Factors influencing transformation and mutagenesis in vitro by high LET radiation

We have shown that 125Iododeoxyuridine (125IdUrd) and 3H-thymidine are more effective than x-rays for the induction of specific gene mutations in TK6 human lymphoblastoid cells. The results of parallel transformation experiments with tritiated water suggest that the enhanced efficiency of 3H-thymidine as compared with x-rays is due to a higher RBE of the tritium beta particle for mutagenesis and transformation, rather than to the fact that the radioactive decay occurs within the DNA molecule. Studies of the cell cycle specificity for the induction of cell killing and mutagenesis by 125IdUrd indicate that late S-phase cells are more radiosensitive than early S-phase cells to the localized deposition of energy characteristic of 125I decay. Cellular localization studies have shown that 125I decay must occur in close proximity to cellular DNA in order to produce mutations; 125IdUrd was very mutagenic in cells which incorporated it into DNA, but not in cells in which it remained in the acid soluble pool. A similar result emerged from preliminary experiments with 131I. These results suggest that effects result largely from a transmutation/fragmentation. Continuous, low dose-rate exposure to fast neutrons (total doses of 1 to 40 rads protracted over periods of 5 to 20 days) was more mutagenic than acute neutron irradiation. No cytotoxicity was observed in cultures continuously irradiated with up to 2 rads/day for a 20 day period (total dose of 40 rads), whereas significant cell killing occurred with acute neutron exposures of 4.6 rads or greater. 11 refs., 6 figs., 1 tab