Tumor radiosensitization with concomitant vone marrow radioprotection: A study in mice using diethyldithiocarbamate (DDC) under oxygenated and hypoxic conditions

Abstract

We have established, both in vitro and in vivo, that Diethyldithiocarbamate (DDC) protects mammalian cells from radiation. The in vivo protection, when non-toxic concentrations of DDC are present one-half hour before irradiation, is reflected by a dose modification factor (DMF) of 1.9 based on LD 50 30 and 1.5 using survival of CFU s as an endpoint. Further experiments in vivo have extended our knowledge to the differential radioprotective effects of DDC on the vone marrow of animals breathing room air compared to a 5.5% oxygen in nitrogen mixture. The DMF ( LD 50 30 ) for DDC in air breathing animals, previously established as 1.9, can be contrasted with a DMF, obtained in the present study, of 1.2 for animals irradiated in the hypoxic state. Moreover the DMF (CFU s survival) previously established at 1.5 for air breathing animals, can be compared to a value of 1.3, obtained in the present study, for mice irradiated under hypoxic conditions. Modification of the dose response by DDC, for both vone marrow and tumor, was also examined in animals bearing a RIF sarcoma. Although protection of the vone marrow was confirmed (DMF = 2.1), the striking finding was that the tumor cells were sensitized, in both air breathing and nitrogen breathing animals, by the addition of DDC one-half hour before the radiation exposure. Moreover, the tumor radiosensitization, a factor greater than 2, in air breathing animals, appeared to be independent of dose (D 0 = 200 rad, with or without DDC). The tumor radiosensitization was even more marked in the nitrogen breathing mice, in which a factor of 10 difference in survival was noted, together with a tendency towards greater sensitization at radiation doses in the clinical range. The results, demonstrating vone marrow radioprotection by DDC (aerobic > hypoxic) with concomitant tumor radiosensitization (hypoxic > aerobic) strongly suggest a large therapeutic gain factor (TGF) which could be further explored in a clinical setting.