Modification of N-methyl-N-nitrosourea initiated carcinogenesis in the rat by subsequent treatment with antioxidants, phenobarbital and ethinyl estradiol.

The modifying effects of butylated hydroxyanisole (BHA), sodium L-ascorbate (SA), phenobarbital (PB) and ethinyl estradiol (EE) were studied by their administration to F344 rats subsequent to initiation with N-methyl-N-nitrosourea (MNU), a wide-spectrum carcinogen inducing tumors in many organs. Rats were initially given 4 doses of MNU (50 mg/kg) intraperitoneally within a 2-week period and then placed on a diet containing BHA (1%), SA (5%), PB (0.05%) or EE (0.001%) for 23 weeks prior to killing. Since the experiment was based on a whole body concept of carcinogenesis, all major organs were examined histologically and histochemically for any preneoplastic lesions. BHA enhanced forestomach and urinary bladder carcinogenesis as did SA also for the urinary bladder, whereas PB enhanced the induction of gamma-glutamyl transpeptidase positive (gamma-GT+) foci in the liver and also the incidence of thyroid carcinoma and forestomach carcinoma. In contrast, EE inhibited the induction of thyroid tumors, malignant lymphoma or leukemia. Thus these compounds, when given after initiation of many organs by a single carcinogen, exert an influence on the site of tumor development by, as yet unknown, organotropic modifying effects.