A radiation-controlled molecular switch for use in gene therapy of cancer

lonising radiation induces the expression of a number of radiation-responsi ve genes and there is current interest in exploiting this to regulate the e xpression of exogenous therapeutic genes in gene therapy strategies for can cer. However, the radiation-responsive promoters used in these approaches a re often associated with low and transient levels of therapeutic gene expre ssion. We describe here a novel radiation-triggered molecular switching dev ice based on promoter elements from the radiation-responsive Egr-1 gene and the cre-LoxP site-specific recombination system of the PI bacteriophage. U sing this system, a single, minimally toxic dose of radiation induced cre-m ediated excision of a lox-P flanked stop cassette in a silenced expression vector and this resulted in amplified levels of CMV-promoter-driven express ion of the exogenous tumour-sensitising gene, HSV-tk. This strategy could b e used in combination with targeted delivery and tumour-specific promoters to elicit the tumour-targeted and prolonged expression of a variety of tumo ur-sensitising genes and provide an unprecedented level of control and tumo ur selectivity.