Mechanisms of enhanced cell killing at low doses: Implications for radiation risk

Abstract

Our overall aim is to gather understanding of the mechanisms underlying low-dose hyperradiosensitivity (HRS) and induced radioresistance (IRR). There is now some direct evidence that this dose-dependent radiosensitivity phenomenon reflects changes in the amount, rate or type of DNA repair, rather than indirect mechanisms such as modulation of cell-cycle progression, growth characteristics or apoptosis. There is also indirect evidence that cell survival-related HRS/IRR in response to single doses might be a manifestation of the same underlying mechanism that determines the well-known adaptive response in the two-dose case, thus HRS can be removed by prior irradiation with both high- and low-LET radiations as well as a variety of other stress-inducing agents such as hydrogen peroxide and chemotherapeutic agents. Our goals in this project are therefore: 1. Identify which aspects of DNA repair (amount, rate and type) determine HRS/IRR, 2. Investigate the known link we have discovered between the extent of HRS/IRR and position in the cell cycle, focusing on changes in DNA structure and conformation which may modulate DNA repair, 3. Use the results from studies in (1) and (2) to distinguish, if necessary, between HRS/IRR and the adaptive response. The aim is to finally determine if these are separate or interlinked phenomena. Use the results from studies in (1), (2) and (3) to propose a mechanism to explain HRS/IR