ABSTRACT
The concept and development of DNA repair and checkpoint inhibitors is a fi eld of intense interest and as noted above from the recent patent literature seems likely to continue to evolve. In vitro and in vivo preclinical data have shown that the inhibition of the DNA damage PIKKs ATM and ATR, or their downstream targets, the Chks, can potentiate the effects of DNA damage. However, it has to be noted that the inhibitors so far developed have not yet completed validation in clinical trials, and importantly, none have to date been assessed in combination with radiation. As discussed in this Chapter, there are a number of outstanding issues that remain to be resolved including toxicity and patient choice. The fi rst generation Chk1 inhibitor UCN01 showed signifi cant limiting toxicity in phase I trials, and toxicity has been associated with the second generation inhibitors, yet would appear to be drug-specifi c and might refl ect off-target effects. It is hoped that toxicity might be reduced by the use of more specifi c inhibitors in combination with pharmacodynamic biomarkers to follow kinase inhibition. The fi ndings that many tumours have lost the expression of one or more of these four kinases and that a vast majority of tumours are thought to have a defect in G1 control (Massague 2004) would suggest that ATM/ATR and the cell cycle kinase inhibitors could be applied to a wide background. Determining the molecular profi le of individual tissues would allow the variation in responses to be better understood and contribute to determining the criteria necessary for the selection of appropriate patient populations that would most benefi t from such targeted therapies. Clearly, over the next decade with access to technologies that will facilitate personalized medicine (see Chapter 16), many of these issues will be resolved, and the new generation potent inhibitors will then fi nd their place in the clinic.
