Two-Lesion Kinetic Model of Double-Strand Break Rejoining and Cell Killing
- BATTELLE (PACIFIC NW LAB)
To better link biochemical processing of the DSB to cell killing, a two-lesion kinetic (TLK) model is proposed. In the TLK model, the family of all possible DSBs is sub-divided into simple and complex DSBs, and each kind of DSB may have its own repair characteristics. A unique aspect of the TLK model is that break-ends associated with both kinds of DSB are allowed to interact in pairwise fashion to form irreversible lethal and non-lethal damages. To test the performance of the TLK model, non-linear optimization methods are used to calibrate the model based on CHO cell survival data for an extensive set of single-dose and split-dose exposure conditions. Then, some of the postulated mechanisms of action are tested by comparing measured and predicted estimates of the initial DSB yield and the rate of DSB rejoining. TLK model predictions of CHO survival and the initial DSB yield and rejoining rate are all shown to be in good agreement with the measured data. Studies suggest a yield of about 25 DSB Gy-1 cell-1. About 20 DSB Gy-1 cell-1 are rejoined quickly (15-minute repair half-time), and 4 to 6 DSB Gy-1 cell-1 are rejoined very slowly (10 to 15 hour repair half-time). Both the slow- and fast-rejoining DSBs make a substantial contribution to the radiation killing of CHO cells. Although the TLK model provides a much more satisfactory formalism to relate biochemical processing of the DSB to cell killing than earlier kinetic models, some small differences among the measured and predicted CHO survival and DSB rejoining data suggest that additional factors and processes not considered in the present work may affect biochemical processing of the DSB and, hence, cell killing.
- Research Organization:
- Pacific Northwest National Lab., Richland, WA (US)
- Sponsoring Organization:
- US Department of Energy (US)
- DOE Contract Number:
- AC06-76RL01830
- OSTI ID:
- 15001151
- Report Number(s):
- PNNL-SA-35224; TRN: US0400111
- Journal Information:
- Radiation Research, Vol. 156, Issue 4; Other Information: PBD: 1 Nov 2000
- Country of Publication:
- United States
- Language:
- English
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