Residual DNA and chromosomal damage in ex vivo irradiated blood lymphocytes correlated with late normal tissue response to breast radiotherapy (original) (raw)
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International Journal of Radiation Research
Background: There is not yet an appropriate biomarker to predict or follow radiosensitivity of Breast cancer (BC) patients during or after radiotherapy. The aim of this study was to monitor chromosomal aberrations (CA) induced before and during radiotherapy in peripheral blood lymphocytes of BC patients. Materials and Methods: Age-matched twenty normal healthy individuals and 20 invasive ductal BC patients were enrolled in this study. A blood sample was obtained from normal healthy women and BC patients before and after the first, two and four weeks after radiotherapy. Lymphocyte microculture was initiated in 4.5ml complete RPMI-1640 medium. Cells were harvested 50 hours after culture initiation. Cells were harvested based on standard protocols. Hundreds of well-spread mitoses were scored under a light microscope with a magnification of x1000 for various types of CA. Data were statistically analyzed and p<0.05 was considered a significant difference. Results: Results indicated a higher frequency of CA in lymphocytes of un-irradiated BC patients compared to healthy normal individuals, although not statistically significant (p>0.05). High frequencies of CA were observed in lymphocytes of BC patients after radiotherapy, significantly different from the un-irradiated group (p<0.01). The increase in the frequency of CA was increased with increasing radiation dose. Conclusion: Genome instability may contribute to high background and radiationinduced CA in lymphocytes of BC patients. However, there is also the possibility of a radio-adaptation of cells during the course of radiotherapy. Results imply that dicentric chromosomes might be valuable cytogenetic bioindicators to monitor the response of BC patients to radiotherapy.
International Journal of Radiation Oncology*Biology*Physics, 2002
Purpose: Stable chromosomal aberrations (SCAs) have been found in circulating lymphocytes from patients treated for breast carcinoma. Therefore, we tried to define their incidence in such patients, to determine an in vitro dose-effect relationship, and to correlate these data with clinical parameters. Methods and Materials: This prospective study included 25 patients who, after surgery, underwent either radiotherapy (RT) alone (n ؍ 15) or RT combined with chemotherapy (n ؍ 10). SCAs were scored using the fluorescent in situ hybridization technique before RT and 4 and 12 months after RT. Dose-effect curves were established by in vitro irradiation of blood samples with 2 and 4 Gy, before and after treatment. Results: In all patients, the rate of SCAs increased significantly after external irradiation. No significant decrease in SCAs was observed during the first year after RT. RT and chemotherapy had no effect on the lymphocyte in vitro dose-effect relationship. No relationship was found in the distribution of patients between the yield of SCAs scored after external irradiation and after in vitro irradiation. SCAs after RT or in vitro irradiation did not correlate with family history of breast carcinoma or acute toxicity of treatment. More significantly, the yield of SCA after external irradiation was strongly related to the irradiation of the internal mammary chain and the supraclavicular lymph node area, suggesting that the volume of irradiated blood vessels was an essential parameter in determining the rate of SCAs. Conclusion: A high and stable yield of SCAs persisted at least 1 year after external irradiation. The nature of the volume irradiated containing large blood vessels was the major determinant of the observed biologic dose.
International Journal of Radiation Oncology*Biology*Physics, 2003
Purpose: To measure chromosomal aberrations in blood lymphocytes from breast cancer patients treated with radiotherapy after quadrantectomy or tumorectomy. Methods and Materials: Twenty-two breast cancer patients treated with breast-conserving surgery and radiation were evaluated. Adjuvant chemotherapy was also given to 9 patients. Blood samples were obtained before radiotherapy, after about one-half of the fractions, and at the end of the treatment of the whole breast (50 Gy). Chromosome aberrations in peripheral blood lymphocytes were measured using chemical-induced premature chromosome condensation combined with fluorescence in situ hybridization. Results: Radiation treatment produced a significant increase in the yield of chromosomal aberrations. A large interindividual variability was observed. The variability was not related to field size, previous chemotherapy, or treatment morbidity. Chromosome aberrations in lymphocytes at the end of the treatment were significantly higher in the group of patients with no lymph nodes surgically removed before the treatment than in the group of patients with more than 10 lymph nodes removed. Conclusions: The number of lymph nodes within the radiation field is an important factor affecting the yield of radiation-induced chromosomal aberrations in breast cancer patients.
Biomedicines
About 5% of patients undergoing radiotherapy (RT) develop RT-related side effects. To assess individual radiosensitivity, we collected peripheral blood from breast cancer patients before, during and after the RT, and γH2AX/53BP1 foci, apoptosis, chromosomal aberrations (CAs) and micronuclei (MN) were analyzed and correlated with the healthy tissue side effects assessed by the RTOG/EORTC criteria. The results showed a significantly higher level of γH2AX/53BP1 foci before the RT in radiosensitive (RS) patients in comparison to normal responding patients (NOR). Analysis of apoptosis did not reveal any correlation with side effects. CA and MN assays displayed an increase in genomic instability during and after RT and a higher frequency of MN in the lymphocytes of RS patients. We also studied time kinetics of γH2AX/53BP1 foci and apoptosis after in vitro irradiation of lymphocytes. Higher levels of primary 53BP1 and co-localizing γH2AX/53BP1 foci were detected in cells from RS patients a...
Breast Cancer …, 2005
Introduction Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects. Methods Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes obtained from breast cancer patients before radiotherapy. Acute reactions were assessed in 108 of these patients on the last treatment day. Late morbidity was assessed after 7 years of follow-up in some of these patients. The Radiation Therapy Oncology Group (RTOG) morbidity score system was used for both assessments. Results Radiosensitivity values obtained using the in vitro test showed no relation with the acute or late adverse skin reactions observed. There was no evidence of a relation between acute and late normal tissue reactions assessed in the same patients. A positive relation was found between the treatment volume and both early and late side effects. Conclusion After radiation treatment, a number of cells containing major changes can have a long survival and disappear very slowly, becoming a chronic focus of immunological system stimulation. This stimulation can produce, in a stochastic manner, late radiation-related adverse effects of varying severity. Further research is warranted to identify the major determinants of normal tissue radiation response to make it possible to individualize treatments and improve the outcome of radiotherapy in cancer patients.
Journal of Environmental Science and Health, Part A, 2010
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British journal of cancer, 2001
A substantial proportion of women with breast cancer exhibit an abnormally high radiosensitivity as measured by the frequency of chromatid breaks induced in G2-phase, PHA stimulated lymphocytes. Chromatid break frequencies were compared for a cohort of previously untreated sporadic breast cancer patients and hospital outpatient controls. In the breast cancer group 46% showed high radiosensitivity compared to 14% of controls (P< 0.001). Comparison of those breast cancer patients with a high G2 radiosensitivity (G2RS) versus those with a low G2RS showed no difference in menopausal status or age but the high G2RS group had on average a lower score on the Nottingham Prognostic Index. Predicted survival in the high G2RS group at 15 years was 55% compared to 36% for the low G2RS group. Furthermore, 81% of tumours from the high G2RS were oestrogen receptor positive compared to 45% from the low G2RS group. Thus high G2RS identifies a sub-population of patients with distinctive tumour cha...