Production of urinary tract tumors by co-administration of uracil and N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide in F344 rats.

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.

Seasonal arsenic exposure from burning chromium-copper-arsenate-treated wood.

All eight members of a rural Wisconsin family experienced recurring neurological and medical illness over three years, especially during the winter months. Arsenic, in concentrations of 12 to 87 ppm, was noted in the hair of the mother and father, and analysis of hair and fingernails of all family members demonstrated pathological levels of arsenic. For four years the five-room home had been heated with a small wood stove in which outdoor or marine plywood and wood remnants had been preferentially burned. Stove ashes that contained more than 1,000 ppm of arsenic contaminated the living area, and the ratio of copper, chromium, and arsenic pentoxide in this ash matched the ratio used in the chromium-copper-arsenate-treated wood.

Tumor production in germ-free rats fed 5-nitrofurans.

Weanling female germ-free Sprague-Dawley rats were divided into 3 groups: the control group rats were fed an autoclaved 5010C diet for 2 years; the nitrofurantoin (NF) group rats were fed this diet supplemented with 0.188% NF for 2 years; and the N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) group rats were fed this diet supplemented with 0.188% FANFT for 20 weeks followed by 20 additional weeks of the control diet. The FANFT-group rats were killed following the early appearance of bladder tumors. Six of 11 control rats had tumors: 2 with mammary fibroadenomas, 1 with adrenal adenoma, 1 with leukemic spleen, and 2 with mesenchymal sarcoma of the colon. Ten of 12 NF-group rats had tumors: 9 with mammary fibroadenomas, 1 with adrenal adenoma, and 1 each with leukemic spleen and cervical squamous cell carcinoma. Eight of 12 FANFT-group rats had tumors: 7 with bladder and 1 with renal pelvis transitional cell carcinoma. The incidences of mammary fibroadenoma in the NF group and of lower urinary tract tumors in the FANFT group were significantly greater (P less than 0.01) than those of these tumors in the control group.

Carcinogenicity of 2-amino-4-(5-nitro-2-furyl) thiazole in rats by oral and subcutaneous administration.

Female Fischer rats were divided into two groups and fed either basal diet or basal diet containing 0.166% 2-amino-4-(5-nitro-2-furyl) thiazole for 52 weeks followed by basal diet for an additional 16 weeks. Our of the 24 rats fed 2-amino-4-(5-nitro-2-furyl) thiazole, 23 had forestomach tumors, four had fibroadenomas and two had adenocarcinomas in the mammary glands, two had renal pelvic carcinomas, five had papillomas and six had carcinomas in the bladder, and two had cutaneous tumors. None of the 10 rats fed basal diet developed tumors. In another study, two-week-old Fischer rats of both sexes were injected s.c. once a week for the first eight weeks with 2-amino-4-(5-nitro-2-furyl) thiazole at a dose of 10 mg/kg and then 1.4 mg/rat for an additional 46 weeks. The control rats were injected with solvent (dimethyl sulfoxide: water, 1:1) only. The experiment was terminated at the end of 58 weeks. Malignant fibrous histiocytomas were found in five out of eight male rats and four out of 11 female rats, and an angiosarcoma was found in one out of eight male rats injected with 2-amino-4-(5-nitro-2-furyl) thiazole. None of the control rats developed tumors.

Effects of ferrous chloride and iron dextran on lipid peroxidation in vivo in vitamin E and selenium adequate and deficient rats.

The effects of intraperitoneally injected ferrous chloride and iron-dextran on lipid peroxidation in vivo were assessed. Peroxidation was estimated by measuring ethane, a volatile autoxidation product of omega-3-unsaturated fatty acids. Rats supplemented with 0.1 ppm dietary selenium and rats supplemented with 0.1 ppm selenium and 200 IU vitamin E/kg diet were injected with ferrous chloride at 30 mg iron/kg, or with sodium chloride, or left uninjected. In both dietary groups ferrous chloride increased ethane production while sodium chloride did not, but the iron-caused ethane increase was 8 times greater in the low E group. Iron-dextran injected at 500 mg iron/kg was fatal to rats fed a basal diet deficient in selenium and vitamin E or diet supplemented with 0.5 ppm selenium; supplemental vitamin E at 200 IU/kg diet prevented this mortality. Iron-dextran quadrupled ethane production in rats fed the basal diet and tripled ethane production in rats fed the selenium-supplement diet. Vitamin E supplementation prevented the iron-dextran-caused rise in ethane production. A histological examination of rats killed by iron-dextran showed severe generalized necrosis of the diaphragm and severe focal necrosis of thigh muscle. Vitamin E protected more effectively than selenium against iron-dextran-caused peroxidation as well as against acute iron-dextran-caused mortality.

Relative refractoriness of guinea pigs to carcinogenesis by 5-nitrofurans.

Guinea pigs were observed to be refractory to carcinogenesis by 3 different carcinogenic 5-nitrofurans administered at 0.1% of the diet for 50 weeks followed by 74 weeks of control diet. In view of the evidenced involvement of nitroreduction in the metabolic activation of 5-nitrofurans, it is of interest that guinea pig refractoriness is not due to a quantitative nitroreductase deficiency in guinea pig liver.

13-cis-retinoic acid: effect on urinary bladder carcinogenesis by N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide in Fischer rats.

The failure of 13-cis-retinoic acid to inhibit either the incidence or severity of bladder carcinoma in female Fischer rate initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) suggests that inhibition of bladder carcinogenesis by natural and synthetic retinoids is carcinogen-class specific, and adds an element of complexity to approaches in chemoprevention.

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.

Surface characteristics of malignant human urinary bladder epithelium studied with scanning electron microscopy.

Biopsies were obtained from 28 male and seven female patients with cystoscopically and histologically confirmed urinary bladder carcionoma. Tissue specimens for light microscopy and scanning electron microscopy (SEM) were obtained from the tumours as well as from cystoscopically tumour-free mucosa of the dome, the lateral walls and the trigone of the urinary bladder and also from the proximal urethra. Certain surface structural changes, which seem to represent malignancy, present in different regions of the urinary bladder were detected by SEM, although not visible by light microscopy.

Scanning electron microscopy of exfoliated malignant and non-malignant human urothelial cells.

Midstream urine samples were taken from 35 patients with histologically diagnosed urinary bladder carcinoma, from 27 patients without history or sign of malignancy or infection in the urinary tract, and from eight patiens with cystitis. The urine was filtered through Millipore filters, or Nuclepore filters, pore size 5.0 microns, on which the cells were caught. From the same patients biopsies were obtained from different anatomic regions of the urinary bladders as well as from the carcinomas that were present. The filters and the biopsies were examined with scanning electron microscopy (SEM). The exfoliated cells trapped on the filters were in good morphological condition. Idential characteristics of the cell surface morphology were recognized in the biopsies and the exfoliated cells from each patient. In non-malignant cases the cells displayed the regional morphological charcteristics of the urinary bladder. Bacteria and an increased number of red and white blood cells were attached to the cell surface of numerous exfoliated cells in patients with cystitis, but no pleomorphic microvilli were detected in these patients. In cases of malignancy exfoliated cells with pleomorphic microvilli on their surface were detected. A large majority of the exfoliated cells shed in the urine with pleomorphic microvilli on their surfaces still retained enough regional surface characteristics to determine their origin. Some of the cells were completely covered with pleomorphic microvilli and it was impossible to determine their origin.

Characterization of different regions of the normal human urinary bladder by means of scanning electron microscopy.

A study of the normal human urinary bladder and the proximal urethra was performed using scanning electron microscopy (SEM). Biopsies were evaluated from 27 male patients with benign prostatic hyperplasia, without history or sign of urinary tract malignancy and with cystoscopically normal mucosal finding. The specimens were obtained from the dome, the side-walls and the trigone of the bladder. The characteristic surface architecture of the transitional epithelium was observed in different anatomical regions of the human urinary bladder.

Collection and evaluation of normal exfoliated urinary bladder cells in man using scanning electron microscopy.

Normal exfoliated urinary bladder cells were collected from midstream urine samples from 21 male patients. Procedures for urine filtration using Millipore filters of Nucleopore filters, cell fixation and preparation for scanning electron microscopy investigation were developed. Correlations were made between the surface morphology of exfoliated cells and that of biopsies from different anatomical regions of the urinary bladder. Scanning electron microsocopy (SEM) of exfoliated normal urinary bladder cells proved to be a more sensitive method for discovering cellular surface details than light microscopy. This information forms the basis for further SEM studies of cell surface alterations due to urothelial diseases.

Effect of age, sex, and intestinal flora on the induction of colon tumors in rats.

Germfree and conventional Sprague-Dawley rats were assessed for their susceptibility to intrarectally injected N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methyl-N-nitrosourea (MNU). Adenocarcinoma of the colon was induced in germfree and conventional rats by both MNNG and MNU. The colons of germfree rats were more susceptible to the direct-acting carcinogens, as manifested by earlier morbidity and development of colon tumors (50% tumors within 30-35 wk), than were those of conventional rats (50% colon tumors within 48-50 wk). Germfree and conventional male rats were more susceptible to the carconogens than were their female germfree and conventional counterparts. Young (30 days old at the start of the experiment) germfree rats developed colon tumors more quickly (15-20 wk) than did older (60 days) germfree rats after intrarectal injections of MNNG. No colon tumors were observed in germfree and conventional rats after 75 weekly intrarectal injections with a buffer. Transplantation of an adenocarcinoma induced with MNU in a female rat to germfree and conventional rats showed that it was easily transplantable, required no immunosuppression, and had essentially the same morphologic characteristics as did the primary tumor.

Urinary bladder effects of levodopa in hamsters.

Levodopa (3,4-dihydroxyphenyl-L-alanine) was fed at 1.0% of the diet to 60 male weanling Syrian golden hamsters for 48 weeks, followed by control diet for an additional 38 weeks. The incidence of tumors were: three of 60 hamsters with forestomach squamous cell papillomas, one of 60 with leiomyosarcoma of the skin, and one of 60 with cortical adrenal adenoma. Two of 30 control animals developed adrenal adenomas. Hyperplasia of the urinary bladder epithelium occurred in 33 of the treated group, and hyperplasia was not found in the bladders of the control group.

Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.

Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously. Male and female Sprague-Dawley and female Buffalo rats were susceptible to the carcinogenicity of DTIC. A 50% incidence of mammary adenocarcinomas was induced in males within 18 weeks. Type of tumor and tumor incidence were dose dependent. Single and multiple intraperitoneal injections of DTIC did not alter organ specificity. DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable. Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity. Metabolites of DTIC were tested for carcinogenic activity. Animals administered 5-diazoimidazole-4-carboxamide orally, intraperitoneally, or intragastrically developed low incidences of thymic, stomach, bladder, or mammary tumors. A low incidence of mammary tumors developed in rats fed 2-azahypoxanthine. A variety of tumors, including several ependymoblastomas, were induced in rats that received 5-aminoimidazole-4-carboxamide orally. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC), when fed or given in single or multiple intraperitoneal injections, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Control rats had low incidences of mammary adenocarcinomas and adenofibromas after 52 weeks. These data show that the carcinogenic properties of DTIC resemble those of carcinogenic N-nitroso compounds, hydrazine, azo, and azoxy-alkanes and aryltriazenes and thus suggest similar mechanism(s) of action. These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC.