro in Human Leukocytes and in Vivo in Fetal Sheep Cells: A Possible Role for “Vitamin K Deficiency” in the Fetus

Journal ArticleDOI
TL;DR: It is confirmed that vitamin C (greater than or equal to 0.1 mM) potentiates the genetic toxicity of oxygen radicals and that this effect is mediated by toxic oxygen intermediates.
Abstract: The mechanism of vitamin C-induced sister-chromatid exchanges in cultured mammalian cells was studied. Chinese hamster ovary cells, when exposed to an enzymatic oxygen radical-generating system (xanthine oxidase plus hypoxanthine), develop increased numbers of sister-chromatid exchanges. Inclusion of ascorbate (≥0.1 mM) in these incubations resulted in an augmentation of this effect. Superoxide dismutase (100 μl/ml) and catalase (220 μl/ml) caused a significant reduction in the number of sister-chromatid exchanges induced by xanthine oxidase, hypoxanthine and vitamin C. Their heat-inactivated counterparts had no effect. These results confirm that vitamin C (≥0.1 mM) potentiates the genetic toxicity of oxygen radicals and that this effect is mediated by toxic oxygen intermediates.

Journal ArticleDOI
TL;DR: The results show that both psoralens induce a dose-dependent increase in the SCE rate as well as in structural chromosome aberrations and sister chromatid exchanges.

Journal ArticleDOI
TL;DR: The results suggest that PEMF with the magnetic intensity examined does not interfere with DNA replication nor produce DNA lesions, thereby leading to an increased frequency of sister-chromatid exchanges.
Abstract: Exposure of Chinese hamster cells to pulsing electromagnetic field (PEMF) with 0.18–2.5 mT did not influence the baseline frequency of sister-chromatid exchanges (SCE). The results suggest that PEMF with the magnetic intensity examined does not interfere with DNA replication nor produce DNA lesions, thereby leading to an increased frequency of SCE.

Journal ArticleDOI
TL;DR: In vitro studies in peripheral lymphocytes from three patients with the nevoid basal cell carcinoma syndrome are described, showing cellular responses in vitro to ultraviolet and x-ray irradiation correspond to the clinical features of the ne void basal cell cancer syndrome.
Abstract: Demographic studies in patients with skin cancer have demonstrated the importance of exposure to ultraviolet and x-ray irradiation. This paper describes in vitro studies in peripheral lymphocytes from three patients with the nevoid basal cell carcinoma syndrome. Particular stress was placed on the following factors: (1) the distribution of the lymphocyte subsets, (2) the frequency of spontaneous sister chromatid exchange, (3) the effect of ultraviolet C (UVC) (254 nm) on deoxyribonucleic acid (DNA) synthesis, (4) the effect of UVC on the phytohemagglutinin-stimulated lymphocyte proliferation, and (5) the capacity to repair x-ray-induced DNA damage. Our data indicate that the distribution of the peripheral lymphocytes was normal, while the frequency of spontaneous sister chromatid exchange was high. The capacity of the lymphocytes to repair x-ray-induced DNA damage was low in all three patients. In two patients the UVC-induced DNA synthesis was reduced, while an increased UVC-induced inhibition of lymphocyte proliferation was observed. These cellular responses in vitro to ultraviolet and x-ray irradiation correspond to the clinical features of the nevoid basal cell carcinoma syndrome. A clearly defective in vitro cellular response to x-ray irradiation, reflecting the clinically evident x-ray sensitivity in the nevoid basal cell carcinoma syndrome, has not been reported previously.

Journal ArticleDOI
TL;DR: The bone marrow cells of male and female NMRI mice were found to be more sensitive than those of Chinese hamsters to the genotoxic activity of DEB, and the systemic DEB dose obtained by inhalation was determined on the basis of blood concentrations and inhalation duration after the investigation of the blood kinetics.
Abstract: Diepoxybutane (DEB), a direct-acting animal carcinogen, was found to increase the frequency of structural chromosomal abnormalities (CA) and sister-chromatid exchange (SCE) in bone marrow cells of mice and Chinese hamsters, when inhaled from an aerosol during a 2-h head-only exposure or administered as a single intraperitoneal injection. For the purpose of comparing the genotoxicity in the 2 species, both after inhalation and intraperitoneal administration, the systemic DEB dose obtained by inhalation was determined on the basis of blood concentrations and inhalation duration after the investigation of the blood kinetics. The bone marrow cells of male and female NMRI mice were found to be more sensitive than those of Chinese hamsters to the genotoxic activity of DEB.