A general framework for quantifying the effects of DNA repair inhibitors on radiation sensitivity as a function of dose.
OBJECTIVE
Current methods for quantifying effects of DNA repair modifiers on radiation sensitivity assume a constant effect independent of the radiation dose received. The aim of this study was to develop and evaluate a modelling strategy by which radiation dose dependent effects of DNA repair inhibitors on clonogenic survival might be identified and their significance assessed.


METHODS
An indicator model that allowed quantification of the Sensitiser Effect on Radiation response as a function of Dose (SERD) was developed. This model was fitted to clonogenic survival data derived from human tumour and rodent fibroblast cell lines irradiated in the presence and absence of chemical inhibitors of poly(ADP-ribose) polymerase (PARP) activity.


RESULTS
PARP inhibition affected radiation response in a cell cycle and radiation dose dependent manner, and was also associated with significant radiation-independent effects on clonogenic survival. Application of the SERD method enabled identification of components of the radiation response that were significantly affected by PARP inhibition and indicated the magnitude of the effects on each component.


CONCLUSIONS
The proposed approach improves on current methods of analysing effects of DNA repair modification on radiation response. Furthermore, it may be generalised to account for other parameters such as proliferation or dose rate to enable its use in the context of fractionated or continuous radiation exposures.
Chalmers
Anthony J
AJ
Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, UK. a.j.chalmers@sussex.ac.uk
Bentzen
Soeren M
SM
Buffa
Francesca M
FM
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology
C115774:NU 1025; D011799:Quinazolines