PARENT SESSION
1:30 PM to 3:30 PM
Sunday, April 21, 2002
Poster Session 7 Radioprotectors
Room: Nevada Exhibition Center
(P12-113) Early and late changes in radiation-induced gene expression arrays following radioprotection with amifostine.
Hilyard, Edward1, Gelhaus, Martin1, Ghose, Shameek1, Dobson, Michael1, Seed, Thomas*,1, 1 Radiation Casualty Management, Bethesda, MD
ABSTRACT-
Differential cDNA gene expression arrays have been utilized to examine early (1 d) and late (63 d) occurring changes within hematopoietic tissues of sublethal (3 Gy) 60Co gamma irradiated (0.6Gy/min) or sham-irradiated (0 Gy) C3H/HEN mice that were administered either radioprotectant, amifostine (100 mg/kg), or drug vehicle 30 min prior to exposure. Sublethal irradiation initiated both early and late-arising gene responses that were both specific and global in nature, with some responses significantly modified by amifostine. Of the early occurring global changes, ~12% of the 588 genes analyzed were up-regulated 24 hrs following 3 Gy. However, with amifostine prophylaxis, ~74% of these up-regulated genes were significantly dampened in activity. Similar late-occurring changes were noted, although a smaller fraction (~9 %) of genes were up-regulated by 3 Gy, and a smaller fraction of these genes were dampened by amifostine prophylaxis. Similarly, amifostine tended to dampen the down-regulation exhibited by the cohort of responsive genes. In addition to these global responses, specific genes and gene groups were identified having distinctive early and late response patterns. For example, in a constellation of protoonogenes, 100% (7/7) were significantly up-regulated 1 day after 3 Gy and all were significantly suppressed in activity by amifostine prophylaxis. Sixty three days following irradiation, however, only three genes (50%) were still up-regulated and only one significantly so. However, in contrast to the early dampening responses elicited by amifostine, the late effects of amifostine prophylaxis appeared to be one of enhancing protooncogene activity: greater than seventy percent (5/7) of the protooncogenes examined exhibited heightened activity following amifostine prophylaxis and 3 Gy irradiation. Specific gene responses by c-erbA and PTMA were representative of the protooncogene group, whereas responses by c-fms and lck protooncogenes illustrated the more global gene responses. In sum, this study serves to illustrate the potential power and utility of the differential display cDNA array assay in identifying and dissecting critical gene events altered by ionizing radiation over a time course and selectively targeted and modulated by radioprotective, pharmacologic agents such as amifostine.
KEYWORDS: cDNA arrays, hematopoiesis, amifostine, radioprotectors