Individual variation in the production of a 'bystander signal' following irradiation of primary cultures of normal human urothelium

The existence of a bystander effect following both alpha and gamma irradiat ion of many cell lines is not now in dispute. The significance of this effe ct for cancer risk assessment and radiotherapy treatment planning requires demonstration of its relevance in vivo. The problem in demonstrating the ex istence of the effect in vivo is that other systemic effects may mask or co nfound the effect being investigated and it is practically impossible to at tribute an effect in a particular cell to a signal produced in another irra diated cell. To approach this problem, we have developed an assay where fra gments of human tissue can be irradiated ex vivo and the media harvested an d added to unirradiated, allogenic explants or to a clonogenic cell line wh ich has a well characterized and stable response to the bystander signal. T he variation in production of the signal from patient to patient can thus b e assessed using molecular and cellular endpoints. A study using tissue fro m over 100 patients and from mouse strains with well characterized response s to low level radiation exposure shows that there is variation in the effe ct of the signal produced by irradiated tissue from different patients. Gen der, smoking status and the existence of a bladder malignancy influence the expression of the signal by normal urothelium. The effects of exposure to medium containing the signal are transmitted to distant progeny of the expo sed cell population. The results may be important not only for understandin g radiation risk mechanisms for protection but also for radiotherapy treatm ent planning where they may open new avenues for development of drugs for c ombined therapy.