FOLLOW-UP GENOTOXICOLOGICAL MONITORING OF NURSES HANDLING ANTINEOPLASTIC DRUGS

Some of the restarting events of stalled replication forks lead to sister chromatid exchange (SCE) as a result of homologous recombination (HR) repair with crossing over. The rate of SCE is elevated by the loss of BLM helicase or by a defect in translesion synthesis (TLS). We found that spontaneous SCE levels were elevated approximately 2-fold in chicken DT40 cells deficient in Fanconi anemia (FA) gene FANCC. To investigate the mechanism of the elevated SCE, we deleted FANCC in cells lacking Rad51 paralog XRCC3, TLS factor RAD18, or BLM. The increased SCE in fancc cells required Xrcc3, whereas the fancc/rad18 double mutant exhibited higher SCE than either single mutant. Unexpectedly, SCE in the fancc/blm mutant was similar to that in blm cells, indicating functional linkage between FANCC and BLM. Furthermore, MMC-induced formation of GFP-BLM nuclear foci was severely compromised in both human and chicken fancc or fancd2 cells. Our cell survival data suggest that the FA proteins serve to facilitate HR, but not global TLS, during crosslink repair.

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: effects on levels of sister chromatid exchanges and chromosomal aberrations

Cytogenetic damage in workers exposed to ethylene oxide

Sister chromatid exchange (SCE) frequencies were studied in peripheral lymphocytes from 16 patients with newly diagnosed acute lymphoblastic leukemia (ALL) prior to the initiation of chemotherapy. The mean SCE frequency (mean +/- SE) for these patients was 12.2 +/- 0.2 per metaphase, which was significantly higher (P less than 0.001) than the mean SCE score for 14 age-matched controls, 7.6 +/- 0.2. Five of these patients were studied again while they were receiving maintenance therapy consisting primarily of daily 6-mercaptopurine and weekly methotrexate. Their remission SCE levels remained significantly higher than controls (P less than 0.005). In addition, SCE levels were studied in 7 long-term survivors of ALL. Three of these patients had been receiving continuous maintenance therapy for at least 3 years. Their mean SCE scores were significantly greater than controls (P less than 0.005). The other 4 patients had finished their final course of chemotherapy at least 8 months prior to the time of sampling, and their mean SCE scores were not significantly different from controls (P greater than 0.10). These data indicate that untreated patients with ALL have increased SCE levels which remain elevated during periods of remission maintained with chemotherapy. However, long-term survivors of ALL who are in remission and off chemotherapy do not demonstrate significantly increased SCE frequencies.

Sister chromatid exchange in Waldenström's macroglobulinemia

Sister chromatid exchange: Variation by age, sex, smoking, and breast cancer status

<b>Background:</b> The aim of this study was to estimate the cytogenetic alterations in the cells of allergic and non-allergic asthmatic patients. <b>Methods:</b> The frequencies of sister-chromatid exchanges (SCE) and chromosomal aberrations (CA) and&nbsp;in peripheral blood lymphocytes were scored for 70 asthmatic patients and the micronuclei (MN) levels in buccal epithelial cells for 56&nbsp;ones. The control group consisted of 20 healthy subjects. <b>Results</b> The significant (p&lt;0.05) elevation of SCE and CA frequencies as well as MN levels was revealed in the patients examined as compared with healthy controls. In patients with uncontrolled asthma SCE rates in allergic asthmatics appeared to be significantly (p&lt;0.005) higher than those in non-allergic ones, however CA and MN levels did not differ in patients with different phenotypes. At the same time among the patients with well-controlled asthma both CA and MN levels were found to be significantly higher in non-allergic asthmatics than those in allergic ones (p&lt;0.05), but no significant differences in SCE frequencies were recorded in patients with allergic and non-allergic phenotypes. <b>Conclusions:</b> The data obtained suggest that Asthma is a condition with increased chromosome instability characterized by a high levels of CA, SCE and MN frequencies. The cytogenetic alterations in asthmatic patients may be associated with asthma phenotype. Further studies are needed to elucidate possible pathogenetic role and the significance as phenotypic markers of the cytogenetic alterations in cells of asthmatic patients.

Phenytoin (PHT) is a widely prescribed antiepileptic drug. Its potential to interact with genetic material was investigated in a set of 30 epileptic patients (age 10-30 years) prior to and following the administration of PHT over a period of 9 months (grouped in a multiple of 3 months) and 40 control subjects in relation to age, sex, duration of drug therapy, and plasma concentration of PHT, using the sister chromatid exchange (SCE) frequency assay. Plasma levels of the phenytoin were measured by biochemical assay in epileptic patients before and after the PHT therapy. The peripheral blood lymphocytes were cultured and harvested at 72 h. The frequency of SCE was significantly higher (P < 0.001) in both age groups (10-20 and 21-30 years) for PHT-treated epileptics compared to PHT-untreated and control subjects. However, there were no considerable variations in SCE finding between the control and PHT-untreated patients. Between the two age groups, a significantly higher SCE frequency was observed in PHT-treated patients (P < 0.01) in the older age group (21-30 years). Mean SCE frequency did not differ between the male and female in the controls, PHT-untreated, or treated epileptics. Correlation between the plasma concentration of PHT and the incidence of SCE among 30 patients was insignificant. PHT monotherapy appears to have genotoxic effect as expressed by the induction of increased SCE rates in treated epileptics, while disease does not play any role in inducing genetic damage as shown by no difference in SCE frequencies between control subjects and PHT-untreated epileptic patients.

Phenytoin (PHT) is a widely prescribed antiepileptic drug. Its potential to interact with genetic material was investigated in a set of 30 epileptic patients (age 10–30 years) prior to and following the administration of PHT over a period of 9 months (grouped in a multiple of 3 months) and 40 control subjects in relation to age, sex, duration of drug therapy, and plasma concentration of PHT, using the sister chromatid exchange (SCE) frequency assay. Plasma levels of the phenytoin were measured by biochemical assay in epileptic patients before and after the PHT therapy. The peripheral blood lymphocytes were cultured and harvested at 72 h. The frequency of SCE was significantly higher (P < 0.001) in both age groups (10–20 and 21–30 years) for PHT-treated epileptics compared to PHT-untreated and control subjects. However, there were no considerable variations in SCE finding between the control and PHT-untreated patients. Between the two age groups, a significantly higher SCE frequency was observed in PHT-treated patients (P < 0.01) in the older age group (21–30 years). Mean SCE frequency did not differ between the male and female in the controls, PHT-untreated, or treated epileptics. Correlation between the plasma concentration of PHT and the incidence of SCE among 30 patients was insignificant. PHT monotherapy appears to have genotoxic effect as expressed by the induction of increased SCE rates in treated epileptics, while disease does not play any role in inducing genetic damage as shown by no difference in SCE frequencies between control subjects and PHT-untreated epileptic patients. Teratogenesis Carcinog. Mutagen. 19:61–72, 1999. © 1999 Wiley-Liss, Inc.

Acute non-lymphatic leukaemia and myelodysplasia occur in a larger percentage of patients treated with dibromodulcitol (DBD) than in patients treated with other cytostatics. Sister chromatid exchanges (SCE) in the lymphocytes in peripheral blood as well as other haematological parameters were measured in women with breast cancer to investigate whether women who had previously been treated with DBD as a part of their treatment regime had an increased frequency of SCE or another haematological abnormality attributable to DBD. SCE levels were elevated in women treated with DBD as well as in those treated with other cytostatics compared to the untreated control group. All other haematological parameters were normal. There was no significant difference in the number of SCEs between the patients who received DBD and those treated with other cytostatics. The increased frequencies of SCE in the treated patients are attributable to various cytostatic agents, and there is no significant permanent increase in the frequency of SCE after exposure to DBD.

Genotoxicity assessment in iron deficiency anemia patients using sister chromatid exchanges and chromosomal aberrations assays

Analysis of sister chromatid exchange (SCE) in chorionic villus cells may become useful in measuring the response of fetal tissues to clastogens or mutagens or for prenatal diagnosis of chromosome breakage syndromes such as Bloom syndrome. Previous studies have failed to analyze cytotrophoblastic cells and mesenchymal core cells, or have found no difference between SCE frequencies in directly prepared and cultured cells. Our data indicate significant differences in SCE frequencies between the two cell types: SCE frequency in directly prepared cytotrophoblasts was 6.73 SCE/cell +/- 1.6, whereas SCE frequency in cultured mesenchymal core cells was 10.31 SCE/cell +/- 0.49 (P less than 0.001). SCE analyses involving chorionic villi must take into account cell type.

Our objective was to investigate whether sister chromatid exchange (SCE) frequencies in patients with rheumatoid arthritis (RA) are increased and correlate with disease activity. SCE analysis has been performed on metaphase chromosomes obtained from peripheral blood lymphocyte culture in 20 active RA patients and 20 healthy controls. SCE frequencies were higher in active patients than in patients in clinical remission (p < 0.001). Also, SCE values in inactive patients were increased compared with normal controls (p < 0.001). A significant positive correlation was found between SCE frequencies and disease duration, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. In conclusion, the elevated SCE frequencies may be interpreted as an indicator providing genetic predisposition to RA. DNA damage and DNA repair mechanism defects may contribute to the RA process. In addition, SCE analysis may be a useful marker of disease activity and response to the therapy in RA.

To explore the influence of sex on sister chromatid exchange (SCE) level, a pair of chimeric twins was examined for differences in SCE frequency between the XX and XY cells present in each individual. By this method, the influence of possible differences in environmental exposure was eliminated. SCE levels were varied by growing the cells in media containing 0, 1.3 X 10(-7), or 6.5 X 10(-7) M melphalan. XX cells showed a higher SCE count than XY cells. This difference increased with increasing SCE level and ranged from 5.4% to 7.8% (P = 0.0003) of the SCE counts. Only about 2% of the difference could be explained by the higher amount of DNA present in the XX cells than in the XY cells. In this case XX cells seemed to be more sensitive to SCE-inducing agents than XY cells.

Sister chromatid exchanges and chromosomal aberrations in mouse cells infected with the Abelson and Moloney leukemia viruses.