DNA damage repair inhibitors and radiation- are normal tissues spared?


Year:

Session type:

Theme:

Susan Short1
1University of Leeds

Abstract

DNA repair inhibitors – are normal tissues spared?New classes of DNA repair inhibitors are entering clinical studies with the promise of significant enhancement of delivered dose. Highly conformal radiotherapy permits normal tissue and organ at risk sparing to high dose treatments providing spatial specificity, however this is not absolute as surrounding tissue is often exposed to low doses, sometimes to relatively large volumes. In view of the fact that some repair inhibitors may result in enhancement ratios of 4-5 It is therefore important to understand the effect of repair inhibitors on normal tissue. This is generally less well described than the effects on tumour; the relevant target cell population(s) are not well defined and the relationship between DNA damage, repair and expression of toxicity at organ level is complex. There are also intriguing data suggesting that some repair inhibitors, including PARP inhibitors may spare normal tissues in some circumstances although this is tissue and damage specific. Equally, the effects of repair protein deficiency in knockout models such as ATM deficient mice have suggested radio-protection of some cell populations, including neurons, but it is not clear whether pharmacologic inhibition has the same effect. These findings highlight the importance of developing pre-clinical models to explore effects on normal tissue as well as careful design of clinical studies to address short and long-term toxicities.