RADIATION, HYPOXIA AND GENETIC STIMULATION - IMPLICATIONS FOR FUTURE THERAPIES

The cellular stress response, whereby very low doses of cytotoxic agen ts induce resistance to much higher doses, is an evolutionary defence mechanism and is stimulated following challenges by numerous chemical, biological and physical agents including particularly radiation, drug s, heat and hypoxia. There is much homology in the effects of these ag ents which are manifest through the up-regulation of various genetic p athways. Low-dose radiation stress influences processes involved in ce ll-cycle control, signal transduction pathways, radiation sensitivity, changes in cell adhesion and cell growth. There is also homology betw een radiation and other cellular stress agents, particularly hypoxia. Whereas traditionally, hypoxia was regarded mainly as an agent conferr ing resistance to radiation, there is now much evidence illustrating t he cytokine-like properties of hypoxia as well as radiation. Stress ph enomena are likely to be important in risks arising from low doses of radiation. Conversely, exploitation of the stress response in settings appropriate to therapy can be particularly beneficial not only in reg ard to radiation alone but in combinations of radiation and drugs. Sim ilarly, tissue hypoxia can be exploited in novel ways of enhancing the rapeutic efficacy. Bioreductive drugs, which are cytotoxically activat ed in hypoxic regions of tissue, can be rendered even more effective b y hypoxia-induced increased expression of enzyme reductases. Nitric ox ide pathways are influenced by hypoxia thereby offering possibilities for novel vascular based therapies. Other approaches are discussed. (C ) 1997 Elsevier Science ireland Ltd.