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PubMed1976

Early lesions in experimental bladder cancer: experimental design and light microscopic findings.

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) fed to male and female Fischer rats at a dose of 0.2% of the diet induces lesions of the urinary bladder which progress from mild hyperplasia at 2 to 4 weeks, to moderate hyperplasia at 6 to 8 weeks, severe nodular and papillary hyperplasia at 10 to 14 weeks, and microinvasive carcinomas by 25 weeks as observed by light microscopy. Male Fischer rats fed FANFT for 2 to 4 weeks and then maintained on control diet show regression of the bladder lesions within 2 weeks to normal-appearing mucosa which persists through 50 weeks. Rats fed FANFT for 6 weeks show regression of the moderately hyperplastic epithelium to normal within 4 weeks after being placed on control diet which persists through 50 weeks. Rats fed FANFT for 8 to 10 weeks show regression of the hyperplastic bladder epithelium within 2 weeks of receiving control diet, but focal areas of mild hyperplasia are detectable through the 20th week of the experiment. By the 50th week the rats fed FANFT for 8 weeks all had moderate to marked hyperplasia, but the rats fed FANFT for 10 weeks had transitional cell tumors, one of which was invasive through the entire thickness of the bladder wall. The lesions present in rats fed FANFT for 12, 14, or 20 weeks continued to progress to invasive tumors (microinvasive or invasion of muscle) after the rats had been maintained on control diet through 50 weeks. Thus, the hyperplastic lesions developing through 6 weeks of FANFT administration appear to be reversible if FANFT is discontinued, but later lesions appear to be irreversible.

Animals↗
PubMed1991

Metabolism and disposition of bladder carcinogens in rat and guinea pig: possible mechanism of guinea pig resistance to bladder cancer.

The metabolism and disposition of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) were studied in rat and guinea pig. Rat is susceptible whereas guinea pig is resistant to FANFT-induced bladder cancer. Rats and guinea pigs were p.o. administered either 2-[14C]ANFT or 2-[14C]FANFT (100 mg/kg), and 18-h urine and feces were collected. Tissue distribution of radiolabel was determined. In both species, the highest concentrations of radioactivity expressed as nmol/g tissue were observed in the urine and intestines. Urinary metabolites were separated by high-performance liquid chromatography and radioactivity determined by radioanalytical detection. FANFT was not detected in urine from either species under any experimental condition. More ANFT was observed in urine following FANFT than ANFT administration. This deformylation-dependent excretion of FANFT was demonstrated in both species and has been previously described as renal metabolic/excretory coupling. Less ANFT, the carcinogen more proximate than FANFT, is excreted in guinea pigs compared with rats. A unique ANFT metabolite was identified in guinea pig but not rat urine. This metabolite represented 80 and 18% of radioactivity recovered in guinea pig urine following ANFT and FANFT administration, respectively. A metabolite produced by guinea pig liver and kidney microsomes in the presence of uridine-5'-diphosphoglucuronic acid coeluted with this unique metabolite. The urinary metabolite was characterized using hydrolytic enzymes, acid hydrolysis, and mass spectrometry and identified as an ANFT-N-glucuronide. A unique UDP-glucuronosyl-transferase appears to be responsible, at least in part, for the reduced amount of free ANFT excreted by guinea pigs compared with rats. Reduced levels of urinary ANFT observed in guinea pigs may partially explain the resistance of this species to FANFT-induced bladder cancer.

Animals↗
PubMed1979

Promoting effect of saccharin and DL-tryptophan in urinary bladder carcinogenesis.

The existence of at least two stages in bladder carcinogenesis was evaluated in male Fischer rats using N-[14-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) fed for six weeks at a level of 0.2% of the diet as the initiator. Sodium saccharin and DL-tryptophan were fed at levels of 5 and 2% of the diet, respectively, as possible promoting chemicals, and they were fed either immediately after FANFT administration or after six weeks of FANFT plus six weeks of control diet. All surviving rats were killed at the end of two years. Both chemicals significantly increased the incidence of bladder tumors following FANFT feeding compared to six weeks of FANFT feeding followed by control diet, and the results were similar whether saccharin or tryptophan feeding was started immediately after FANFT feeding was concluded or after a six-week delay. Saccharin was considerably more potent as a promoting agent than was tryptophan, inducing higher incidences of bladder tumors and having a shorter latent period. Long-term administration of FANFT induced a 100% incidence of bladder cancer. Sequential epithelial changes were observed by scanning and transmission electron microscopy as well as by light microscopy. Pleomorphic microvilli were present on the superficial cells of all tumors examined and on the surface cells of hyperplastic bladder epithelium after six weeks of FANFT plus six weeks of saccharin, but not after six weeks of FANFT and six weeks of control diet. Rats fed only saccharin tryptophan, or control diet did not have bladder tumors or pleomorphic microvilli on bladder epithelium. These data suggest that saccharin and tryptophan might act as tumor-promoting agents during bladder carcinogenesis.

Animals↗
PubMed1981

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.

Animals↗
PubMed1984

Effect of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced epithelial proliferation in the urinary bladder and forestomach of the rat.

The co-administration of aspirin with N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) to rats resulted in a reduced incidence of FANFT-induced bladder carcinomas but a concomitant induction of forestomach tumors. An autoradiographic study was performed on male F-344 rats fed diet containing FANFT at a level of 0.2% and/or aspirin at a level of 0.5% to evaluate the effect of aspirin on the increased cell proliferation induced by FANFT in the forestomach and bladder. FANFT-induced cell proliferation in the bladder was significantly suppressed by aspirin co-administration after 4 weeks but not after 12 weeks. In the forestomach, and also in the liver, aspirin did not affect the FANFT-induced increase in labeling index. The present results are consistent with the carcinogenicity experiment suggesting that different mechanisms are involved in FANFT carcinogenesis in the bladder and forestomach, and that aspirin's effect on FANFT in the forestomach is not due to an irritant effect associated with increased cell proliferation. Also, there appears to be an adaptation by the rats to the chronic ingestion of aspirin.

Animals↗
PubMed1979

Effect of dose on urinary bladder carcinogenesis induced in F344 rats by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.

Because of the utility of the N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) rat model in the study of bladder cancer, the effect of dose on FANFT-induced bladder carcinogenesis was evaluated. Weaning male F344 rats were given FANFT in the diet at doses of 0.1, 0.05, 0.01, 0.005, 0.001, and 0.0005% for 30 weeks and then a control diet for 22 weeks. A control group received only the control diet throughout the experiment. Papillary tumors were present at the higher doses, hyperplasia of various degrees of severly was present at the intermediate doses, and minimal hyperplasia was observed in 4 of 16 rats at the 0.005% dose; no mucosal abnormalities were observed at the two lower doses or in the control group. Bladder epithelium from selected animals was also examined by scanning electron microscopy (SEM) after 10 weeks and again at the end of the experiment. Hyperplastic mucosa with pleomorphic microvilli similar to that previously demonstrated for 0.2% FANFT was observed at 10 weeks in rats fed 0.1% FANFT. Hyperplastic mucosa with pleomorphic microvilli was also observed at 52 weeks in rats fed 0.1% and 0.05% FANFT. Hyperplastic mucosa without pleomorphic microvilli was observed in rats fed 0.01 and 0.005% FANFT. The bladder appeared normal by light microscopy and SEM at the two lower doses and in the control group at both the 10- and 52-week intervals. A dose relationship was thus demonstrated for FANFT-induced bladder carcinogenesis in male F344 rats, and more severe surface changes were observed by SEM as the dose increased.

Animals↗
PubMed1987

Enhancement of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced carcinogenesis by urinary tract infection in rats.

Epidemiological studies suggest that urinary tract infection is an important risk factor in the development of bladder cancer. Chronic urinary tract infection in rats is associated with urothelial hyperplasia and papillomatosis. In the Sprague-Dawley strain, exposure to the 5-nitrofuran, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), is associated in particular with the development of renal pelvic tumors. The present study was designed to evaluate whether chronic urinary tract infection could enhance tumor development in FANFT-induced urinary tract carcinogenesis. One hundred forty-four female Sprague-Dawley rats were divided into the following groups. Group 1 received 0.2% FANFT in the diet for 7 wk followed by control diet. Group 2 received 0.2% FANFT in the diet for 7 wk followed by control diet. One wk after completion of FANFT administration, the suspension of 0.5 ml of Escherichia coli (06K13H1) was injected into the bladder through the urethra. Group 3 received 0.2% FANFT in the diet for 7 wk followed by control diet. One wk after completion of FANFT administration, a suspension of heat-killed E. coli (06K13H1) was injected into the bladder through the urethra. Group 4 received a suspension of 0.5 ml of E. coli (06K13H1) through the urethra and received control diet throughout the experiment. Group 5 was fed control diet only. The experiment continued for 104 wk. A significantly higher number of urinary tract tumors, particularly of the renal pelvis, was recorded in Group 2 compared to Groups 1, 3, 4, and 5. The majority of the rats in Groups 2 and 4 had morphological signs of urinary tract infections, particularly pyelitis and/or pyelonephritis. Thus, a single injection of E. coli (06K13H1) into the bladder results in an enhancement of FANFT-induced urinary tract carcinogenesis in the Sprague-Dawley rat, especially for renal pelvic tumors. The formation of dimethylnitrosamine or other nitroso compounds from nitrates in the urine or increased cell proliferation due to chronic inflammation or both may be important pathogenetic factors in the tumor development.

Animals↗
PubMed1985

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.

Animals↗
PubMed1981

The effect of single dose N-methyl-N-nitrosourea on bladder carcinogenesis by N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide in rats.

The effect of a single intravesical dose of N-Methyl-N-Nitrosourea (MNU) on bladder carcinogenesis in Fischer rats by a suprathreshold dose of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) was studied. Animals were sacrificed periodically during the course of the study and the experiment was terminated 50 weeks. Carcinomas were first noted in the MNU + FANFT group at 35 weeks versus 37 weeks for the group receiving FANFT alone. At 50 weeks, carcinomas were seen in 40 of 49 animals in the MNU + FANFT group and in 40 of 48 animals in the FANFT group. Of the animals developing bladder carcinomas 50 per cent receiving MNU + FANFT and 32 per cent receiving FANFT had high grade tumors. Six per cent of the animals receiving MNU alone developed bladder carcinomas whereas none was seen in a control group. In this system, the addition of an inducing dose of MNU did not alter the induction rate or results of carcinogenesis by FANFT. There was a tendency for higher grade tumors in those animals receiving the inducing dose of MNU.

Animals↗
PubMed1989

Effects of sodium salts of phenobarbital and barbital on development of bladder tumors in male F344/NCr rats pretreated with either N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide or N-nitrosobutyl-4-hydroxybutylamine.

Promoting effects of sodium salts of phenobarbital (NaPB) and barbital (NaBB) on the development of bladder tumors were investigated in F344 male rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-nitrosobutyl-4-hydroxybutylamine (BBN). To initiate with FANFT, rats were fed 0.2% FANFT mixed in diet for either 2 or 6 weeks and 2 weeks later were offered diet containing 1000 ppm of NaPB or NaBB. Rats were killed either at 52 or 68 weeks of age. To initiate with BBN, rats were given 0.05% BBN in drinking water for 4 weeks and beginning 1 day later were fed NaBB mixed in diet at 1000 ppm for up to 52 weeks. NaBB promoted bladder carcinogenesis initiated by either FANFT or BBN; the incidence and average number of simple or preneoplastic nodular (PN) hyperplasias, papillomas, and carcinomas per 10 cm of urothelium were significantly increased in the groups receiving NaBB following exposure to FANFT for 6 weeks (p less than 0.05) or BBN for 4 weeks (p less than 0.01). No such effect was seen in rats fed FANFT for only 2 weeks. NaPB also significantly increased (p less than 0.05) the frequency of preneoplastic PN hyperplasias but not the average number of papillomas and carcinomas per 10 cm of urothelium in rats fed FANFT for 6 weeks. NaBB was an effective promoter of bladder carcinogenesis under these experimental conditions, as expected from its known promoting effect on transitional epithelium of the renal pelvis, but NaPB in contrast did not affect the incidence or multiplicity of bladder papillomas or carcinomas under these conditions. NaPB could be considered a promoter for bladder urothelium only by the less rigorous criterion that it increased the frequency of preneoplastic PN hyperplasia.

Animals↗
PubMed1984

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.

Animals↗
PubMed1988

Renal metabolic/excretory coupling.

Renal metabolic/excretory coupling is the enhancement of urinary excretion dependent upon renal metabolism. The nitrofurothiazoles, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), are model compounds used to study metabolic/excretory coupling. FANFT is deformylated to ANFT by renal deformylase enhancing ANFT excretion. In the rat, ANFT excretion after oral FANFT administration was 100-fold greater than ANFT excretion when ANFT was administered. FANFT and ANFT uptake into purified proximal tubules achieved equilibrium within 60 s and was demonstrated in nonviable tubules. FANFT partitioned into oil better than ANFT. Albumin inhibited FANFT and ANFT uptake into oil and decreased tubular uptake by 65%. Tubular FANFT uptake was threefold or greater than that of ANFT uptake with or without albumin. Renal deformylase was predominantly cytosolic and yielded apparent Km and Vmax of 6.7 microM and 6.1 nmol ANFT.min-1.mg protein-1, respectively. Deformylase activity was abolished by boiling, was specific for N-formylated compound, and was not altered by dinitrophenol treatment. Renal metabolic/excretory coupling for FANFT/ANFT combines energy-independent uptake with metabolism (deformylation), resulting in enhanced urinary ANFT excretion.

Animals↗
PubMed1976

Early lesions in experimental bladder cancer: scanning electron microscopy of cell surface markers.

The administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) at a dose of 0.2% of the diet to male Fischer rats results in the appearance of urinary bladder epithelial lesions progressing from hyperplasia to invasive transitional cell carcinomas. These progressive epithelial alterations have been observed by scanning electron microscopy at 2-week intervals with special attention paid to cells covering the luminal surface. After 2 to 4 weeks of FANFT administration there is mild pleomorphism and moderate swelling of the surface cells giving a cobblestone appearance. The normal pattern of microridges of superficial transitional cells is still present, although occasional cells by 4 weeks of FANFT feeding are covered by small uniform microvilli. By 6 weeks these changes are more extensive and more cells are covered with uniform microvilli. By 8 weeks, cells covered with pleomorphic microvilli are found in discrete foci, and by 10 weeks nodular or papillary lesions are present. The 2- and 4-week lesions regress to normal within 2 to 4 weeks of discontinuing FANFT administration, and the 6- and 8-week lesions regress toward normal in 4 to 6 weeks of being fed control diet. The 6-week lesions have regressed entirely to normal 44 weeks after FANFT was stopped, but the 8-week lesions have progressed to moderate or marked hyperplastic lesions by 42 weeks of control diet with pleomorphic cells covered with pleomorphic microvilli. The results of this study suggest that lesions are reversible up to and including 6 weeks of 0.2% FANFT in the diet, and that, by 8 weeks of 0.2% FANFT, irreversible lesions result which do not revert to normal after 42 weeks of control diet.

Animals↗
PubMed1987

Effect of L-tryptophan excess and vitamin B6 deficiency on rat urinary bladder cancer promotion.

To further evaluate the role of tryptophan and vitamin B6 in bladder carcinogenesis, male Fischer 344 rats were fed 0.2% N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) in semipurified diet or were given semipurified diet alone for 4 weeks. One week later, rats from each group were assigned for the remainder of the experiment to one of four experimental diets, labeled as follows: group 1, control semipurified; group 2, L-tryptophan excess (2%); group 3, vitamin B6-deficient (1.0 mg/kg diet); or group 4, L-tryptophan excess, plus vitamin B6-deficient diet. All surviving rats were killed at 80 weeks of the experiment. Throughout the study, body weights were reduced in the groups fed FANFT and, at 70 and 80 weeks, body weights were reduced in the groups given tryptophan excess. The incidence of urinary bladder carcinoma was highest in the group treated with FANFT, followed by diet with control tryptophan and vitamin B6 levels (40%). The disease incidence was reduced in the vitamin B6-deficient group (13%) and of an intermediate range in the groups fed a tryptophan excess with or without vitamin B6 deficiency (28-29%). Tumors at other sites were greatest in number in FANFT-treated rats fed vitamin B6-deficient diet with excess tryptophan and were significantly fewer in FANFT-treated rats fed vitamin B6-deficient diet alone. Animals given diet deficient in vitamin B6 consistently had depressed levels of alanine aminotransferase activity and plasma pyridoxyl phosphate. FANFT pretreatment decreased alanine aminotransferase activities in rats in some groups and the feeding of tryptophan had variable effects on alanine aminotransferase and plasma pyridoxyl phosphate levels. Urinary tryptophan metabolites were influenced by all treatments, but the results did not correlate with tumor yields. Urinary bladder ornithine decarboxylase activity was not altered in vitamin B6-deficient female rats. These results do not support the hypothesis that increased dietary L-tryptophan promotes bladder carcinogenesis in rats, but other dietary factors might modify the process following FANFT initiation.

Alanine Transaminase↗
PubMed1981

Microsomal nitroreductase activity of rabbit kidney and bladder: implications in 5-nitrofuran-induced toxicity.

Reductive metabolism of the aromatic nitro group of 5-nitrofurans is thought to be an important step in the mechanism of their toxicity. Microsomal nitroreductase activity with p-nitrobenzoic acid and N-[4-(5-nitro-2-furyl)-2-thiazolyl[formamide (FANFT) as substrates was assessed in the renal cortex, outer medulla, inner medulla, bladder transitional epithelial and non-epithelial bladder tissue. Cortex and transitional epithelial tissue contained the most p-nitrobenzoic acid reductase activity. However, FANFT reductase activity was similar in all areas tested except nonepithelial bladder tissue, which was 10% of the others. FANFT reduction was inhibited by oxygen, but not by carbon monoxide, allopurinol or aspirin and required NADPH. These results are consistent with NADPH-cytochrome c reductase catalyzed FANFT reduction. In medullary microsomes, the apparent Km and Vmax were 0.125 mM and 0.84 nmol/mg of protein per min, respectively. Transitional epithelial microsomes incorporated approximately 1 and 10% of the total [2-14C]FANFT metabolized into t-RNA and trichloroacetic acid-precipitable material, respectively. Two products of FANFT reduction were demonstrated by high-pressure liquid chromatography. One product was reversibly oxidized to FANFT and the other was tentatively identified by mass spectral analysis as an open chain nitrile. In view of the relatively low oxygen tension in the renal inner medulla and bladder mucosa, these results suggest that medullary and transitional epithelial nitro-reductases may be involved in the pathogenesis of 5-nitrofuran toxicity.

Animals↗
PubMed1980

Neovascularization in rats during urinary bladder carcinogenesis induced by N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide.

Neovascularization in inbred F344 rats during urinary bladder carcinogenesis induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) was examined by scanning electron microscopic observation of vascular casts. FANFT was fed to rats at a level of 0.2% of the diet for 6, 10, or 20 weeks, and vascular casts were examined in these rats at those times and after various times on control diets. Similar foci of vascular proliferation (types I and III) were observed after the use of FANFT as previously reported during bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. However, the vascular proliferations were observed to regress as the FANFT-induced epithelial proliferations regressed, similar to the observation of reversible hyperplasias induced by cyclophosphamide or ulceration. Type I vascular foci were present after 6 and 10 weeks, but no vascular lesions were seen through week 20 after these groups of rats were fed the control diet for 4 or more weeks. The epithelial lesions present after 6 and 10 weeks of FANFT feeding also regressed and the mucosa returned to normal as observed by light microscopy. Type III foci were present after 12 weeks and were observed through week 20 when epithelial tumors appeared. Rats fed FANFT for 10 weeks and then the control diet developed hyperplastic epithelial lesions and carcinomas by week 52, whereas those fed FANFT for 6 weeks had normal bladders through 52 weeks.

Animals↗
PubMed1981

Effect of L-tryptophan and sodium saccharin on urinary tract carcinogenesis initiated by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.

The effect of sodium saccharin (SAC) or L-tryptophan (LT) on urinary bladder carcinogenesis initiated by feeding N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for 4 weeks as 0.2% of the diet to male F344 weanling rats was evaluated. SAC was fed as 5% of the diet, and LT was 2% of the diet. FANFT fed for 4 weeks followed by 100 weeks of control diet did not produce any carcinomas; one of 25 rats developed a bladder papilloma. Of 26 rats fed SAC for 100 weeks after FANFT, two developed papillomas, and five developed carcinomas (p less than 0.03). Of 26 rats fed LT for 100 weeks after FANFT, three developed papillomas, and two developed carcinomas (p greater than 0.1) Eight rats fed FANFT for 72 weeks all developed bladder carcinomas, but rats fed control diet alone, control diet with SAC, or control diet with LT did not develop any bladder tumors. Scanning electron microscopic examination of Week 104 of the experiment showed the presence of pleomorphic microvilli on the bladder surface of some rats fed SAC of LT whether following 4 weeks of control diet alone or 4 weeks of FANFT. Four weeks of FANFT feeding, a lower dose than used previously in our studies, appears to be a subcarcinogenic level. Under these experimental conditions, the promoting activity of SAC is demonstrated with statistical significance. The results with LT were not statistically significant.

Animals↗
PubMed1981

Potentiation of dimethylhydrazine bowel carcinogenesis in rats.

An animal model of organ-specific chemical carcinogenesis has been used to study environmental effects on the incidence of human colorectal adenocarcinoma. Wistar/Furth weanling rats underwent connection of their urinary and fecal streams (ureterosigmoidostomy), connection of their urinary and fecal streams with proximal fecal diversion (rectal bladder), or sham operations. Age-matched, unoperated control and operated animals then received either no carcinogen, 1,2-dimethylhydrazine (DMH) 20 mg/kg body weight, s.c. once weekly for 16 weeks, N-[4-(5-nitro-2-furyl)-2-thiazolylformamide (FANFT) 0.2% of the feed for 16 weeks, or DMH + FANFT concurrently. Thirty-three weeks after carcinogen exposure, surviving animals were killed and examined for bowel and urinary bladder tumors. The incidence of adenocarcinoma of the colon adjacent to the junction between bladder and bowel was significantly higher in animals after ureterosigmoidostomy compared with animals whose fecal stream had been proximally diverted (14/22 vs. 0/34, P less than 0.001). This effect was not dependent upon chemical carcinogen exposure. Nonexposed animals still developed a significantly higher incidence of colon adenocarcinomas adjacent to their bladder-bowel junctions as compared with animals with proximal fecal diversion (5/8 vs. 0/13, P less than 0.01). In unoperated or sham operated animals, adenocarcinomas of the bowel occurred in 33% of DMH-treated animals and transitional cell carcinomas of the urinary bladder in 33% of the FANFT-treated animals. After concurrent exposure to both carcinogens, no increased incidence of bladder tumors was noted when compared with FANFT treatment alone. However, the number of animals with one or more adenocarcinomas of the bowel (22/30 vs. 17/50, P less than 0.001), the mean number of tumors per animal (2.1 +/- 0.2 vs. 1.1 +/- 0.1, P less than 0.01), and the invasiveness of the tumors were all increased after DMH + FANFT as compared with DMH exposure alone. The carcinogenic potential of direct bladder to bowel connection with intact fecal and urinary streams, and the potentiation by FANFT of DMH-induced colon carcinogenesis may have implications in the genesis of human colorectal cancer.

1,2-Dimethylhydrazine↗