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Titolo:
Two-lesion kinetic model of double-strand break rejoining and cell killing
Autore:
Stewart, RD;
Indirizzi:
Pacific NW Natl Labs, Richland, WA 99352 USA Pacific NW Natl Labs Richland WA USA 99352 l Labs, Richland, WA 99352 USA
Titolo Testata:
RADIATION RESEARCH
fascicolo: 4, volume: 156, anno: 2001,
pagine: 365 - 378
SICI:
0033-7587(200110)156:4<365:TKMODB>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
FIELD GEL-ELECTROPHORESIS; RADIATION-SENSITIVE MUTANT; POTENTIALLY LETHAL DAMAGE; ORDER CHROMATIN STRUCTURE; SHORT DNA FRAGMENTS; IONIZING-RADIATION; CHO CELLS; MAMMALIAN-CELLS; DOSE-RATE; CHROMOSOME-ABERRATIONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
57
Recensione:
Indirizzi per estratti:
Indirizzo: Stewart, RD Pacific NW Natl Labs, Battelle Blvd,POB 99,MSIN K3-55, Richland, WA 99352 USA Pacific NW Natl Labs Battelle Blvd,POB 99,MSIN K3-55 Richland WA USA 99352
Citazione:
R.D. Stewart, "Two-lesion kinetic model of double-strand break rejoining and cell killing", RADIAT RES, 156(4), 2001, pp. 365-378

Abstract

Radiobiological models, such as the lethal and potentially lethal (LPL) model and the repair-misrepair (RMR) model, have been reasonably successful at explaining the cell killing effects of radiation. However, the models have been less successful at relating cell killing to the formation, repair and misrepair of double-strand breaks (DSBs), which are widely accepted as the main type of DNA damage responsible for radiation-induced cell killing. Afully satisfactory model should be capable of predicting cell killing for a wide range of exposure conditions using a single set of model parameters. Moreover, these same parameters should give realistic estimates for the initial DSB yield, the DSB rejoining rate, and the residual number of unrepaired DSBs after all repair is complete. 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 subdivided 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 DSBs are allowed to interact in pairwise fashion to form irreversible lethal and nonlethal damages. To test the performance of the TLK model, nonlinear optimization methods are used to calibrate the model based on data for the survival of CHO cells 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. The predictions of the TLK model for CHO cell survival and the initial DSB yield and rejoining rate areall shown to be in good agreement with the measured data. Studies suggest a yield of about 25 DSBs Gy(-1) cell(-1). About 20 DSBs Gy(-1) cell(-1) arerejoined quickly (15-min repair half-time), and 4 to 6 DSBs Gy-1 cell(-1) are rejoined very slowly (10- to 15-h repair half-time). Both the slowly and fast-rejoining DSBs make substantial contributions to the killing of CHO cells by radiation. Although the TLK model provides a much more satisfactory formalism to relate biochemical processing of DSBs to cell killing than did the earlier kinetic models, some small differences among the measured and predicted CHO cell survival and DSB rejoining data suggest that additional factors and processes not considered in the present work may affect biochemical processing of DSBs and hence cell killing. (C) 2001 by Radiation Research Society.

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Documento generato il 01/10/20 alle ore 14:23:00