Grant: Operating Grant

We have recently demonstrated that ultrasound and microbubbles can sensitize tumours to radiation in vivo. The aim of this work is to understand the biological mechanism in vivo behind this new method. We will undertake experiments using genetically modified mice to examine effects of specific genetic pathways and their influence on the enhancement of radiation response in tumours and in normal tissues. We have recently demonstrated that ultrasound-activated microbubble-based endothelial cell perturbation can lead to a significant enhancement of radiation response in vitro. Experiments further conducted in vivo indicate an important role of the ceramide pathway in this process. The work proposed here builds on in vitro and in vivo studies already conducted demonstrating that such vascular treatments can increase radiation tumour cell kill over 10-fold. We will test the hyopthesis that endothelial cell apoptosis, the asmase enzyme and the ceramide pathway is important in the ablity to enhance radiation effects in mice in tumours and in normal tissues. This will be conducted by comparing results obtained from wildtype mice to results obtained from asmase -/- mice using different fractionation regimens and ultrasound treatments. We already have data in vitro demonstrating the involvement of this pathway but need to elucidate its role in vivo. The expected social impact is that we anticipate this new method will make cancer radiation treatments much more effective. It is expected from current understandings of cancer that this will improve local control and thus overall survival. The method should also permit us to spare normal tissues potential side effects of radiation by alternatively permitting lower doses of radiation to be used when possible to spare side effects on normal tissues. With North America's aging population and growing incidence of cancer we anticipate that this will be a very useful technology.