Diamide: mechanisms of action and interactions with other sensitizers.

Diamide (diazenedicarboxylic acid [N,N′-dimethylamide]) is a hypoxic radiosensitizer that has at least two mechanisms of action, decreasing the survival curve shoulder at low concentrations and increasing the slope at high concentrations. Our present focus is on the shoulder effect, which we believe to be due to oxidation of cellular reducing species that normally effect rapid chemical repair of radiation-induced lesions. In the present studies, we analysed survival curves for several cell lines to ascertain whether diamide has selective effects on the α (single-hit) and β (double-hit) components of the linear quadratic model. This analysis indicates that low concentrations of diamide (those that decrease the shoulder) selectively enhance α, whereas high concentrations (those that increase the slope) also increase β. The inference is that combinations of diamide with sensitizers that affect only β, such as misonidazole, should greatly increase the net sensitization obtainable. In current studies we are testing the validity of this hypothesis and examining the interactions between sensitizers and other shoulder-modifying treatments (, 40°C hyperthermia, Actinomycin D). Preliminary results indicate that appropriate combinations greatly increase cell-kill per rad in the low-dose region of the hypoxic survival curve.