Mutation Research Letters最新文献

The effect of pretreatment with metallothionein (MT) inducers (bismuth nitrate or zinc chloride) on clastogenicity of anticancer drugs was investigated. Bismuth nitrate (50 μmol/kg) or zinc chloride (400 μmol/kg) was administered s.c. to mice once a day for two days prior to treatment with 3.3 μmol/kg of cis-diamminedichloroplatinum(II) (cis-DDP), 3.4 μmol/kg of adriamycin (ADR), 72 μmol/kg of cyclophosphamide (CPA) or 0.41 μmol/kg of L-phenylalanine mustard (L-PAM). The frequency of occurrence of erythrocytes with micronuclei in bone marrow was increased by each anticancer drug at 24 h after treatment. Micronucleus formation was significantly prevented by pretreatment with either bismuth nitrate or zinc chloride. MT concentration in bone marrow cells of mice at the time of treatment with anticancer drugs increased to 2- and 3.5-fold by pretreatment with bismuth nitrate and zinc chloride, respectively. These results indicate that MT induction in bone marrow cells effectively prevents micronucleus induction of anticancer drugs.

Tetracycline (TC) exerts DNA damaging properties which are accelerated in the presence of copper(II). Thereby, reactive oxygen species are generated. We investigated, if copper-accumulating cells show a higher sensitivity to TC compared to normal cells. Fibroblasts with an increased copper content were derived from patients of two genetic disorders, Wilson disease (WD) and Menkes disease (MD). Cytotoxic and genotoxic effects of TC were investigated in different human fibroblasts. The inhibition of cell growth by TC was measured in two normal fibroblast lines, fibroblast lines of two patients with WD and one patient with MD. While TC inhibited cell growth at similar concentrations in normal fibroblasts and the MD fibroblasts, the WD cells were much more sensitive. Furthermore, an increased inhibition of DNA synthesis and an enhnaced induction of unscheduled DNA synthesis (UDS) was found in WD cells after a TC-treatment compared to normal cells.

The glycophorin A (GPA) mutation assay was used to examine the risk of in vivo somatic mutation in infants following neonatal administration of vitamin K. The assay assesses damage to erythroid stem cells by measuring the frequency of NO and NN variant red cells of MN blood group heterozygotes using FACS analysis. Blood samples were obtained from 178 infants aged between 10 and 183 days. Twenty-six children were excluded from study having received a blood transfusion. Sixty-four of the remaining 152 infants were of the MN phenotype, samples from whom were analysed using the assay system, providing the first data of NO and NN variant frequencies (vfs) in children aged less than 1 year. Twenty of these 64 infants received vitamin K orally (group A), 17 intramuscularity (group B) and 25 intravenously (group C). Results were compared with those from a reference population of children aged 1–15 years. There were no significant differences in NO, NN and total vf between any of groups A, B and C. For all groups both NO and total vf were significantly lower than those for the control population. This result is of some interest and clearly warrants further investigation. NN and total vfs were greater than the 95th percentile for the pooled data from groups A, B and C in three instances, one in each group. It was thus not possible to demonstrate an association between the route of vitamin K administration and an increase in mutation at the GPA locus.

In human larynx carcinoma cells, resitance to carboplatin (CBDCA) was induced by continuous five-day exposure of parental lines to the increasing CBDCA concentration in culture medium, reaching the clinical level of 9.23 μg/ml. Three clones were selected and characterized; CBP-3, CBP-6 and CBP-7, CBP-3 clone was 2.0-fold, CBP-6 2.1-fold, and CBP-2 2.9-fold more resistant to carboplatin. The response of these sublines to different cytostatics was compared to the response of the parental cell lines to the same drug. CBP-7 and CBP-6 clones exhibited cross-resitance to cisplatin (cis-DDP), CBP-7 clone became markedly more sensitive and CBP-3 slightly more sensitive to 5-fluorouracil (5-FU), CBP-6 became sensitive to cloposite (Et), CBP-6 became sensitive and CBP-7 resistant to vinblastine (VBL). Other clones did not change change their sensitivity to cis-DDP, 5-FU, Et or VBL. None of the three clones did alter the sensitivity to mitomycin C, doxorubicin (Dox) or vincristine (VCR). There was no change in the growth rate. Glutathione (GHS) levels were elevated in all three clones, but the increase was significant only for CBP-7 clone. Similarly, the activity of glutathione transferase (GST) was elevated in all clones, but this increase was not significant for CBP-7 clone. The analysis of the c-myc, c-Ha-ras and c-fos genes reveal no change in the c-myc expression, induction of the c-Ha-ras oncogene in CBP-6 and CBP-7 cells, and increased expression of the c-fos in CBP-6 and CBP-7 clones. The cross-resistance profiles, GSH and GST biochemistry and oncogene expression indicate that the acquired resistance to carboplatin is a complex, multifactorial process in these cells.

Background radiation is likely to constitute one of the factors involved in biological evolution since radiations are able to affect biological processes. Therefore, it is possible to hypothesize that organisms are adapted to environmental background radiation and that this adaptation could increase their ability to respond to the harmful effects of ionizing radiations. In fact, adaptive responses to alkylating agents and to low doses of ionizing radiation have been found in many organisms. In order to rest or effects of adaptation, cell susceptibility to treatments with high doses of radiomimetic chemical agents has been studied by growing them in a reduced environmental radiation background. The experiment has been performed by culturing yeast cells (Saccharomyces cerevisiae D7) in parallel in a standard background environment and in the underground Gran Sasso National Laboratory, with reduced environmental background radiation. After a conditioning period, yeast cells were exposed to recombinogenic doses of methyl methanesulfonate. The yeast cells grown in the Gran Sasso Laboratory showed a higher frequency of radiomimetic induced recombination as compared to those grown in the standard environment. This suggests that environmental radiation may act as a conditioning agents.

The clastrogenicity of seven anthraquinones was investigated in a V79 Chinese hamster cell line expressing only the reductive pathway enzymes and in three derived cell lines transfected and expressing three rat cytochrome P450 (1A1, 1A2, 2B1). The result have shown that chromosomal aberrations are modulated in similar manner both in parenal and transfected V79 cell lines, suggesting that the clastogenicity of these compounds is not mediated by cytochrome P450 dependent monooxygenases.

Lymphocytes from chimetric individuals of the species Callithrix jacchus (Primates) were examined to evaluate differences in the frequency of sister chromatid exchanges (SCE) between XX and XY cells. The aim was to discover whether SCE differ according to genetic sex and whether XX and XY cells show a different sensitivity to SCE inducing agents. This experimental model has enabled us to eliminate the possible differences caused by environmental factors. The results obtained do not reveal significant differences between male and female cells, in either the baseline SCE frequency or that induced by mitomycin C at concentrations of 0.01 and 0.03 μg/ml. No signficant differences were observed in the distribution of high SCE frequency cells (HFC), even if it is possible to observe a higher level of exchanges in XX cells in each trial. With regard to the phenotypic sex, there appears to be a trend towards slightly higher SCE rates in females, even if results are not statistically significant.

Previously, we reported that dominant lethal mutations were induced in spermatids after inhalation exposure of male (102/El × C3H/El)F₁ mice to 1300 ppm of 1,3-butadiene on 5 days for 6 h per day (exposure dose 39 000 ppm h). The same inhalation exposure was given to male C3H/El inbred mice which were mated to inbred line 102/El females 8–14 d after the end of exposure. Male and female F₁ hybrid progeny were tested for the presence of heritable translocations by observation of litter sizes and by cytogenetic analyses in meiotic and somatic cells. 1,3-Butadiene induced heritable translocations in late spermatids. The translocation frequency after 1,3-butadiene exposure to 39 000 ppm h was 2.7% (16 translocation heterozygotes among 599 F₁ offspring). This frequency is 54 times higher than the historical control frequency (0.05%; 5 translocation heterozygotes among 9500 F₁ offsping). Thus, 1,3-butadiene causes heritable germ cell effects in mice.