Low-LET radiotoxicity from incorporated 3H or 125I during the cell cycle: Implications for mechanisms of high-LET damage

The unique cytotoxicity of DNA-incorporated Auger-emitting radionuclides offers the tantalizing possibility of DNA-targeted radiotherapies. However, much remains to be understood about the fundamental mechanism of cytotoxicity of these agents. Recent reports demonstrate a puzzling aspect of the radiotoxicity of I-125 incorporated in Chinese Hamster Ovary (CHO) cells. When these cells are pulse-labeled with 125IUdR in early S-phase, then frozen at various times later in the cell cycle, the radiotoxicity of 125I is found to increase dramatically over the course of about 5 hours, and the shape of the log-survival curve also changes from a shouldered curve to linear during this time. To better understand these results and better characterize the microdosimetry of incorporated nuclides, the authors have performed several studies on the radiotoxicity of tritium incorporated in CHO cells. The tritium beta particle actually has a similar spectrum to the low-LET portion of the I-125 electron emission, making it an excellent microdosimetric model. In the process, the authors have found that the cytotoxicity of a given nuclear dose from incorporated tritium is quite different from the toxicity of whole-cell irradiation. The results answer the question about the importance of I-125's low-LET radiation, and also shed light on other issues, such as the target for induced radioresistance