DNA-DAMAGING AND CELL PROLIFERATIVE ACTIVITY OF 1-METHYL-1-NITROSOUREA IN RAT GLANDULAR STOMACH MUCOSA

The DNA damaging and cell proliferative activity of 1-methyl-1-nitroso urea (MNU), a glandular stomach carcinogen, was studied in the pyloric mucosa of male F344 rats after administration by gastric tube. DNA da mage was measured with unscheduled DNA synthesis (UDS) and DNA single strand scission as markers, while cell proliferation was measured with replicative DNA synthesis (RDS) and ornithine decarboxylase (ODC) as markers. MNU at doses of 30 and 60 mg/kg body wt and 80 min after admi nistration dose-dependently induced UDS (49 and 79 (0 dose, 19) dpm/mu g DNA) measured by liquid scintillation counting in the presence of h ydroxyurea (an inhibitor of RDS). RDS (DNA synthesis in the absence of hydroxyurea; 239 dpm/mu g DNA at 0 dose) did not increase at that tim e. MNU at doses of 10 and 60 mg/kg body wt and 2h after administration dose-dependently induced DNA single strand scission of 8.2 and 43.5 ( 0 dose, 1.4) elution rate constant (x10(-3)/ml). MNU at doses of 30 an d 60 mg/kg body wt and 24h after administration dose-dependently induc ed an increase in RDS (1362 and 2393 (0 dose, 682) dpm/mu g DNA). MNU at doses of 60, 90 and 120 mg/kg body wt and 24h after administration dose-dependently induced an increase in ODC activity (22.0, 29.4 and 3 8.4 (0 dose, 6.3) p mol CO2/30 min/mg protein). These results suggest that MNU has possible tumor initiating activity (UDS and DNA single st rand scission) and tumor promoting activity (RDS and ODC) in rat stoma ch mucosa.