title: The role of radiation quality in the stimulation of intercellular induction of apoptosis in transformed cells at very low doses.
abstract: An important stage in tumorigenesis is the ability of precancerous cells to escape natural anticancer signals. Apoptosis can be selectively induced in transformed cells by neighboring normal cells through cytokine and ROS/RNS signaling. The intercellular induction of apoptosis in transformed cells has previously been found to be enhanced after exposure of the normal cells to very low doses of both low- and high-LET ionizing radiation. Low-LET ultrasoft X rays with a range of irradiation masks were used to vary both the dose to the cells and the percentage of normal cells irradiated. The results obtained were compared with those after α-particle irradiation. The intercellular induction of apoptosis in nonirradiated src-transformed 208Fsrc3 cells observed after exposure of normal 208F cells to ultrasoft X rays was similar to that observed for γ rays. Intercellular induction of apoptosis was stimulated by irradiation of greater than 1% of the nontransformed 208F cells and increased with the fraction of cells irradiated. A maximal response was observed when ∼10-12% of the cells were irradiated, which gave a similar response to 100% irradiated cells. Between 1% and 10%, high-LET α particles were more effective than low-LET ultrasoft X rays in stimulating intercellular induction of apoptosis for a given fraction of cells irradiated. Scavenger experiments show that the increase in intercellular induction of apoptosis results from NO(•) and peroxidase signaling mediated by TGF-β. In the absence of radiation, intercellular induction of apoptosis was also stimulated by TGF-β treatment of the nontransformed 208F cells prior to coculture; however, no additional increase in intercellular induction of apoptosis was observed if these cells were also irradiated. These data suggest that the TGF-β-mediated ROS/RNS production reaches a maximum at low doses or fluences of particles, leading to a plateau in radiation-stimulated intercellular induction of apoptosis at higher doses.
authors.affiliation: CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
authors.forename: Abdelrazek B
authors.initials: AB
authors.lastname: Abdelrazzak
authors.forename: David L
authors.initials: DL
authors.lastname: Stevens
authors.forename: Georg
authors.initials: G
authors.lastname: Bauer
authors.forename: Peter
authors.initials: P
authors.lastname: O'Neill
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hill
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D051381:Rats