Enhancing effects of sodium phenobarbital and N,N-dibutylnitrosamine on tumor development in a rat wide-spectrum organ carcinogenesis model

Abstract

A wide-spectrum organ carcinogenesis model for detection of cancer modifiers in various organs was assessed in F344 male rats. After sequential treatment with diethylnitrosamine, N-methylnitrosourea, and dihydroxy-di-N-propylnitrosamine, rats were fed 500 p.p.m. sodium phenobarbital (PB: carcinogen for the liver, promoter for the thyroid) in the diet or 50 p.p.m. N,N-dibutylnitrosamine (DBN: carcinogen for the upper digestive tract, liver and urinary bladder) in the drinking water. Upon histopathological investigation at experimental weeks 18 and 24, PB was found to increase significantly the incidences of hyperplasias and adenomas of the thyroid and the numbers and areas of placental glutathione S-transferase-positive foci in the liver. DBN increased the lung tumor incidences at week 18, and brought about significant increases in both numbers and areas of lung tumors per rat at week 24. Furthermore, DBN enhanced the occurrences of hyperplasias and papillomas of the esophagus as well as hyperplasia for the forestomach at both time points. In addition, significant numbers of esophageal carcinomas and lingual papillomas developed in the group given DBN after pretreatment with the three carcinogens at week 24. Assessment of lesion yield thus clearly revealed enhancement of carcinogenesis by the test chemicals in their respective target organs, indicating the advantage of the wide-spectrum organ carcinogenesis model for detection of cancer modifiers within a limited time period in multiple organs.