Enhancement of radiation damage in cellular DNA following unifilar substitution with iododeoxyuridine.

Abstract

The exact mechanism of x-ray radiosensitization with iododeoxyuridine (IdUrd) is not known. Using log phase V79 cells, we compared radiosensitization following unifilar (9 hr exposure) and bifilar (17 hr exposure) substitution with 10(-5) M IdUrd. The % thymidine replacement was 8% and 16%, respectively. Significant radiosensitization was found with unifilar (Do = 1.35 Gy, n = 5.8) and bifilar substitution (Do = 1.2 Gy, n = 4.0) compared to controls (Do = 1.7 Gy, n = 8.5). Using filter elution techniques, the enhancement ratios (ER) for double strand breaks (SB) were 1.5 and 2.0 for unifilar and bifilar substitution, respectively, whereas the enhancement ratio for single strand breaks were both greater than or equal to 2.1. Comparing the enhancement ratios with unifilar substitution for single strand breaks in substituted (2.4) and unsubstituted complement strands (1.9) as well as in unsubstituted duplex DNA (1.4) in cells containing IdUrd substituted DNA, there was increased damage in unsubstituted strands compared to irradiated controls. These data suggest that in vitro radiosensitization following unifilar substitution with IdUrd results, in part, from damage to unsubstituted complementary strand and adjacent doubly unsubstituted DNA. The radiolysis of halogenated DNA produces mobile reactive intermediates which may cause intermolecular DNA damage such as single strand breaks in unsubstituted DNA and resultant double strand breaks and this damage is probably responsible for increased lethality after x-irradiation.