EXPLOITATION OF HYPOXIA FOR RADIATION-THERAPY - A LESSON FROM PHENOTHIAZINES

In experimental radiation therapy of tumours, phenothiazines are known to sensitize hypoxic cancer cells while offering protection to the no rmal surrounding tissue. It is hypothesized that the differential radi osensitization of tumour cells and radioprotection of normal cells by phenothiazines is related to the presence of Fe2+ and Fe3+ ion concent ration respectively. As a result of changed biochemical environment su ch as pH, hypoxia and accumulation of ferritin, the Fe2+ ion concentra tion in tumours, especially in the hypoxic cells, is expected to be hi gher (and to be further enhanced by irradiation) than in the well-oxyg enated normal cells. In normal cells, iron would predominantly be in t he Fe3+ form, which might increase the protective effect of phenothiaz ines. A many-fold increase in radiation effect has been shown by us in in vivo as well as in vitro systems in the combined presence of pheno thiazines and Fe2+ ions. Our findings suggest that the hypoxic conditi on can be exploited for radiation therapy by employing suitable metal- based chemomodulation.