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 normal surrounding tissue. It is hypothesized that the differential radiosensitization of tumour cells and radioprotection of normal cells by phenothiazines is related to the presence of Fe2+ and Fe3+ ion concentration respectively. As a result of changed biochemical environment such as pH, hypoxia and accumulation of ferritin, the Fe2+ ion concentration in tumours, especially in the hypoxic cells, is expected to be higher (and to be further enhanced by irradiation) than in the well-oxygenated normal cells. In normal cells, iron would predominantly be in the Fe3+ form, which might increase the protective effect of phenothiazines. A many-fold increase in radiation effect has been shown by us in vivo as well as in vitro systems in the combined presence of phenothiazines and Fe2+ ions. Our findings suggest that the hypoxic condition can be exploited for radiation therapy by employing suitable metal-based chemomodulation.