RESUMEN
Uroplakins are the major integral membrane proteins synthesized in terminally differentiated, superficial urothelial cells. Alteration of cell differentiation during rat urinary bladder carcinogenesis was analyzed immunohistochemically for the expression of uroplakins. Expression of uroplakins was compared in N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT)-, uracil-, sodium saccharin- or sodium ascorbate-induced urothelial simple hyperplasia, papillary-nodular hyperplasia, papilloma and carcinoma. In controls, uroplakins were located only in superficial cells, especially the luminal surface membrane. In FANFT-induced hyperplasia, including simple hyperplasia, intermediate cells also stained and the staining pattern was disorderly and intermittent. In uracil-induced simple hyperplasia, intermediate cells were stained but in an orderly fashion. In sodium saccharin- or sodium ascorbate-induced simple hyperplasia, superficial cells were swollen but alterations were not observed in the staining pattern. In carcinoma induced by FANFT and uracil, uroplakin expression was very disorderly and focal, usually with no expression on surface cells. It appears that disorderly differentiation is an index of bladder malignancy and is an early event in FANFT-induced lesions but a late event in uracil-, sodium saccharin- and sodium ascorbate-induced lesions.
Asunto(s)
Glicoproteínas de Membrana/análisis , Proteínas de la Membrana/análisis , Neoplasias de la Vejiga Urinaria/química , Animales , FANFT/toxicidad , Masculino , Ratas , Ratas Endogámicas F344 , Sacarina/toxicidad , Uracilo/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Uroplaquina II , Uroplaquina IIIRESUMEN
The effects of indomethacin on the urinary bladder and renal pelvis in rats treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) were studied. Two hundred female Sprague-Dawley rats were divided into four groups. Group 1 received control diet without added chemicals. Group 2 was treated with indomethacin (1 mg/kg per day) in the drinking water throughout the experiment. Groups 3 and 4 received 0.2% FANFT in the diet for seven weeks followed by control diet. In addition to FANFT, Group 4 received indomethacin, 1 mg/kg per day, for the entire experiment. The rats were sacrificed after 92 weeks. There were no urothelial tumors in the control group, one renal pelvic tumor in the indomethacin group, 4 tumors in the FANFT group and 10 urothelial tumors in the FANFT + indomethacin group. The difference between Groups 3 and 4 was statistically significant (P < 0.05). Moderate and severe hyperplasia of the renal pelvic and papillary epithelium was found in 15 of 48 rats in Group 2 (indomethacin only) as compared with 6 of 49 control rats (P < 0.05). Moderate and severe hyperplasia was equally frequent in Groups 3 and 4 (14 and 17 animals in each group, respectively). Twenty-four rats in Group 2 had mammary tumors as compared to 12 animals in Group 1 (P < 0.01). Five of the tumors in Group 2 were adenocarcinomas. There was no difference between the number of mammary tumors in Groups 3 and 4 (36 and 32 animals in each group, respectively). The results suggest that indomethacin enhances FANFT-induced urinary tract carcinogenesis. Indomethacin also seems to exert some tumorigenic activity in the mammary gland.
Asunto(s)
Cocarcinogénesis , FANFT/toxicidad , Indometacina/toxicidad , Neoplasias Urológicas/inducido químicamente , Animales , Peso Corporal/efectos de los fármacos , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Transicionales/inducido químicamente , Sinergismo Farmacológico , Femenino , Hematuria/inducido químicamente , Pelvis Renal/efectos de los fármacos , Neoplasias Mamarias Experimentales/inducido químicamente , Ratas , Ratas Sprague-Dawley , Neoplasias de la Vejiga Urinaria/inducido químicamenteRESUMEN
Extrapolation of results from rodent bioassays involving high-dose exposures to possible carcinogenic risk in humans exposed to low doses is based on the assumptions of species relevance and high- to low-dose extrapolation. For genotoxic chemicals, such as 2-acetylaminofluorene and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, these assumptions appear to be appropriate, although the dose response can be greatly modified by cell proliferation effects of these chemicals at high doses. In contrast, nongenotoxic chemicals, such as chemicals causing urinary calculi or sodium saccharin and related sodium and potassium salts, frequently are carcinogenic only at high doses and/or only in specific species. Consequently, for extrapolation of results for nongenotoxic chemicals these assumptions may not be appropriate.
Asunto(s)
Pruebas de Carcinogenicidad , Modelos Animales de Enfermedad , 2-Acetilaminofluoreno/toxicidad , Animales , Cocarcinogénesis , FANFT/toxicidad , Femenino , Humanos , Masculino , Ratones , Ratas , Ratas Endogámicas F344 , Sacarina/toxicidad , Cálculos Urinarios/inducido químicamenteRESUMEN
A multistage, probabilistic, biologically based model of carcinogenesis has been developed involving qualitative and quantitative aspects of the process. A chemical can affect the risk of cancer by directly damaging DNA and/or increasing the number of cell divisions during which errors in DNA replication can occur. Based on this model, carcinogens are classified as genotoxic versus nongenotoxic; nongenotoxic chemicals are further divided on the basis of whether or not they act through a specific cell receptor. Nongenotoxic compounds, particularly those acting through a nonreceptor mechanism, are likely to have dose and/or species-specific thresholds. This classification also implies the existence of chemicals that will be carcinogenic at high doses in animal models, but because of dose and/or mechanistic considerations, will not be carcinogenic to humans at levels of exposure. N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) and 2-acetylaminofluorene (AAF) are classical genotoxic bladder carcinogens that also cause proliferative effects at higher doses. Although there is an apparent no-effect level for the urinary bladder carcinogenicity of these two compounds at low doses, in reality, DNA adducts form at these low levels, and it is likely that there is a cancer effect (no threshold), but it is below the level of detection of the bioassay. These conclusions are based on studies involving multiple doses and time points in rodents, including results from the ED01. Pellets implanted directly into the rodent bladder lumen or calculi formed in the urine as a result of an administered chemical cause abrasion of the urothelium, and a marked increase in cell proliferation and cell number, and ultimately tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
División Celular , Modelos Biológicos , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias de la Vejiga Urinaria/patología , 2-Acetilaminofluoreno/toxicidad , Animales , División Celular/efectos de los fármacos , Cocarcinogénesis , FANFT/toxicidad , Femenino , Humanos , Masculino , Factores de RiesgoRESUMEN
The formation of thioether conjugates is an important pathway for inactivation of certain carcinogens. This study assessed the mechanism by which the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT) forms a glutathione conjugate (ANFT-SG). Peroxidatic metabolism of ANFT, in the presence of glutathione, results in ANFT-SG formation. Both prostaglandin H synthase and horseradish peroxidase can catalyze this reaction. Metabolism of the reducing co-substrates ANFT, phenol, and aminopyrine elicit increases in oxidized glutathione (GSSG). ANFT-SG formation is potentiated by phenol and aminopyrine. tert-Nitrosobutane (tNB), a thiyl radical trap, prevented increases in both GSSG and ANFT-SG. Increasing concentrations of ANFT elicited corresponding increases in both GSSG and ANFT-SG. Peroxidatic metabolism of ANFT in the presence of glutathione, but not in the absence of glutathione, resulted in oxygen uptake. The formation of GSSG and oxygen uptake are consistent with the presence of thiyl radicals during ANFT metabolism. 5,5-Dimethyl-1-pyrroline N-oxide, a thiyl radical trap, was not as effective as tNB in inhibiting the formation of ANFT-SG and GSSG. Ascorbic acid, a reducing cosubstrate and antioxidant, was very effective in preventing ANFT-SG and GSSG formation, while the strong nucleophile methionine was ineffective. To clarify effects of different test agents, their effects on aminopyrine cation radical formation were assessed. Results are consistent with ANFT reacting with thiyl radicals to form ANFT-SG. ANFT appears to be a thiyl radical trap. Peroxidatic metabolism of ANFT probably results in the formation of a cation radical rather than a carbon-centered radical.
Asunto(s)
Carcinógenos/química , FANFT/análogos & derivados , Sulfuros/química , Neoplasias de la Vejiga Urinaria/inducido químicamente , Carcinógenos/toxicidad , FANFT/química , FANFT/toxicidad , Radicales Libres , Glutatión/metabolismo , Peroxidasa de Rábano Silvestre/metabolismo , Oxígeno/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismoRESUMEN
N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) administration to rats followed by sodium saccharin results in transitional cell carcinomas of the bladder, of which 24% harbor an activated H-ras gene. Since 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) is the mutagenic and carcinogenic metabolite of FANFT in vivo, we wished to examine ras activation in in vitro ANFT-transformed rat bladder epithelial cells as well as four cell lines established in culture from in vivo FANFT-induced rat bladder tumors. Screening by Western blotting revealed no enhanced levels of p21ras in ANFT-transformed cells nor in cells established in culture from FANFT-induced rat bladder carcinomas. Further investigations using immunohistochemical staining with a different pan-reactive p21 monoclonal antibody (Cetus Corporation) specific for this method, however, showed two groups of cells from FANFT-induced rat bladder tumors had enhanced immunoreactivity. Apart from this, p21ras expression of most of the cells groups varied little from the controls. We examined the reported hot spots (exons 1 and 2) of each of the ras genes (H-, K- and N-ras) by direct sequencing of amplified DNA. No mutations were present. We conclude, therefore, that ANFT transformation of primary rat bladder epithelial cells in vitro may not in this case be mediated by ras activation, although this is difficult to determine since others have observed that optimal culture conditions can select for certain populations of cells without ras activation.
Asunto(s)
Carcinógenos/toxicidad , Transformación Celular Neoplásica , FANFT/análogos & derivados , FANFT/toxicidad , Genes ras , Neoplasias de la Vejiga Urinaria/genética , Animales , Secuencia de Bases , Western Blotting , Transformación Celular Neoplásica/genética , Células Cultivadas , ADN , Células Epiteliales , Inmunohistoquímica , Datos de Secuencia Molecular , Oligonucleótidos , Reacción en Cadena de la Polimerasa , Ratas , Vejiga Urinaria/citología , Neoplasias de la Vejiga Urinaria/inducido químicamenteRESUMEN
To establish a rat urinary bladder carcinogenesis model in vitro, primary rat bladder epithelial cells were grown in media containing 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), the water-soluble metabolite of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT), for 4 weeks followed by long-term (4-7 months) exposure to control medium, sodium saccharin (NaS), or urea. Another set of cultures were exposed to ANFT, NaS and urea simultaneously. Several phenotypic changes were observed in the chemically exposed cell cultures, namely differences in cell morphology, increased growth rate and the ability to grow on plastic instead of rat-tail collagen support. All of the chemically exposed cultures were anchorage independent except one of those treated with NaS. The ANFT-treated cells followed by control medium or urea and cells treated with ANFT, NaS and urea were tumorigenic when transplanted to nude mice, whereas NaS or ANFT followed by NaS treatment were not. The tumors were carcinomas and their epithelial differentiation was verified by strong positive staining for cytokeratin. These studies demonstrate the urothelial transforming capability of ANFT in cell culture without the necessity for a long exposure to a secondary chemical.
Asunto(s)
Carcinógenos/toxicidad , Transformación Celular Neoplásica/inducido químicamente , FANFT/análogos & derivados , Neoplasias de la Vejiga Urinaria/inducido químicamente , Vejiga Urinaria/efectos de los fármacos , Animales , Células Cultivadas , Sinergismo Farmacológico , Células Epiteliales , Epitelio/efectos de los fármacos , FANFT/toxicidad , Femenino , Masculino , Ratones , Ratones Endogámicos , Ratones Desnudos , Trasplante de Neoplasias , Ratas , Ratas Endogámicas F344 , Sacarina/toxicidad , Urea/toxicidad , Vejiga Urinaria/citologíaRESUMEN
Ochratoxin A is ubiquitous in regions where Balkan endemic nephropathy is common. It damages the kidney cortex in a range of experimental animals and induces renal parenchymal carcinoma in mice, but it is not a potent carcinogen, nor is there experimental evidence to link it to upper urothelial carcinoma (UUC). A model UUC can be induced experimentally in rodents by urothelial initiation, followed by an acutely induced papillary necrosis. This two-stage experimental model may help to clarify the role of ochratoxin A in initiating or promoting upper urothelial cells and increase our understanding of the development of UUC in patients with Balkan endemic nephropathy.
Asunto(s)
Analgésicos/efectos adversos , Nefropatía de los Balcanes , Modelos Animales de Enfermedad , Neoplasias Renales/inducido químicamente , Necrosis Papilar Renal/inducido químicamente , Neoplasias Ureterales/inducido químicamente , Animales , Butilhidroxibutilnitrosamina/análogos & derivados , Butilhidroxibutilnitrosamina/toxicidad , Pruebas de Carcinogenicidad , Carcinógenos/toxicidad , Cocarcinogénesis , Epitelio/efectos de los fármacos , Epitelio/patología , Europa (Continente)/epidemiología , FANFT/toxicidad , Humanos , Hiperplasia , Incidencia , Neoplasias Renales/epidemiología , Modelos Biológicos , Micotoxicosis/complicaciones , Micotoxicosis/epidemiología , Ocratoxinas/efectos adversos , Ocratoxinas/toxicidad , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/patología , Ratas , Ratas Endogámicas , Roedores , Fumar/efectos adversos , Trastornos Relacionados con Sustancias/complicaciones , Neoplasias Ureterales/epidemiologíaAsunto(s)
División Celular/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/inducido químicamente , Vejiga Urinaria/patología , 2-Acetilaminofluoreno/toxicidad , Animales , Pruebas de Carcinogenicidad , FANFT/toxicidad , Masculino , Modelos Biológicos , Ratas , Factores de Riesgo , Vejiga Urinaria/citología , Vejiga Urinaria/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
The possibility that nitrofurantoin is a complete carcinogen or is an initiator or promoter of urinary bladder carcinogenesis was evaluated in male weanling F344 rats. No increase in tumor incidence was observed in rats fed nitrofurantoin at a level of 0.187% of the diet for 2 years compared to a control group. Also, no evidence of bladder initiating activity by nitrofurantoin was observed using sodium saccharin (5% of the diet) as a promoter, and no promoting activity was observed when nitrofurantoin was fed after initiation by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (0.2% of the diet for 4 weeks). In a second experiment, nitrofurantoin (at a dose of 0.187% of the diet) was administered for 6 weeks to rats with a rapidly proliferating bladder epithelium following freeze ulceration, and then the rats were treated with 5% sodium saccharin in the diet for 98 weeks. In additional rats, labelling index following [3H]thymidine injection, determined after 12 weeks of feeding nitrofurantoin, was not increased above control levels in the urinary bladder, stomach, duodenum, or liver. Metabolism of nitrofurantoin by prostaglandin H synthase (PHS) was examined using solubilized ram seminal vesicle microsomes. The rate of nitrofurantoin metabolism by PHS was much less than that observed with benzidine, and the proportion of total metabolite bound to protein was also much less than that with benzidine. These results are consistent with previous reports describing the lack of effect of nitrofurantoin on urinary bladder carcinogenesis.
Asunto(s)
Nitrofurantoína/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Administración Oral , Animales , Autorradiografía , Bencidinas/toxicidad , Peso Corporal/efectos de los fármacos , Cocarcinogénesis , FANFT/toxicidad , Masculino , Nitrofurantoína/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ratas , Ratas Endogámicas F344 , Sacarina/toxicidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Male F344 rats were fed N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for up to 4 wk, then were given the basal diets (Prolab 3200 or AIN-76A) with or without 5% sodium saccharin for up to 100 wk. Eleven transitional cell carcinomas (TCCs), one undifferentiated carcinoma, and two sarcomas of the urinary bladder were examined for the expression of ras gene product, p21, by immunohistochemical staining and western blot analysis. Point mutation in codons 12 or 61 of the Ha-ras genes amplified by polymerase chain reaction was examined by a slot-blot screening procedure using allele-specific oligonucleotide probes. Immunohistochemical staining showed enhanced immunoreactivity with the antibody to ras p21 in seven TCCs and one undifferentiated carcinoma. Western blot analysis showed faster migration of the p21 band in 6 of 11 TCCs. Oligonucleotide hybridization revealed the point mutation in codon 12 of Ha-ras gene (GGA----GTA in 1 TCC) and in codon 61 (CAA----CGA in 5 TCCs and CAA----CTA in 1 TCC). Two mutations in codons 12 and 61 coexisted in one tumor, which were found to be present in different Ha-ras alleles. The incidence of Ha-ras gene mutations were similar in groups treated with (3 of 6) or without (3 of 8) sodium saccharin. These results suggest the involvement of activated Ha-ras gene in rat urinary bladder carcinogenesis induced by FANFT.
Asunto(s)
Codón , FANFT/toxicidad , Genes ras/efectos de los fármacos , Mutación , Neoplasias de la Vejiga Urinaria/genética , Animales , Secuencia de Bases , Western Blotting , ADN/efectos de los fármacos , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Ratas , Ratas Endogámicas F344 , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Urothelial carcinogenesis progresses through several morphologically identifiable stages from simple hyperplasia, to nodular and papillary hyperplasia, to papilloma, and to noninvasive and invasive carcinoma. Unfortunately, no specific identifiable markers on any of the early lesions are available to distinguish those which will become neoplasms from those that are potentially reversible. Urothelial toxicity secondary to cyclophosphamide injection also progresses through several phases, beginning with vacuolization of the epithelium, to necrosis and ulceration, followed by an inflammatory infiltrate, granulation tissue formation, and marked regenerative hyperplasia of the epithelium, with ultimate repair and return to normal. Numerous changes related to toxicity are similar to those seen during carcinogenesis. In addition, several apparent morphologic "changes" occurring in the adult bladder can be mistaken for evidence of toxicity, and more importantly, many of the changes seen during regenerative repair and during carcinogenesis occur in the normal fetal urothelial development.
Asunto(s)
Lesiones Precancerosas/etiología , Neoplasias de la Vejiga Urinaria/inducido químicamente , Vejiga Urinaria/efectos de los fármacos , Xenobióticos/toxicidad , Animales , Ciclofosfamida/toxicidad , Desarrollo Embrionario y Fetal/efectos de los fármacos , Epitelio/efectos de los fármacos , Epitelio/ultraestructura , FANFT/toxicidad , Congelación , Hiperplasia/inducido químicamente , Masculino , Índice Mitótico , Necrosis/inducido químicamente , Ratas , Vejiga Urinaria/embriología , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/orinaRESUMEN
Human over-use of analgesics containing phenacetin, antipyrene (phenazone) and caffeine has been associated with the development of both renal pelvic and bladder tumors. In Sprague-Dawley rats antipyrene has been shown to be a weak complete urinary tract carcinogen. The present study was designed to evaluate the promoting capacity of antipyrene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced urinary tract carcinogenesis. One hundred and eighty male Sprague-Dawley rats were divided into groups of 30 and were treated with the following chemicals in the diet: group 1 received a control diet without chemicals; group 2 was treated with 0.2% FANFT in the diet for five weeks followed by control diet; group 3 received 0.2% FANFT for five weeks followed by 0.535% antipyrene in the diet; group 4 was treated with 0.535% antipyrene; group 5 was treated with 0.102% caffeine; and group 6 was treated with 0.535% antipyrene and 0.102% caffeine in the diet. Ten of 27 rats in group 3 (37%) developed urinary tract tumors (P greater than 0.001, five of which were renal pelvic tumors and five were bladder tumors. The majority of the tumors were well differentiated non-invasive urothelial carcinomas. None of the rats in other groups developed urinary tract tumors. In addition, renal papillary necrosis (RPN) was found in 33% of the rats in group 3, 50% in group 4, and 10% in group 6. The present study clearly shows that antipyrene acts as a promoter of FANFT-induced urinary tract carcinogenesis and that it is nephrotoxic to the renal papilla resulting in renal papillary necrosis.
Asunto(s)
Antipirina/toxicidad , FANFT/toxicidad , Neoplasias Renales/inducido químicamente , Tiazoles/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Animales , Cocarcinogénesis , Neoplasias Renales/patología , Necrosis Papilar Renal/inducido químicamente , Pelvis Renal/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Co-administration of uracil and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) to weanling female Fischer rats produced uracil stones in the bladder and significantly reduced the incidence of bladder tumors. Contrary to bladder tumors, the incidence of renal pelvic and ureteric tumors was increased by this regimen. Feeding of uracil alone produced bladder tumors, in addition to the hyperplasia of renal pelvis, ureter and bladder. The mechanism of uracil's effect on FANFT carcinogenesis is not known.
Asunto(s)
FANFT/toxicidad , Tiazoles/toxicidad , Uracilo/toxicidad , Cálculos de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/inducido químicamente , Animales , Peso Corporal/efectos de los fármacos , Carcinoma/inducido químicamente , Cocarcinogénesis , Femenino , Hiperplasia , Pelvis Renal/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Uréter/efectos de los fármacos , Vejiga Urinaria/patologíaRESUMEN
The N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced murine bladder carcinoma cell line MBT-683 contains growth-stimulating (TGF) and growth-inhibiting factors (GI). These activities coeluted on BioGel P-30 between molecular weights 6,000 and 29,000 daltons. They can be separated by high performance liquid chromatography. Both activities were destroyed by trypsin and dithiothreitol. However, they were resistant to acid and heat. Pool 1 (TGF) stimulated the growth of normal rat kidney cells, whereas pool 2 (GI) inhibited the colony formation of the cell lines MBT-683 and RBTCC-8.
Asunto(s)
Carcinoma de Células Transicionales/inducido químicamente , Transformación Celular Neoplásica , FANFT/toxicidad , Sustancias de Crecimiento/análisis , Péptidos/análisis , Tiazoles/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Animales , Carcinoma de Células Transicionales/análisis , Línea Celular , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Ratones , Ratas , Factores de Crecimiento Transformadores , Neoplasias de la Vejiga Urinaria/análisisRESUMEN
In a study primarily designed to evaluate the inhibitory effects of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-initiated and saccharin-promoted bladder carcinogenesis, significant renal lesions were observed. Thus, administration in the diet of aspirin and sodium saccharin to F344 male rats for 68 weeks resulted in significant lesions of the renal papilla. In contrast to the bladder, aspirin enhanced the frequency and severity of the proliferative action of sodium saccharin on the epithelium of the renal papilla (p less than 0.05 compared to rats treated with either compound alone). The majority of rats administered the two chemicals together demonstrated moderate to severe urothelial hyperplasia of the renal papilla. Columnar metaplasia of the papillary epithelium also occurred frequently in rats fed the combination of chemicals. The rats treated with a combination of sodium saccharin and aspirin had a high incidence of renal papillary necrosis which was also present to a lesser extent among rats treated with aspirin only. Papillary calcification was also frequently observed in the rats fed the combination of aspirin and sodium saccharin. Sodium saccharin or aspirin alone reduced the light microscopic incidence and severity of rat nephropathy, a common finding in aging rats. It would appear that the hyperplastic and renal papillary toxic effects of aspirin and sodium saccharin are independent responses, and that the administration of the two chemicals together greatly accentuates these responses.
Asunto(s)
Aspirina/toxicidad , Carcinógenos , FANFT/toxicidad , Necrosis Papilar Renal/inducido químicamente , Sacarina/toxicidad , Tiazoles/toxicidad , Administración Oral , Animales , Interacciones Farmacológicas , Necrosis Papilar Renal/patología , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) is metabolically activated by several enzyme systems, including prostaglandin H synthase. Aspirin is an inhibitor of prostaglandin H synthase and has been shown to inhibit FANFT-induced bladder carcinogenesis when coadministered in the diet. To further evaluate the effects of aspirin on bladder carcinogenesis in the rat, we have coadministered aspirin with FANFT during the initiation phase and with sodium saccharin during the promotion phase of carcinogenesis. FANFT was administered in the diet at a level of 0.2% for 6 weeks as the initiator and sodium saccharin was administered in the diet at a level of 5% for 61 weeks as promoting stimulus. Aspirin was administered at a level of 0.5% with FANFT or with sodium saccharin, and appropriate control groups were included. Weanling male Fischer 344 rats were utilized and the chemicals were added to Agway Prolab 3000 rat chow. A 1-week interval was included between the FANFT and sodium saccharin administration during which the rats received either aspirin containing diet or control chow, depending on the treatment regimen of the group. Thirty rats were included in each group at the beginning of the experiment, except for the control group which contained 40. Rats given FANFT followed by saccharin had a bladder carcinoma incidence of 83%. Rats given aspirin with FANFT but not with saccharin had a carcinoma incidence of 20% and the rats fed aspirin with the saccharin but not with the FANFT had an incidence of 28%. FANFT followed by control diet resulted in a bladder carcinoma incidence of 10%, as was true for the rats given FANFT plus aspirin followed by control diet. However, the hyperplastic effects induced in the bladder epithelium by saccharin without prior FANFT administration were inhibited by coadministration with aspirin. These results indicate that aspirin inhibits both FANFT initiation and sodium saccharin promotion of bladder carcinogenesis, but the mechanisms involved would most probably be different for each.
Asunto(s)
Aspirina/farmacología , Cocarcinogénesis , FANFT/toxicidad , Sacarina/toxicidad , Tiazoles/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Animales , Peso Corporal/efectos de los fármacos , Concentración de Iones de Hidrógeno , Masculino , Ratas , Ratas Endogámicas F344 , Sacarina/metabolismo , Neoplasias de la Vejiga Urinaria/prevención & controlRESUMEN
The administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide FANFT) by gavage to female NMRI-mice resulted in a high incidence of neoplasms of the forestomach. From 117 effective animals which were pooled from 3 dosed groups, 30 squamous cell carcinomas and 26/117 papillomas of the forestomach were diagnosed. Only 5/117 neoplasms of the urinary bladder occurred. The average cumulative dose administered was 1180 mg/mouse, and the mean latent period for the induction of forestomach tumours was 574 days. The mode of application seems to be an important factor in the carcinogenicity of FANFT.
Asunto(s)
Adenocarcinoma/inducido químicamente , Carcinoma de Células Escamosas/inducido químicamente , FANFT/toxicidad , Papiloma/inducido químicamente , Neoplasias Gástricas/inducido químicamente , Tiazoles/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Administración Oral , Animales , FANFT/administración & dosificación , Femenino , Ratones , Ratones EndogámicosRESUMEN
The effect on urothelial proliferation of a urinary bladder carcinogen, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), fed to male F344 rats at doses of 0.2, 0.1, 0.05, 0.01, 0.005 and 0.001% of diet for 4 or 10 weeks was evaluated by autoradiography, using [3H-methyl]thymidine, and by histopathology. At week 4, hyperplasia was induced in 10/11 and 6/11 rats given 0.2% and 0.1% FANFT, respectively. The dose-related increase of labeling index in the bladder epithelium was significant for the groups given 0.01% or higher doses of FANFT. At week 10, histopathologic lesions were observed in groups given 0.05% or higher doses of FANFT. This was accompanied by a significant increase in labeling index for these groups. The results are consistent with the long-term carcinogenicity studies conducted with the same dose levels of FANFT. The interrelationships between numbers of cells (hyperplasia), cell proliferation (labeling index) and cancer induction are discussed utilizing a computerized model of bladder carcinogenesis.