Evaluation of the effects of cotinine and nicotine-N'-oxides on the development of tumors in rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.

The effects of cotinine and nicotine-N'-oxides on tumor development in F344 rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide [(FANFT) CAS: 24554-26-5] were evaluated. When rats were 6 weeks old, FANFT in an agar diet was administered for a 6-week period. Subsequently, cotinine, trans-nicotine-N'-oxide, and a mixture of cis-nicotine-N'-oxide and trans-nicotine-N'-oxide in drinking water were given as promoters in concentrations of 0.1, 0.02, and 0.02%, respectively. These nicotine metabolites were offered ad libitum for 78 weeks. Control groups consisted of rats that received tap water with or without prior administration of FANFT. Cotinine, trans-nicotine-N'-oxide, and the mixture of cis- and trans-nicotine-N'-oxides were neither carcinogens nor promoters of urinary bladder tumors in rats initiated with FANFT. A reduced incidence of urinary bladder tumors was observed in FANFT-pretreated animals that also received a mixture of cis- and trans-nicotine-N'-oxides. FANFT administration increased the incidences of mesothelioma of the peritoneum and thyroid tumors. Tumor formation in the tongue and palate observed in FANFT-treated rats was not affected by administration of these nicotine metabolites. There was, however, a significant increase in the incidence of forestomach tumors in rats that were initiated with FANFT and subsequently received either trans-nicotine-N'-oxide or a mixture of cis- and trans-nicotine-N'-oxides.

Indomethacin and poly I:C in the inhibition of carcinogen-induced bladder cancer in an experimental animal model.

Fischer rats, in whom superficial transitional cell cancers of the urinary bladder were induced by the carcinogen N-[4-(5- nitrofuryl )-2-thiazolyl] formamide, were inoculated intraperitoneally with either phosphate buffered saline, indomethacin (a prostaglandin synthetase inhibitor), poly I:C (an interferon inducer), or indomethacin together with poly I:C. While indomethacin alone appeared to have a significant albeit variable inhibitory effect on tumor size, poly I:C had a far more pronounced significant inhibitory effect. The combination of poly I:C and indomethacin together, however, led to the greatest inhibition in tumor growth, and in some instances, to tumor regression. Splenic lymphocytes from the same animals demonstrated enhanced natural cytotoxicity after treatment with poly I:C. Surprisingly, levels of natural cytotoxicity seen in animals treated with indomethacin and poly I:C together were lower than those seen with poly I:C alone. No enhancement of cytotoxicity could be demonstrated in vitro in lymphocytes from indomethacin-treated animals. Macrophages were also treated in this system under identical conditions. However, the activity of macrophages alone and of macrophages and lymphocytes together did not appear to be modified either by indomethacin alone or by the combination of prostaglandin synthetase inhibition and interferon induction together, the combination of which in vivo was suggested to be most effective in controlling tumor progression. Further studies to determine timing of these interactions and doses of immune response modifiers in order to characterize mechanisms possibly at work in modifying tumor growth in this system therefore seem highly indicated.

Inhibition by aspirin of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced bladder carcinogenesis and enhancement of forestomach carcinogenesis.

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) is a potent urinary bladder carcinogen in the rat, and it can be metabolically activated in vitro by a variety of enzyme systems including aerobic cooxidation by prostaglandin H synthase. The latter enzyme is present in the rat bladder mucosa and can be inhibited by the oral administration of aspirin (ASA). To determine if ASA could inhibit the bladder carcinogenicity of FANFT, FANFT (0.2%) was co-administered in the diet with ASA (0.5%) for 12 weeks followed by 1 week of ASA only and then 56 weeks on control diet. 0.2% FANFT followed by control diet induced bladder carcinomas in 18 of 21 (87%) rats, but when ASA was co-administered, only 10 of 27 (37%) rats developed bladder carcinoma (p less than 0.001). However, forestomach tumors, not seen in rats fed only FANFT, developed in 7 rats fed FANFT plus ASA. No tumors occurred in control rats or those fed only ASA. Possible mechanisms, including the role of prostaglandin H synthase in FANFT metabolism, are discussed.

Aspirin inhibition of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced lesions of the urinary bladder correlated with inhibition of metabolism by bladder prostaglandin endoperoxide synthetase.

The effects of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) -induced urinary bladder lesions, endogenous bladder prostaglandin E2 synthesis, and the metabolism of FANFT by bladder epithelial microsomes were examined. Rats were fed 0.5% aspirin and/or a diet containing 0.1% or 0.2% FANFT. Bladder lesions were observed with light and scanning electron microscopy, and the prostaglandin E2 content of rat bladder was measured by radioimmunoassay. Metabolism of FANFT was measured by decreased absorbance at 400 nm. Aspirin inhibited the appearance of hyperplastic lesions induced by feeding 0.1% or 0.2% FANFT for 6 or 12 weeks. Aspirin reduced bladder prostaglandin E2 content at 1, 2, 6, and 13 weeks compared to corresponding control values. Rat and rabbit microsomal metabolism of FANFT were dependent upon specific fatty acid substrate and prevented by specific inhibitors (including aspirin) of prostaglandin endoperoxide synthetase. Other inhibitor and substrate specificity studies suggest that FANFT was not metabolized by xanthine oxidase, lipoxygenase, lipid peroxidation, or mixed-function oxidases. These results suggest that the metabolism of FANFT by prostaglandin endoperoxide synthetase may be involved in the metabolic activation of FANFT necessary for the induction of bladder cancer in rats.

Synthetic retinamides: effect on urinary bladder carcinogenesis by FANFT in Fischer rats.

The failure of N-ethylretinamide and N-(2-hydroxyethyl)retinamide to inhibit the incidence or severity of bladder carcinoma in female Fischer rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide supports the concept that the inhibition of bladder carcinogenesis by natural and synthetic retinoids is carcinogen-class specific.