ABSTRACT
The activity of a DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (AGT), was studied in gastric mucosa of 15 Macaca fascicularis monkeys before and during chronic oral exposure to the ethylating carcinogen N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in order to investigate possible causes of inter-individual differences in susceptibility to its gastrocarcinogenic effect. A wide range of AGT activity (307-1903 fmol/mg protein, mean 695) was found before treatment and it decreased during the first year of exposure (means 627, 479 and 452 fmol/mg protein respectively at 6, 12 and 18 months after the beginning of the experiment). The carcinogenesis study is under way and to date four monkeys with low initial AGT level in gastric mucosa died of gastric cancer. The relevance of AGT level measurement for prediction of individual susceptibility to ENNG is discussed.
Subject(s)
Carcinogens/toxicity , Gastric Mucosa/drug effects , Methylnitronitrosoguanidine/analogs & derivatives , Methyltransferases/metabolism , Administration, Oral , Animals , Carcinogens/administration & dosage , Female , Gastric Mucosa/enzymology , Macaca fascicularis , Male , Methylnitronitrosoguanidine/administration & dosage , Methylnitronitrosoguanidine/toxicity , O(6)-Methylguanine-DNA Methyltransferase , Stomach Neoplasms/chemically inducedABSTRACT
1,2-Dimethylhydrazine (DMH) was administered subcutaneously to nine Macaca fascicularis monkeys (6 males and 3 females) at doses of 16 mg/kg body weight, three times a month for two years. Colon cancer was detected in two male monkeys after total DMH doses of 1080 and 3696 mg (528 and 400 mg/kg body wt., respectively). A uterine tumor was induced in one female monkey which received 3648 mg of DMH (608 mg/kg body wt.). Latent periods of tumor development were 34, 47 and 55 weeks, respectively. Histologically, the colon tumors had the structure of adenocarcinoma in both cases and the uterine tumor was diagnosed as fibromyoma.
