Radiosensitizers and Thymine Base Damage

Abstract

The use of radiosensitizers in the therapy of cancer in conjunction with radiation has been of considerable interest. The mechanism by which they act, however, is not clear. Because these compounds have an electron affinity similar to oxygen and/or are free radicals, it was postulated that their presence might have an effect on the formation of DNA base damage induced by radiation. The effect of three sensitizers, misonidazole, p-nitroacetophenone and 4-hydroxy-2,2,6,6-tetramethylpiperidino-1-oxy (TMPN), on formation of thymine damage of the 5,6-dihydroxydihydrothymine type by irradiation with gamma rays was characterized in HeLa cells. The three sensitizers have different electron affinities, or, in the case of TMPN, are a stable free radical. The formation of thymine base damage was measured in the presence of increasing concentrations of each of the three sensitizers with and without 500 Gy of cobalt-60 gamma rays, at ice temperature. Each sensitizer gave a different result. Increasing concentrations of misonidazole suppressed the formation of base damage in air but had no apparent effect under hypoxia. In the presence of p-nitroacetophenone, similar amounts of base damage were formed under both aerobic and hypoxic conditions. TMPN, on the other hand, resulted in a complex pattern, with suppression at higher concentrations (60 mM). The overall conclusion is that the sensitizers do not result in increased base damage but, if anything, suppress its formation. Therefore, the mechanism by which they sensitize under hypoxic conditions, such as found in solid tumors, is not by an increase in thymine base damage.