The effect of the number of weekly intratracheal Instillations of N-methyl-N-nitrosourea (MNU) on induction of tracheal tumors was studied in male noninbred Syrian golden hamsters. The histogenesis of metaplastic and neoplastic lesions was also characterized. Treatment of hamsters once weekly for either 6, 8, 10, 12, or 14 weeks with a 0.5% solution of MNU resulted in the induction of a 0, 6, 11, 26, and 42% incidence of carcinoma, respectively, at 6 months after the first MNU treatment. Of the carcinomas induced, 87% were combined epidermoid and adenocarcinomas, whereas 13% were epidermoid carcinomas. In animals killed 1 week following either 1, 3, 6, 8, 10, 12, or 14 treatments, a continuum of metaplastic and neoplastic changes was observed that correlated well with the cancer incidence exhibited at the termination of the study. Mucous cells were found to be of prime importance in the development of the metaplastic and neoplastic tracheal lesions observed.
The chemopreventive activity of two synthetic retinamides of relatively low toxicity against N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer was studied in F344 rats and C57BL/6 X DBA/2 F1 mice. Female and male rats were given a total dose of either 1800 or 3200 mg OH-BBN over a period of 6 or 8 weeks, respectively. Male mice were given a total dose of either 90 or 180 mg OH-BBN over a period of 9 weeks. Seven days after the final intubation of a period of 9 weeks. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or a diet supplemented with the following retinoids: for rats, 0.8 mmol 13-cis-retinoic acid, 2 mmol N-(ethyl)-all-trans-retinamide, or 2 mmol N-(2-hydroxyethyl)-all-trans-retinamide per kg diet; and for mice, either 0.5 or 1.0 mmol of N-(ethyl)-all-trans-retinamide or N-(2-hydroxyethyl)-all-trans-retinamide per kg diet. Animals were killed 6 months after the initial gastric intubation. In comparison to male and female rats fed placebo diets, all three retinoids reduced the incidence, number, and severity of the low-grade papillary transitional cell carcinomas of the urinary bladder. Similarly, treatment of mice with either of the two retinamides reduced the incidence of highly invasive urinary bladder carcinomas. The chemopreventive effect of the less toxic retinamides was equal to or greater than that of 13-cis-retinoic acid.
1) Effect of ovariectomy and replacement with 1 μg estradiol benzoate (EB) and/or 3 mg progesterone (P) upon daily thyroxine secretion rate (TSR) has been studied in mature rats. 2) Ovariectomy reduces TSR approximately 33% within 2-6 days postcastration. Increasing the interval to approximately 90 days between ovariectomy and TSR determination did not result in a further reduction in TSR. EB alone and with P prevented decrease in TSR following ovariectomy but P alone had no effect. 3) It is suggested that ovariectomy reduces the circulating estrogen level which, in turn. may reduce thyrotropin secretion and, subsequently, lower daily TSR.
Groups of 50-day-old virgin female Sprague-Dawley rats received a single oral administration of 20 mg 9,10-dimethyl-1,2-benzanthracene and 50 µCi 9,10-dimethyl-1,2-benzanthracene-9-14C in 1 ml sesame oil and were sacrificed at various hours after carcinogen feeding. The abdominalinguinal mammary glands from the right side of the rat were used to determine the radioactivity contained within the mammary teat, fat pad, and vascular areas. The mammary glands from the left side were enzymatically separated into mammary parenchymal cell and fat cell fractions with collagenase. Intracellular lipid of the parenchymal cells was extracted and subjected to quantitative determination. The dry, lipid-extracted residue contained the radioactivity insoluble in lipid solvents. Maximum specific activity of the mammary parenchymal cell fraction was attained at 6 hr while that of all other tissue fractions peaked at 16 hr after carcinogen feeding. The specific activity of those tissue fractions containing the smaller percentage of total lipid (mammary teat and vascular area) was less than, but the same pattern as, those fractions containing the greater percentage of total lipid (perirenal fat, mammary fat pad, and isolated mammary fat cells). However, a concomitant increase in the specific activity of the parenchymal cells did not occur while the specific activity of the isolated mammary fat cells was decreasing. The pattern of total parenchymal cell specific activity was almost identical with that of the parenchymal cell intracellular lipid although the values were much lower. While the parenchymal cell intracellular lipid reached a peak uptake and began to decline rapidly, the lipid-extracted parenchymal cell specific activity continued to rise. During the rapid decrease in intracellular lipid specific activity, the lipid-extracted parenchymal cells reached a peak and then apparently leveled off.
These data suggested that the concentration of the carcinogen in mammary adipose tissue obscured the uptake of the carcinogen by mammary parenchymal cells because of the lipid solubility of the compound. Furthermore, since the uptake of the carcinogen by the mammary parenchymal cells and fat cells occurred simultaneously and independently, it was apparent that mammary fat cells were of minor importance in the uptake of the carcinogen by mammary parenchymal cells. These data also indicated that the carcinogen was first concentrated in the intracellular lipid of the parenchymal cell and released to other cellular constituents. The dimethylbenzanthracene released from the parenchymal cell intracellular lipid was apparently firmly bound by some cellular component and the level of bound dimethylbenzanthracene was maintained by a continued release from intracellular parenchymal cell lipid.
The effects of pretreatment with N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR) and phenobarbital (PB) on the distribution and metabolism of 4-HPR, and on the levels of hepatic cytochromes, were investigated in female BDF mice. Pretreatment of mice for 3 days with 10 mg/kg 4-HPR had no effect on the disposition of 4-HPR in the serum, liver, mammary gland, or urinary bladder. 4-HPR pretreatment also had no effect on the pharmacokinetics of any of its metabolites in the liver, or on the levels of hepatic cytochromes P450 or b5. By contrast, pretreatment of mice for 3 days with 80 mg/kg PB had a significant effect on the disposition of 4-HPR in all the tissues examined; the areas under the concentration-time curves for PB-pretreated mice were half those for vehicle-pretreated mice. PB pretreatment also significantly reduced the levels of four metabolites of 4-HPR in the liver and increased the levels of hepatic cytochromes P450 and b5. These data suggest that prior or concomitant administration of drugs that induce the mixed function oxidase system could result in changes in retinoid disposition and metabolism; such changes may alter retinoid chemopreventive activity.
Journal Article Influence of 15 retinoic acid amides on urinary bladder carcinogenesis in the mouse Get access R.C. Moon, R.C. Moon 2 1Laboratory of Pathophysiology, IIT Research InstituteChicago, IL 60616 2 To whom requests for reprints should be addressed. Search for other works by this author on: Oxford Academic PubMed Google Scholar D.L. McCormick, D.L. McCormick 1Laboratory of Pathophysiology, IIT Research InstituteChicago, IL 60616 Search for other works by this author on: Oxford Academic PubMed Google Scholar P.J. Becci, P.J. Becci 3Food and Drug Research Laboratories, Inc.Waverly, NY 14892 Search for other works by this author on: Oxford Academic PubMed Google Scholar Y.F. Shealy, Y.F. Shealy 4Southern Research InstituteBirmingham, AL 35255, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Frickel, F. Frickel 5BASF Aktiengesellschaft, Ludwigshafen am RheimFRG Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Paust, J. Paust 5BASF Aktiengesellschaft, Ludwigshafen am RheimFRG Search for other works by this author on: Oxford Academic PubMed Google Scholar M.B. Sporn M.B. Sporn 6National Cancer InstituteBethesda, MD 20205, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Carcinogenesis, Volume 3, Issue 12, 1982, Pages 1469–1472, https://doi.org/10.1093/carcin/3.12.1469 Published: 01 January 1982 Article history Published: 01 January 1982 Received: 25 August 1982 Accepted: 16 October 1982
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