Targeting Recombination to Enhance Radiation Therapy
Ionizing radiation induces the expression of a number of radiation-responsive genes and triggers a variety of DNA repair pathways. Both provide potential targets for enhancing radiation therapy of cancer. Thus a radiation-activated molecular switch has been developed consisting of radiation-responsive promoter elements driving the expression of the cre recombinase gene. Radiation results in the expression of Cre which in turn activates a lox-p silenced HSVtk expression vector resulting in sensitisation to gancyclovir. This produces an exceptionally high radiation dose modifying factor of ~4. In related studies, the homologous recombination repair pathway has been targeted. A ribozyme encoding "minigene" designed to attenuate expression of the strand transferase, RAD51, has been constructed into a novel vector harbouring the green fluorescence protein reporter gene. Stable cell lines demonstrated substantial down-regulation of RAD51 and increased sensitivity to gamma irradiation, corresponding to dose-modifying factor of ~ 2. These recombination-based approaches will be described in more detail and future possibilities explored.
Supported by the Cancer Research Campaign, The "Friends of Rosie" and Christie Gospital Endowment Fund.
Geoff Margison1, Spenser Collis1,2, Anthony Tighe1,2, Brian Marples1,2, Simon Scott1,2, Simon Scott1,2, Linda Lashford3, Anthony Howell4, Robin Hunter5, Jolyon Hendry1,2
1CRC Carcinogenesis Group, 2CRC Experimental Radiation Oncology Group, 3Academic Unit of Pediatric Oncology, 4Dept. of Medical Oncology, 5Dept. of Clinical Oncology