Title: Adaptive responses to ionizing radiation in normal human skin fibroblasts. Authors: Azzam, Edouard Alexandre. Date: 1995 Abstract: Plateau-phase normal human skin fibroblasts (AG1522) pre-exposed to low-dose-rate ionizing radiation (IR) became less susceptible to the lethal effect of a subsequent acute challenge dose of radiation. A threshold and an optimum adapting dose were observed. This adaptive response (AR) at the survival level was accompanied by a decreased number of chromosomal breaks due to the challenge dose, as indicated by a reduction in the frequency of micronucleus formation. The frequency of micronucleus formation was further reduced when an incubation period at 37$\sp\circ$C separated the challenge dose and the adapting dose delivered at either low- or high-dose-rate. The rate of reduction of micronucleus formation was higher for the low dose-rate as compared to the high dose-rate adapting dose, suggesting that the ability of human cells to adapt to radiation increases with decreasing rates of damage. A certain amount of damage per unit time with which the cell can cope appears to be necessary to trigger the AR to IR. The rate of repair of DNA double-strand breaks, as indicated by the frequency of micronucleus formation, was higher in adapted cells, suggesting that the mechanism of adaptation could include increased repair capacity and/or an increased ease of access of repair enzymes to the lesion. Adapted cells also showed a much longer delay in reaching the binucleate state than non-adapted cells, suggesting a second mechanism of adaptation which may increase the time available for DNA repair. The analysis of RNA from adapted cells showed a decreased level of cyclin A and cyclin B transcripts consistent with a mechanism leading to a delay in the progression of the cells in the cell cycle. The transcript levels of other genes possibly involved in the cellular response to IR were also altered. Rodent C3H 10T${1\over2}$ cells showed a similar adaptation when assayed for micronucleus formation. The adapted cells were also protected against transformation to malignancy by a subsequent high dose of radiation. Transformation frequency was reduced about two-fold by low-dose-rate adapting doses ranging from 0.1 to 1.5 Gy. Flow cytometric measurements showed that the cell cycle distribution of the plateau phase cells used was unaltered during the various treatments, indicating that the observed AR cannot be attributed to selection of cells at a radioresistant stage of the cell cycle. URL: http://hdl.handle.net/10393/9592http://dx.doi.org/10.20381/ruor-7872 Collection Thèses, 1910 - 2010 // Theses, 1910 - 2010