17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis.

We explored the relationship between the cytogenetic/biologic characteristics of B-chronic lymphocytic leukemia (B-CLL) cells and their tendency to undergo spontaneous or fludarabine-induced apoptosis in vitro. B cells from 36 B-CLL patients were incubated with or without fludarabine for 48 h. Apoptosis was determined by two assays: annexin V staining and DNA staining. Fluorescence in situ hybridization was used for detection of trisomy 12, 11q deletion, and 17p deletion. Bcl-2 and CD38 expressions were determined by flow cytometry. Five patients had 17p deletion, 6 had trisomy 12, and another 6 had 11q deletion. B-CLL cells with 17p deletion had significant resistance to apoptosis induced by fludarabine and a slight spontaneous resistance to apoptosis. Bcl-2 and CD38 were not associated with in vitro spontaneous and fludarabine-induced apoptosis. In conclusion, 17p deletion, which causes loss of p53 gene, is associated with resistance to fludarabine-induced apoptosis in vitro. New treatment modalities should be tried in B-CLL patients with 17p deletion.

Clastogenicity of selective serotonin-reuptake inhibitors.

OBJECTIVE: Selective serotonin-reuptake inhibitors (SSRIs) are used in the treatment of various forms of psychiatric disorders. Preclinical studies in laboratory animals have indicated that SSRIs were not genotoxic, but clear results from in vitro testing of SSRIs in a human cell system are currently scarce. The purpose of this study was to investigate whether SSRIs might be genotoxic. Sertraline was chosen as model SSRI, since it appears to be at least as well-tolerated as other SSRIs and may even have a more favourable side-effect profile. Unlike fluoxetine, fluvoxamine and paroxetine, sertraline has low potential for pharmacokinetic drug interactions. So, sertraline would be considered first in the treatment of psychiatric disorders requiring SSRI therapy in the future. We therefore examined peripheral lymphocytes from sertraline-treated patients for both sister chromatid exchanges (SCEs), cells with a high frequency of SCEs (HFC) and chromosome aberrations (CA) to evaluate the clastogenicity of SSRIs. METHOD: Ten sertraline-treated patients meeting 'Structured Clinical Interview for DSM-IV' criteria for both generalized anxiety disorder and major depression were compared with 18 healthy volunteers and 18 non-treated patients with similar psychopathology. Sertraline hydrochloride was administered orally at 50 mg daily for 10 months to 1 year. The participants were selected on the basis of similar responses to a questionnaire assessing risk of genotoxicity related to other aspects of life. All participants had very similar lifestyles, medical histories, biological and dietary factors. All subjects were non-smokers. RESULT: A statistically significant difference between patients with both generalized anxiety disorder and major depression (sertraline-treated or non-treated) and healthy volunteer groups was found by both SCE frequencies and HFC percentages. Both patient groups showed higher frequencies of SCEs than the healthy controls. No statistically significant difference was found between SCE frequencies or HFC percentages observed in sertraline-treated and non-treated patient groups. No statistical difference was found between groups with respect to the frequency of CA. CONCLUSION: There are no adequate studies analysing the clastogenicity of SSRIs, in particular of sertraline. The SCE frequency, the percentage HFC and the frequency of CA in patients with both generalized anxiety disorder and major depression exposed to daily doses of sertraline do not indicate a possible clastogenic hazard. The increased SCE frequencies in patients with both generalized anxiety disorder and major depression in our study-irrespective of sertraline treatment-indicate a possible genotoxic effect. However, our observations were based on a limited number of patients; the results may be explained by psychogenic stress.

Sister chromatid exchanges in lymphocytes of nuclear medicine physicians.

OBJECTIVE: The aim of this study was to assess whether occupational exposure to chronic, low doses of Iodine 131 (I-131) and Technetium 99m (Tc-99m) may lead to genotoxicity. Medical personnel occupied in nuclear medicine departments are occupationally exposed to low doses of I-131 and Tc-99m. The determination of the frequency of sister chromatid exchanges (SCEs) and of cells with a high frequency of SCEs (HFC) is considered to be a sensitive indicator for detecting genotoxic potential of mutagenic and carcinogenic agents. Therefore, we examined peripheral lymphocytes from nuclear medicine physicians for the presence of both SCE and HFC. METHODS: Sixteen exposed nuclear medicine physicians (non-smokers) were compared to 16 physicians (non-smokers) who had not been exposed to chemical or physical mutagens in their usual working environment at the same hospital. RESULTS: A statistically significant difference was found between SCE frequencies and HFC percentages measured in lymphocytes from the exposed and control groups. CONCLUSIONS: The present observation on the effect of chronic low doses of I-131 and Tc-99m indicates the possibility of genotoxic implications of this type of occupational exposure. Hence, the personnel who work in nuclear medicine departments should carefully apply the radiation protection procedures and should minimize, as low as possible, radiation exposure to avoid possible genotoxic effects.