WR-1065 AND RADIOPROTECTION OF VASCULAR ENDOTHELIAL-CELLS .1. CELL-PROLIFERATION, DNA-SYNTHESIS AND DAMAGE

Normal tissue toxicity limits radiation therapy and could depend on th e extent of damage to the vascular endothelium. Aminothiols such as WR -1065 [N-(2-mercaptoethyl)-1,3-diaminopropane] provide radioprotection for normal tissues, but little is known about how the aminothiols spe cifically affect the endothelium. Bovine aortic endothelial cells in c ulture were exposed to WR-1065 for 2 h before irradiation (Cs-137 gamm a rays, 1 Gy/min). Alone, WR-1065 demonstrated an antiproliferative ef fect that was related to dose (0.5-4 mM) and was evident by lowered co unts of adherent cells 48 h after exposure. WR-1065 was clearly radiop rotective when assessed by colony formation and incorporation of [H-3] thymidine. However, when the number of adherent cells was evaluated, r adioprotection appeared to be slight and evident only in logarithmical ly growing cells. WR-1065 at 2 mM suppressed single-strand DNA breaks after 3 Gy by 22% and double-strand breaks after 9 Gy by 47%. Also in the irradiated cells, WR-1065 more than doubled the rate of progressio n of cells from G(1) to S phase. WR-1065 pretreatment elevated cellula r glutathione (GSH) content more than twofold. Although pretreatment w ith buthionine sulfoximine inhibited the elevation of GSH, the radiopr otective impact of WR-1065 on total DNA strand breaks and colony forma tion was unaffected. These results suggest that WR-1065 may enable tis sue recovery from irradiation by promoting the replication of endothel ial cells, possibly by mechanisms independent of GSH. (C) 1996 by Radi ation Research Society