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Besides its use in the treatment of a variety of presumed autoimmune diseases, azathioprine is given as an immunosuppressant to patients who have had renal transplants. Though epidemiological studies have provided "sufficient" evidence of its carcinogenicity in humans, the carcinogenicity tests in rats and mice are considered to be inconclusive because of limitations in the design and results of these tests (IARC, 1981, 1987). Rosenkranz and Klopman (1991) used the CASE program to identify the structural features responsible for its carcinogenicity. They concluded that this genotoxic chemical was a carcinogen due to the presence of the molecular fragment C"-S-C=. The finding was based on the presence of this biophore fragment in five other compounds, namely: 2-amino-5-nitrothiazole, 2-mercaptobenzothiazole, fenthione, 4,4'-thiodianiline and nithiazide. Recently, Ashby (1992) has expressed concern over the validity of their findings. With the aim of contributing to this debate on the mechanism of carcinogenicity of azathioprine, we have analyzed the structural basis of carcinogenicity of azathioprine and the five support compounds using the carcinogenicity predictor of our toxicity prediction program, TOPKAT. The results, more in line with Ashby's concerns, indicate that no molecular fragment involving the S atom is associated with the carcinogenic properties of these molecules. According to the TOPKAT program the carcinogenicity, if any, of azathioprine is due to the NO2 electrophile because its other major structural features are found to be either associated with non-carcinogenicity or do not discriminate carcinogens from non-carcinogens.

THE preceding papers in this series by Cuckler et al. (1956) and Cuckler and Malanga (1956) showed that nithiazide [1-ethyl-3-(5-nitro-2-thiazolyl) urea] was the most effective antihistomonad (blackhead) agent in a series of closely related compounds. Furthermore, nithiazide was found more potent and less toxic than 2-amino-5-nitrothiazole in experimental enterohepatitis. This paper presents the results of studies on the absorption and excretion of nithiazide by turkeys and chickens and the effect of this compound on their growth, maturation and reproduction. These studies have shown that chickens and turkeys tolerated nithiazide better than 2-amino-5-nitrothiazole or 2-acetylamino-5-nitrothiazole, chemically related compounds. MATERIALS AND METHODS The turkeys and chickens used in these studies were obtained from commercial sources when 1 day of age. Straight run Beltsville White turkeys and White Rock cross chicks were used in the laboratory experiments, and the birds were kept in electrically heated battery brooders. The floor-pen growth trials involved White . . .

Summary1. The data presented show that nithiazide [1-ethyl-3-(5-nitro-2-thi-azolyl) urea | was more potent and less toxic than 2-amino-5-nitrothiazole when fed to turkeys with enterohepatitis. 2. Nithiazide was most effective when administered prior to infection or beginning 3 to 7 days after infection. It prevented mortality from enterohepatitis produced either by oral exposure to cecal worm eggs or by rectal inoculation of Histomonas meleagridis cultures. Nithiazide may be administered in the feed or water and is equally effective in either form. 3. The therapeutic feeding of rations containing 0.05% nithiazide, starting 3 days after infection, prevented mortality from infectious enterohepatitis which was lethal for 73% to 83% of the untreated control turkeys.

Summary1. The preparation of 1-mono-substituted and 1,1-disubstituted nitrothia-zolylureas has been described. 2. Antihisto-monad activity was demonstrated for mono-substituted thiazolylureas with not more than 4 carbon atoms. The 1-methyl compound was more toxic and less effective than the 1-ethyl derivative. The dimethyl compound was less toxic and also less effective than the mono-methyl compound. 3. In addition to therapeutic activity in enterohepatitis, nithi-azide [l-ethyl-3-(5-nitro-2-thiazolyl) urea] was found to have antitrichomonal activity but antimalarial, antitrypanosomal or anticoc-cidial activity was not demonstrable.