Tumor radiosensitization with concomitant bone marrow radioprotection: a study in mice using diethyldithiocarbamate (DDC) under oxygenated and hypoxic conditions.
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 LD50/30 and 1.5 using survival of CFUs as an endpoint. Further experiments in vivo have extended our knowledge to the differential radioprotective effects of DDC on the bone marrow of animals breathing room air compared to a 5.5% oxygen in nitrogen mixture. The DMF (LD50/30) 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 (CFUs 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 bone marrow and tumor, was also examined in animals bearing a RIF sarcoma. Although protection of the bone 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 (D0 = 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 bone marrow radioprotection by DDC (aerobic greater than hypoxic) with concomitant tumor radiosensitization (hypoxic greater than aerobic) strongly suggest a large therapeutic gain factor (TGF) which could be further explored in a clinical setting.
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D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000528:radiation effects; D004050:Ditiocarb / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D010100:Oxygen / Q000502:physiology*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D013859:Thiocarbamates / Q000627:therapeutic use*
D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; D013859:Thiocarbamates; D004050:Ditiocarb; D010100:Oxygen