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PARENT SESSION
1:30 PM to 3:30 PM
Wednesday, April 24, 2002
Poster Session 30 Bystander Effects
Room: Nevada Exhibition Center

(P35-352) Oxidative metabolism mediates bystander effects in -particle-irradiated normal human fibroblast cultures.

Azzam, Edouard*,1,3, de Toledo, Sonia1,3, Spitz, Douglas2, Little, John3, 1 New Jersey Medical School, Newark, NJ3 Harvard School of Public Health, Boston, MA2 University of Iowa, Iowa City, IA

ABSTRACT-
Induced genetic changes were shown to occur in bystander cells neighboring those that have been targeted by ionizing radiation, but the mechanisms underlying such effects are not well understood. The role of oxidative metabolism in producing bystander effects was investigated in confluent fibroblast cultures exposed to very low fluences of -particles. By western blotting and in situ immunofluorescence techniques, CuZn superoxide dismutase (CuZnSOD; 100 g/ml) inhibited the bystander-mediated up-regulation of p21Waf1 when added directly to irradiated cultures for 3 hours after irradiation. Increased SOD activity associated with vigorously washed cell pellets was observed. CuZnSOD also suppressed the induction of micronuclei, a measure of DNA damage, in bystander cells. Inhibition of these bystander effects with 0.2 M diphenyliodonium suggested that reactive oxygen species (ROS) derived from flavin containing oxidases were involved. Rapid activation of NFB, Raf1, ERK1/2, JNK and p38-MAPK and their effectors AP-1, ELK-1, p90RSK and ATF2 was observed in bystander cells from irradiated cultures; significant attenuation of these effects occurred in cultures treated with either CuZnSOD or catalase. Overall, the results support the hypothesis that ROS produced by metabolic processes involving flavin-containing oxidases contribute to bystander effects in low fluence -particle irradiated cell cultures. In addition, the role of nitric oxide and various cell permeable or cell impermeable nitroxides will be highlighted.

KEYWORDS: bystander effect, oxidative metabolism, alpha-particles, gene expression