Abstract
Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA damage after radiotherapy was assessed in eight dogs using repeated in vivo samples of tumor and co-irradiated normal tissue analyzed with comet assay and phosphorylated H2AX (γH2AX) immunohistochemistry. In vivo results were then compared (in silico) with a dynamic mathematical model for DNA damage formation and repair. Maximum %DNA in tail was observed at 15–60 min after irradiation, with a rapid decrease. Time-courses of γH2AX-foci paralleled these findings with a small time delay and were not influenced by covariates. The evolutionary parameter search based on %DNA in tail revealed a good fit of the DNA repair model to in vivo data for pooled sarcoma time-courses, but fits for individual sarcoma time-courses suffer from the heterogeneous nature of the in vivo data. It was possible to follow dynamics of comet tail intensity and γH2AX-foci during a course of radiation using a minimally invasive approach. DNA repair can be quantitatively investigated as time-courses of individual patients by integrating this resulting data into a dynamic mathematical model.
Highlights
Monitoring the formation of damage in a cell after radiotherapy (RT) and the evaluation of DNA repair markers may be a means to provide information on intrinsic radiosensitivity and radio-responsiveness [1,2,3]
Ionizing radiation used as a cancer treatment relies on the formation of direct DNA damage or on creating sufficient cellular damage leading to double strand breaks (DSBs), which in turn trigger the activation of cellular death pathways
Neither DNA damage induction, nor repair time-courses have been described from patients undergoing radiation therapy up to the present date
Summary
Monitoring the formation of damage in a cell after radiotherapy (RT) and the evaluation of DNA repair markers may be a means to provide information on intrinsic radiosensitivity and radio-responsiveness [1,2,3]. Monitoring the responses towards damage formation and repair from individual tumors may offer a legitimate chance to monitor cancer treatment and even a possibility to predict clinical response to treatment [6,7]. This is thought to hold true even in spite of the high inter-tumoral and inter-patient heterogeneity that is to be expected from patient samples [6,7]
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