Genotoxic effects of radiotherapy and chemotherapy on the circulating lymphocytes of breast cancer patients. II. Alteration of DNA repair and chromosome radiosensitivity

Rigaud, O.; Guédeney, Geneviève; Duranton, I.; Leroy, Ancy; Doloy, M.T.; Magdelénat, H.

doi:10.1016/0165-1218(90)90096-k

Cited by 20 publications

(9 citation statements)

References 15 publications

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“…This difference was statistically significant at the 0.01 level but may reflect the fact that only one breast cancer patient smoked cigarettes, whereas 14 women with benign masses were smokers. Frequencies of chromosome anomalies and SCE in this population were similar to those reported by others in adult women with [Rigaud et al, 1990;Tucker et al, 19901. There was no correlation between the hprt mutant frequency and either aberrations or SCE, a finding consistent with the observation of others that mutation at the hprt locus is seldom associated with karyotypic abnormalities [He et al, 19891. The mechanisms of induction of chromosome aberration and SCE may be different, and other laboratories likewise have not found strong correlations between these genetic endpoints [Wasserman et al, 1990;Swierenga et al, 1991 1.…”

Section: Chromosome Aberrations and Sister Chromatid Exchangessupporting

confidence: 87%

Factors influencing mutation at the hprt locus in T‐lymphocytes: Studies in normal women and women with benign and malignant breast masses

Branda

O’Neill

Jacobson‐Kram³

et al. 1992

Environ and Mol Mutagen

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A prospective, longitudinal study was performed to test the hypothesis that environmental factors (e.g., diet or cigarette smoking) modulate genetic damage caused by treatment for breast cancer and render these women more susceptible to developing second malignancies. A total of 107 women (49 with breast cancer, 52 with benign breast masses, and 6 normal women) were enrolled. This report describes initial studies at the time of enrollment and disease presentation. Mutant frequency at the hprt locus and cloning efficiency of peripheral blood lymphocytes did not differ significantly among the 3 groups. Mutant frequency increased with age, with a history of cigarette smoking, and with the number of years that current smokers used cigarettes. There was no correlation in women with benign masses between mutant frequency and the incidence of chromosome aberrations (28 women) or sister chromatid exchanges (23 women). A maternal history of breast cancer did not influence mutant frequency. There was no significant relationship between dietary intake of vitamins A, B12, C and E, folacin, selenium, calcium, caffeine, or multivitamin pills, and mutant frequency. Serum folate levels in the deficient range were associated (P = 0.02) with elevated mutant frequencies, whereas SCE rates inversely correlated with serum vitamin B12 levels. These results confirm the importance of age and, less so, cigarette smoking as factors that influence mutant frequency and suggest that a micronutrient, folic acid, may modify genetic damage at the hprt locus. To the extent that somatic mutation contributes to carcinogenesis, these environmental factors may enhance the risk of developing malignant transformation.

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Section: Chromosome Aberrations and Sister Chromatid Exchangessupporting

confidence: 87%

Factors influencing mutation at the hprt locus in T‐lymphocytes: Studies in normal women and women with benign and malignant breast masses

Branda

O’Neill

Jacobson‐Kram³

et al. 1992

Environ and Mol Mutagen

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“…Defects in processing the type of DNA damage induced by ionising radiation have been reported in prospective analyses of lymphocytes in a high proportion of breast cancer patients compared with healthy donors. These studies have been performed using fluorimetric analysis of alkaline DNA unwinding (Rigaud et al, 1990) or chromosomal radiosensitivity of lymphocytes irradiated in the G 2 phase of the cell cycle (Scott et al, 1994;Parshad et al, 1996;Patel et al, 1997). The increased frequency of G 2 chromosomal radiosensitivity in breast cancer patients with a familial history (Parshad et al, 1996) and in first-degree relatives of breast cancer cases (Patel et al, 1997) favours a genetic origin of this defect and suggests that, besides the BRCA1 and BRCA2 genes, other genes with lower penetrance, involved in the processing of radiation-induced DNA damage, may predispose to breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Analysis by alkaline comet assay of cancer patients with severe reactions to radiotherapy: Defective rejoining of radioinduced dna strand breaks in lymphocytes of breast cancer patients

Alapetite,

Thirion,

de la Rochefordière

et al. 1999

Int. J. Cancer

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Therapeutic exposure to ionising radiation reveals interindividual variations in normal tissue responses. To examine whether a defect in DNA repair capacity might be involved in such hypersensitive phenotypes, we analysed, using the alkaline comet assay, the response as a function of time to in vitro irradiation at 5 Gy of lymphocytes from 17 breast cancer and 9 Hodgkin's disease patients who developed severe reactions to radiotherapy in comparison with 22 patients with ''average'' reactions and 24 healthy donors. A difference between breast cancer over-reactors and both patients with normal reactions and healthy donors was observed 30 and 60 min after exposure. A subgroup of breast cancer over-reactors (7/17) reproducibly demonstrated increased levels of residual damage. When the kinetic analyses were prolonged to 120 min, results were in favour of delayed kinetics of rejoining in these patients. Among Hodgkin's disease over-reactors, only one patient showed defective repair. Interestingly, all patients with the most severe complications (grade 4 RTOG/ EORTC), i.e., 5 breast cancer and 1 Hodgkin's disease, showed impaired rejoining. Our results suggest that impairment in DNA strand break processing may be associated, in specific subgroups of breast cancer patients, with an individual risk of major toxicity of radiation therapy. Thus, the alkaline comet assay appears to be useful for documenting the DNA repair phenotype in cancer patients. Int. J. Cancer 83:83-90, 1999.1999 Wiley-Liss, Inc.

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“…The most extensively used biomarkers for the assessment of genotoxic and carcinogenic risks evoked by cancer chemotherapy involve cytogenetic endpoints as chromosomal aberrations, sister chromatid exchanges and micronuclei in mitogen-stimulated peripheral blood lymphocytes [9,10]. However, most of them are restricted, with the need for cell proliferation in vitro, as DNA damage must be processed into microscopically visible lesions.…”

Section: Introductionmentioning

confidence: 99%

Alkaline comet assay study with breast cancer patients: evaluation of baseline and chemotherapy-induced DNA damage in non-target cells

et al. 2006

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The sensitivity of the alkaline comet assay for the evaluation of baseline and treatment-induced DNA damage in white blood cells of breast cancer patients receiving adjuvant chemotherapy according to three conventional anthracycline- and cyclophosphamide-containing protocols was investigated. Additionally, baseline DNA damage in cancer patients was compared with the levels of DNA damage recorded in healthy women. Altogether 30 patients with diagnosed breast cancer and 30 female blood donors with no known familial history of breast cancer participated in the study. Alkaline comet assay was performed according to standard protocol and DNA migration in peripheral blood leukocytes was measured by a computer-based image analysis system. For each subject the frequency of "damaged" cells, i.e., long-tailed nuclei (LTN) with tail length exceeding 95th percentile for the considered parameter among controls, is also reported. Breast cancer patients had significantly increased background levels of DNA damage in their peripheral blood leukocytes as compared to healthy women. Prior to the chemotherapy, a majority of patients showed a statistically significant increase in the number of LTN compared to healthy blood donors. Marked interindividual variations in baseline DNA damage among patients were recorded, some of them related to the disease stage and status. The present study confirmed the alkaline comet assay as a sensitive technique able to detect significantly elevated DNA migration in blood cells of patients already one hour after completion of the first cycle of chemotherapy. Administration of antineoplastic drugs in three chemotherapy protocols studied induced a similar increase of primary DNA damage in nontarget cells. The evaluation of the LTN frequencies indicates the best response to the protocol containing cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Our results point to the significance of simultaneous evaluation of DNA migration and frequency of LTN in the same subject and approved the use of alkaline comet assay as a suitable method for the routine detection of critical DNA lesions produced after administration of antineoplastic drugs in the clinical settings.

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Genotoxic effects of radiotherapy and chemotherapy on the circulating lymphocytes of breast cancer patients. II. Alteration of DNA repair and chromosome radiosensitivity

Cited by 20 publications

References 15 publications

Factors influencing mutation at the hprt locus in T‐lymphocytes: Studies in normal women and women with benign and malignant breast masses

Factors influencing mutation at the hprt locus in T‐lymphocytes: Studies in normal women and women with benign and malignant breast masses

Analysis by alkaline comet assay of cancer patients with severe reactions to radiotherapy: Defective rejoining of radioinduced dna strand breaks in lymphocytes of breast cancer patients

Alkaline comet assay study with breast cancer patients: evaluation of baseline and chemotherapy-induced DNA damage in non-target cells

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