Predicting normal tissue radiosensitivity

[摘要] Two methods of predicting normal cell radiosensitivity were investigated in different patient groups. Plasma transforming growth factor beta one (TGFbeta1) levels were measured by ELISA, using a commercially available kit. Residual DNA double strand breaks were measured in normal epidermal fibroblasts following 150 Gy. After allowing 24 hours for repair, the DNA damage was assayed using pulsed field gel electrophoresis (PFGE). Pretreatment plasma TGFbeta1 levels were investigated retrospectively in patients with carcinoma of the cervix in relation to tumour control and late morbidity following radiotherapy. Plasma TGFbeta1 levels increased with increasing disease stage. They also correlated with two other known measures of tumour burden i.e. plasma levels of carcinoma antigen 125 (CA125) and tissue polypeptide antigen (TPA). Elevated pretreatment plasma TGFbeta1 levels predicted for a poor outcome both in terms of local control and overall survival. Plasma TGF?l levels did not predict for the development of radiotherapy morbidity of any grade. In conclusion pre-treatment plasma TGFbeta1 levels predict for tumour burden and tumour outcome in patients with carcinoma of the cervix. Changes in plasma TGFbeta1 levels measured prospectively may predict for radiation morbidity and should be investigated. A prospective study was undertaken in patients with carcinoma of the head and neck region. Changes in plasma TGFbeta1 levels between the start and the end of a course of radical radiotherapy were investigated in relation to the development of acute radiation toxicity. Patients were categorised according to the pattern of response of their TGFbeta1 levels over the course of their treatment. Those patients whose TGFbeta1 levels decreased, but did not normalise during radiotherapy were assigned to category 2. Category 2 predicted for a severe acute reaction, as measured using the LENT SOMA score, with a sensitivity of 33% and a specificity of 100%. The positive predictive value of was 100%. As part of the validation of the commercially available TGFbeta1 kit, samples were obtained from sixty-six normal volunteers with a wide age distribution. This large series demonstrated an unexpected age-related rise in TGFbeta1 levels that had not been previously demonstrated in the literature. In breast carcinoma patients, two assays were performed retrospectively. Both pre-treatment plasma TGFbeta1 levels and residual DNA double strand breaks (measured using PFGE) were correlated with clinical outcome. Outcome was in the form of a total LENT SOMA score and late radiation fibrosis score, as measured by clinical palpation. No relationship was demonstrated between either pretreatment TGFbeta1 levels or residual DNA double strand breaks and late radiotherapy outcome. This failed to validate a similar series of patients investigated in the same department using the same technique. This work has shown that measurement of residual DNA double strand breaks using PFGE is not sufficiently robust to be used clinically as a predictor of normal tissue radioresponse. In conclusion, changes in TGFbeta1 plasma levels occurring over time during a course of radical radiotherapy, hold promise for the development of a rapid test of intrinsic radiosensitivity.

[发布机构] University:University of Glasgow

[关键词] Nuclear physics and radiation, Biophysics, Cellular biology