title: WR-1065 and radioprotection of vascular endothelial cells. I. Cell proliferation, DNA synthesis and damage.
abstract: Normal tissue toxicity limits radiation therapy and could depend on the 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 specifically affect the endothelium. Bovine aortic endothelial cells in culture were exposed to WR-1065 for 2 h before irradiation (137Cs gamma rays, 1 Gy/min). Alone, WR-1065 demonstrated an antiproliferative effect that was related to dose (0.5-4 mM) and was evident by lowered counts of adherent cells 48 h after exposure. WR-1065 was clearly radioprotective when assessed by colony formation and incorporation of [3H]thymidine. However, when the number of adherent cells was evaluated, radioprotection appeared to be slight and evident only in logarithmically 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 progression of cells from G1 to S phase. WR-1065 pretreatment elevated cellular glutathione (GSH) content more than twofold. Although pretreatment with buthionine sulfoximine inhibited the elevation of GSH, the radioprotective impact of WR-1065 on total DNA strand breaks and colony formation was unaffected. These results suggest that WR-1065 may enable tissue recovery from irradiation by promoting the replication of endothelial cells, possibly by mechanisms independent of GSH.
authors.affiliation: Department of Medicine, Rush University Medical College, Chicago, Illinois 60612, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Rubin
authors.forename: E A
authors.initials: EA
authors.lastname: Drab
authors.forename: H J
authors.initials: HJ
authors.lastname: Kang
authors.forename: F E
authors.initials: FE
authors.lastname: Baumann
authors.forename: E R
authors.initials: ER
authors.lastname: Blazek
mesh_terms: D000818:Animals; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000528:radiation effects*; D005720:Gamma Rays; D005978:Glutathione / Q000502:physiology*; D008297:Male; D008624:Mercaptoethylamines / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*
chemical_list: D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D005978:Glutathione