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.