Quantitative spectrophotometric determination of human and rat urinary dimethylamine.
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Animals↗
Biomedical subjects
G T Bryan
Publications and source records attributed to G T Bryan.
Mutagenicity of some commercially available nitro compounds for Salmonella typhimurium.
Benzoyl chloride and 53 commercially available aromatic heterocyclic and aliphatic nitro compounds were tested for mutagenicity in Salmonella typhimurium TA98 and TA100. 34 of 53 nitro compounds (64%) were mutagenic, 4 in TA100 only, 15 in TA98 only, and 15 in both strains. 13 of the heterocyclic derivatives of pyridine, indole, indazole, quinoline, and benzimidazole were mutagenic. 21 of 34 mutagenic nitro compounds were bactericidal. Nitromethane was the only aliphatic tested and was not mutagenic. Benzoyl chloride, a human carcinogen, was mutagenic for TA98.
Anti-Bacterial Agents↗
Natural history of papillary lesions of the urinary bladder in schistosomiasis.
Variable epithelial hyperplasia was observed in urinary bladder of nine capuchin monkeys (Cebus apella) when examined at cystotomy 94 to 164 weeks after infection with Schistosoma haematobium. These hosts were followed for 24 to 136 weeks postcystotomy to determine the status of bladder lesions in relation to duration of infection and to ascertain whether lesion samples removed at cystotomy reestablished themselves in autologous and heterologous transfers. There was involution of urothelial hyperplasia in eight of nine animals and no evidence for establishment of transplanted bladder lesions.
Animals↗
Carcinogenic and mutagenic activities of milk from cows fed bracken fern (Pteridium aquilinum).
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Animals↗
Effect of p-hydroxyacetanilide, sodium sulfate, and L-methionine on the leukemogenicity of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide.
Dietary administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide to mice for 14 weeks followed by 16 weeks of control diet resulted in a high incidence of lymphocytic leukemia and a low incidence of forestomach squamous cell papillomas. The coadministration of p-hydroxyacetanilide at a dose of 1.0% with either 250 or 500 ppm of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide resulted in inhibition of leukemogenesis, whereas when p-hydroxyacetanilide was coadministered with 1000 ppm of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide the leukemia incidence was not significantly reduced, but the latent period was prolonged. When sodium sulfate was administered with p-hydroxyacetanilide and N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide, leukemogenesis was partially restored. L-Methionine, fed in place of sodium sulfate, unblocked leukemogenicity inhibition by p-hydroxyacetanilide. None of these chemicals, p-hydroxyacetanilide, sodium sulfate, or L-methionine, significantly affected the incidence of forestomach papillomas induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide, although tumor incidences in all groups were low. p-Hydroxyacetanilide and sodium sulfate had no significant effect on the high incidence of stomach tumors induced by formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]hydrazide or bladder tumors induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.
Acetanilides↗
Inhibition of carcinogenic effect of bracken fern (Pteridium aquilinum) by various chemicals.
The inhibitory effect of butylated hydroxyanosole (BHA), disulfiram, calcium chloride, and polyvinylpyrrolidone (PVP) on the intestinal and urothelial carcinogenicity of bracken fern (BF) was determined in albino rats. Of 10 groups of rats, one group received a normal diet, one received a BF-containing diet (one-third of diet by weight), four received a normal diet with one of the following supplements, and four received BF-containing diet with one of the following: BHA (5 mg/g diet); disulfiram (5 mg/g diet); PVP (50 mg/g diet); or calcium chloride (20 mg/g diet). At 12 months of the experiment, the following results were noted: in the BF-treated group, 30 rats (100%) exhibited intestinal tumors and 22 of 30 (73%) urinary bladder tumors. In the BF-BHA group, 15 of 20 rats (75%) showed intestinal tumors and 12 of 20 rats (60%) urinary bladder tumors. Of the 16 rats in the BF-disulfiram group, 12 (80%) had intestinal and 10 (62.5%) had urinary bladder tumors. In the BF-calcium chloride group, intestinal tumors arose in 16 of 23 rats (70%) and urinary bladder tumors in 4 of 23 rats (17%), while in the 28 BF-PVP rats, 26 (93%) exhibited tumors of the intestine and 5 (18%) tumors of the urinary bladder. Dietary BHA, disulfiram and calcium chloride decreased the incidence of intestinal tumors by about 25--30% (p less than 0.01). Similarly, PVP and calcium chloride inhibited BF-induced urinary bladder carcinogenesis by about 80% (p less than 0.001). No tumors were detected in groups receiving either normal diet or normal diet supplemented with BHA, disulfiram, calcium chloride or PVP.
Animals↗
Hexamethylmelamine treatment of sarcomas and lymphomas.
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Adolescent↗
Aryl and heterocyclic diazo compounds as potential environmental electrophiles.
4-Aminoimidazole-5-carboxamide, a component of human urine derived from the de novo purine biosynthetic pathway, was evidenced to undergo in vivo diazotization in rats following its sequential administration with NaNO2. The diazotization product, 4-diazoimidazole-5-carboxamide, undergoes intramolecular cyclization to yield 2-azahypoxanthine, the urinary presence of which was confirmed mass spectrometrically. 4-Diazoimidazole-5-carboxamide demonstrated dose-related mutagenicity in Salmonella typhimurium TA 100 and represents a potent electrophilic reactant similar to the proposed ultimate carcinogenic forms of arylalkylnitrosamines and arylnitrosamides. It is suggested that aryl and heterocyclic diazo compounds, as a class, warrant further study as environmental electrophiles representing potential biological hazard.
Animals↗
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.
Adenocarcinoma↗
Mutagenicity for Salmonella typhimurium of urine obtained from humans receiving nitrofurantoin.
Urine samples from 12 humans receiving oral therapeutic doses of nitrofurantoin were mutagenic for Salmonella typhimurium strain TA 100 and nonmutagenic for strain TA 100-FR1. Mutagenic activity of the urine was not increased by treatment with beta-glucuronidase. Spot mutation assay of the chromatogram of urine revealed that the mutagenic activity of the urine was mainly due to unmetabolized nitrofurantoin.
Humans↗
Internal review as a means of maintaining quality education in a medical school.
In order to focus attention on education, the University of Texas Medical Branch at Galveston adopted a system of internal review. The process was initially conducted for courses in the basic sciences by an ad hoc dean's committee consisting of representatives from the teaching faculty, administration, and student body as well as experts in medical education. As a consequence of the experience with the review of the basic science courses, the internal review process was applied to the clinical science courses and the elective programs at UTMB. The activities of the internal review process have resulted in improvements in instructional procedures and structural changes in the medical school's approach to educational planning, implementation, and evaluation.
Curriculum↗
Suppression of antibody-mediated and cell-mediated murine immunity by the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide.
N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) administered at 1000 ppm in diet to mice for 12 weeks induced a high incidence of lymphocytic leukemia. Effects of NFTA on antibody-mediated immunity and cell-mediated immunity of BALB/c mice were studied using the spleen plaque assay for detection of immunoglobulin M-producing cells and the graft-versus-host (GVH) reaction, respectively. NFTA suppressed both responses. With the spleen plaque assay, the number of antibody-forming cells (AFC) to sheep red blood cells was significantly less than in unmedicated, control mice after treated mice received NFTA at 1000 ppm for 6 days. The GVH reaction was not suppressed at 21 days, but was severely suppressed at 70 days, prior to the histological appearance of leukemia. Effect of dose was studied by administering NFTA at 100, 250, 500, and 1000 ppm of diet for 13 to 14 weeks and then determining the response in the spleen plaque assay and GVH reactions. The ratio of AFC/spleen of NFTA-treated groups to AFC/spleen of an unmedicated control group, at the above specified doses, was 0.86, 0.22, 0.33, and 0.54 in ascending dosage order beginning with 100 ppm. For the GVH reaction, the suppression of the cell-mediated immunity was directly proportional to the dose of NFTA. Suppression of the antibody-mediated immunity in relation to the induction of leukemia at 28 weeks was studied by feeding NFTA at 500 ppm for 14 weeks, followed by unmedicated diet for 14 weeks. During the 11th week, mice were immunized with SRBC; 5 days later the spleens were removed and the spleen plaque assay was performed. Eight of 18 mice fed NFTA developed leukemia. The number of AFC/spleen was 78 X 10(3) +/- 34 for those with leukemia and 68 X 10(3) +/- 24 (p greater than 0.5) for those without leukemia, compared with 170 X 10(3) +/- 74 for the control mice (p less than 0.01 for both groups, compared with controls). A closely related carcinogenic nitrofuran, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, did not suppress the antibody-mediated immunity response measured during the 11th week of administration.
Animals↗
The pathogenesis of experimental bladder cancer.
The pathogenesis of signal morphological lesions of the urinary bladder induced in several species following administration of N-butyl-N-(4-hydroxybutyl)nitrosamine, bracken fern, or N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide is presented. Incidences of bladder neoplasia exceeding 80% were generated in the rat by each compound. Bladder neoplasia was induced in the following species by each substance: by N-butyl-N-(4-hydroxybutyl)nitrosamine in the mouse, hamster, guinea pig, and dog; by bracken fern in the guinea pig, mouse, and cow; and by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide in mouse, hamster, and dog. The guinea pig appeared resistant to the bladder oncogenicity of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. Different species displayed a gradient of bladder neoplastic responsiveness. Hyperplasia was a consistent early lesion and was usually focal. Early hyperplastic lesions regressed following removal of the carcinogenic stimulus, but later lesions appeared to be irreversible. These animal systems appear useful in providing opportunities for investigations relevant to human bladder cancer.
Animals↗
Carcinogenicity of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2) fed to female Sprague-Dawley rats.
The carcinogenicity of 2-(2-furyl)-3-(5-nitro-5-furyl)acrylamide (AF-2) was investigated by administering it orally to Sprague-Dawley female weanling rats in a grain diet at a dose of 0.2% for 46 weeks, followed by 20 weeks of unmedicated control diet. The total mean cumulative dose of AF-2 was 10.1 g (41.6 mmol) per rat during the 46 weeks of the experiment. Weight gains of rats fed AF-2 was comparable to that of unmedicated control rats. Survival of rats fed AF-2 was 52 +/- 12 (SD) weeds compared to 65 +/- 5 weeks for the unmedicated controls (P less than 0.001). Twenty-four of 29 rats fed AF-2 developed multiple breast tumors, 15 of which were adenocarcinomas. Two of 29 unmedicated control rats had single fibroadenomas of the breast.
Adenocarcinoma↗
Further clinical studies with megestrol acetate in advanced breast cancer.
A previous study showed activity of megestrol acetate in advanced breast cancer; as a result the study was expanded. Of 101 patients treated with this compound, 26 (26%) met our criteria of improvement. The drug was well tolerated and produced no toxicity and, as opposed to androgens and estrogens, no endocrine effects were observed. Prior hormonal or cytotoxic compounds, including alkylating agents, did not appear to reduce the subsequent responsiveness to this potent progestational compound. We now include it, often as the initial hormonal trial in postmenopausal patients, in our sequential treatment of disseminated breast cancer because of its favorable therapeutic ratio.
Breast Neoplasms↗
Mutagenicities of nitrofuran derivatives on a bacterial tester strain with an R factor plasmid.
Many nitrofuran derivatives are known to be mutagenic on Escherichia coli WP2 but not on Salmonella typhimurium TA1535, TA1536, TA1537 or TA1538. Ames and coworkers recently obtained a new tester strain of S. typhimurium, TA100, by putting an R factor plasmid, pKM101, into TA1535. We found that all mutagenic nitrofuran derivatives previously found to be mutagenic on E. coli WP2 were mutagenic on this new strain (TA100).
Drug Resistance, Microbial↗
Enzymic deacetylation of carcinogenic arylacetamides by tissue microsomes of the dog and other species.
The relative ability of arylacetamide deacetylase enzyme systems of dog liver to carry out the deacetylation of the carcinogens, 4-acetylaminobiphenyl, 2-acetylaminofluorene, and 2-acetylaminaphthalene, was examined. The arylacetamides were incubated with unfortified dog liver microsomes, and enzyme activity (nmol arylamine/mg protein/hr) was estimated by colorimetric quantitation of the resulting arylamines. The dog liver enzyme system displayed characteristics similar to those described for the rodent liver enzyme system in that enzyme activity was greatest in liver tissue, was localized in the microsomal subcellular fraction, required no cofactors, and was inhibited by heat, sodium fluoride, and thiol reagents. In five replicate assays, the relative rates of deacetylation were about 10, 6, and 1 with 4-acetylaminobiphenyl (84.8 +/- 12.4), 2-acetylaminofluorene (52.5 +/- 5.1), and 2-acetylaminonaphthalene (8.8 +/- 3.3), respectively. As a canine urinary bladder carcinogen, 4-acetylaminobiphenyl is considered more potent than 2-acetylaminofluroene, while 2-acetylaminonaphthalene is devoid of detectable carcinogenic activity, despite the fact that 2-aminoaphthalene is a well-established canine urinary bladder carcinogen. Removal of the acetyl group may be a requirement for urinary bladder carcinogenesis; accordingly, the present studies demonstrate the appearance of a direct relationship between dog liver deacetylase enzyme specificity and urinary bladder susceptibility to these carcinogenic arylacetamides.
2-Acetylaminofluorene↗
Identification of carcinogenic tannin isolated from Bracken fern (Pteridium aquilinum).
We attempted to isolate a carcinogenic substance from bracken fern (Pteridium aquilinum), a naturally occurring toxicant responsible for the production of chronic enzootic hematuria and urinary bladder cancer of cattle and carcinogenic for various target organs of several species. Hot methanol extracts of bracken fern were solubilized in water and extracted with chloroform followed by a mixture of n-butanol-butanone (1:1). That fraction was dried and triturated with ether-methanol (4:1), n-butanol, and finally absolute ethanol. The insoluble residue was dissolved in 10% aqueous methanol and passed through Dowex 1 OH-, Dowex 50 H+, or Dowex 1 OH- and then Dowex 50 H+ ion exchange resins. A condensed tannin, isolated from one ot the fractions, was identical to that isolated from bracken fern by the caffeine procedure used for the separation of tannins from other plant constituents. Three systems were used for bioassay; induction of bladder carcinoma by implantation of cholesterol pellets containing bracken fern fractions into the bladder lumens of mice; acute toxicity by ip injection of brachen fern fraction into mice; and growth inhibition of Escherichia coli. The following fractions induced significantly greater incidences of bladder carcinoma than did cholesterol pellets only: tannin, Dowex 50 H+, residue, n-butanol, and methanol. Tiliroside, a component of bracken fern fractions into the bladder lumens of mice; acute genic acid, and quercetin were not carcinogenic. Tannin was the most toxic (mean lethal dose: 0.16 mg/g) and carcinogenic. None of the carcinogenic fractions inhibited growth of E. coli.
Escherichia coli↗