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Biomedical subjects

R C Moon

Publications and source records attributed to R C Moon.

At least 91 records · Page 5Linked to original sources
PubMed1981

Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea.

Dose-response relationships for the induction of mammary tumors by a single i.v. injection of N-methyl-N-nitrosourea (MNU) were studied. At 50 days of age, groups of 20 virgin female Sprague-Dawley rats received single doses of 50, 45, 40, 35, 30, 25, 20, 15, or 10 mg MNU per kg body weight; a group of 10 control rats received 0.85% NaCl solution only. Animals were observed for the appearance of mammary tumors over their life span or until 600 days after carcinogen administration. Both malignant and benign mammary tumors appeared in all groups; however, malignant tumors appeared earlier and at a faster rate than did benign tumors. Incidence of cancer and number of cancers per animal increased with increasing MNU dose; the latent period for cancer increased with decreasing dose. The number of benign tumors induced as a percentage of total tumors increased with decreasing dose, ranging from approximately 10% in groups receiving more than 30 mg MNU per kg to 58% in the group receiving 10 mg/kg. Foci of metastatic mammary carcinoma were found in lungs of animals in several MNU dose groups. Data from the present study indicate that a single i.v. administration of MNU induces mammary cancer in a dose-related fashion, with little toxicity and a short latent period; induced cancers metastasize to distant sites. The single-dose MNU model thus appears to be superior to both the 7,12-dimethylbenz(a)anthracene and multiple-dose MNU models, particularly for use in studies of modification of mammary carcinogenesis.

Adenocarcinoma↗
PubMed1981

N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder cancer in C57BL/6 X DBA/2 F1 mice as a useful model for study of chemoprevention of cancer with retinoids.

Highly invasive carcinomas of the urinary bladder were induced in male C57BL/6 X DBA/2 F1 (hereafter called B6D2F1) mice by gastric intubation of N-butyl-(4-hydroxybutyl)nitrosamine (OH-BBN) using a quantitative dosing schedule. Animals received either 5 or 10 mg OH-BBN per intubation, two times each week, for 9 weeks for a total dose of either 90 or 180 mg, and they were killed 6 months after the first carcinogen intubation. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or diet supplemented with either 150 or 200 mg 13-cis-retinoic acid per kg of diet. A 41 and 43% incidence of urinary bladder cancer was observed in mice given the low and high dose of carcinogen, respectively, and fed a placebo diet. Sixty-seven % of the carcinomas induced in these animals invaded either into or through the urinary bladder wall. Varying degrees of transitional and either squamous or glandular or both squamous and glandular differentiation were observed in the carcinomas. Feeding of diet supplemented with 13-cis-retinoic acid reduced cancer incidence; the degree of reduction was proportional to the dose of retinoid administered. The highly invasive nature of the carcinomas induced by quantitative administration of OH-BBN in B6D2F1, mice provides a useful animal model of the highly invasive variant of human transitional cell urinary bladder cancer in which to study chemoprevention by retinoids as well as other compounds.

Animals↗
PubMed1981

Inhibition of urinary bladder cancer by N-(ethyl)-all-trans-retinamide and N-(2-hydroxyethyl)-all-trans-retinamide in rats and mice.

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.

Animals↗
PubMed1980

Androgen receptors in chemically-induced colon carcinogenesis.

Cytoplasmic extracts (105,000 x g supernatants) prepared from the colon of 1,2-dimethylhydrazine hydrochloride (DMH) treated male BD-IX rats bound 3H-5 alpha-dihydrotestosterone (DHT) with high affinity (Kd = 3 x 10(-9) M) and low capacity (n = 20 fmoles/mg protein). Unoccupied saturable binding sites were not detected in normal intact colon but were observed in colons from gonadectomized rats. DHT receptors were present in both the ascending and descending segments of the colon. The DHT binding components sedimented as 7--8S species on linear sucrose density gradients and were effectively displaced by cyproterone acetate, but not by progesterone. Forty percent of the DMH-induced colon tumors also bound DHT with high affinity and limited capacity. These results suggest that the sex steroids are involved in carcinogen-induced colon tumorigenesis, and the action is mediated by their association with sex steroid specific receptors.

Animals↗
PubMed1980

Distribution of retinoic acid-binding proteins in normal and neoplastic mammary tissues.

Cellular retinoic acid-binding proteins were detected in chemically induced mammary tumors using sucrose density gradient analysis. Unlabeled retinoic acid did not displace nonspecific binding in the 5S region but was, however, a competitive inhibitor for the specifically binding 2S component. Mammary gland cytosol fractions from both 1-methyl-1-nitrosourea-treated and untreated as well as from lactating rats contained low levels of retinoic acid-binding proteins. 1-Methyl-1-nitrosourea treatment did not result in the increased number of binding sites. Thus, the increase in the levels of binding proteins in tumors most probably occurred during tumor development and probably was not a result of the carcinogen per se. Retinoids which have been shown to be effective in the chemoprevention of mammary carcinogenesis only partially competed for the binding sites, indicating that they may be metabolized prior to their action as an active chemopreventive agent.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Inhibition of DNA synthesis by retinyl acetate during chemically induced mammary carcinogenesis.

The effect of retinoids on DNA synthesis was studied in the female Sprague-Dawley rat. Animals were treated with either solvent, 7,12-dimethylbenz(a)anthracene, or 1-methyl-1-nitro-sourea at 50 days of age and were placed on either placebo or retinyl acetate diet at 57 days of age. [3H]Thymidine incorporation into purified DNA isolated from mammary parenchymal cells was determined. Retinyl acetate effectively inhibited mammary cell DNA synthesis in both 1-methyl-1-nitrosourea- and 7,12-dimethylbenz(a)anthracene-treated animals; however, DNA synthesis in solvent-treated animals was unaffected.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Synergistic effect of chronic prolactin suppression and retinoid treatment in the prophylaxis of N-methyl-N-nitrosourea-induced mammary tumorigenesis in female Sprague-Dawley rats.

Two hundred forty Sprague-Dawley rats were treated i.v. with 2.5 or 1.25 mg of N-methyl-N-nitrosourea (MNU) per 100 g body weight at 50 and 57 days of age. At 60 days of age, rats given either dose were divided into 4 groups (30 rats/group) and treated as follows: Group 1, controls; Group 2, 0.4 mg 2-bromo-alpha-ergocryptine (CB-154) per 100 g body weight injected s.c. once daily; Group 3, retinyl acetate (328 mg/kg diet) fed daily; and Group 4, CB-154 and retinyl acetate treatments combined. Rats that received the 2.5-mg dose of MNU were treated for 129 days; those that received the 1.25-mg dose of MNU were treated for 175 days. The rats that were treated with the high dose of MNU were maintained without any treatment for an additional 13 weeks, after which they were sacrificed. The rats that were treated with the low dose of the carcinogen were sacrificed immediately after treatment. All rats were palpated once weekly for palpable mammary tumors. The number of rats with mammary tumors and the total number of mammary tumors at cessation of treatments were, respectively, as follows. MNU (2.5 mg): Group 1, 22 of 30 (73%), 82: Group 2, 11 of 30 (37%), 17; Group 3, 11 of 30 (37%), 19: Group 4, 2 of 30 (7%), 2. MNU (1.25 mg): Group 1, 8 of 30 (27%), 14; Group 2, 4 of 30 (13%), 5; Group 3, 3 of 30 (10%), 4; Group 4, 0 of 30, (0%), 0. Thus, chronic CB-154 treatment or retinyl acetate feeding markedly reduced the percentage of rates bearing mammary tumors and the total number of mammary tumors. The combined treatments were superior to either treatment alone, inasmuch as mammary tumorigenesis was nearly completely blocked in the rats of Group 4 that received the 2.5-mg dose of MNU and was totally blocked in the rats of Group 4 that received the 1.25-mg dose of MNU. Retinyl acetate feeding or CB-154-induced prolactin suppression appear to be equally effective treatments in the prophylaxis of MNU-induced mammary tumorigenesis in rats; the combined modality, however, appears to be far superior than either treatment alone.

Adrenal Glands↗
PubMed1980

Histogenesis and dose dependence of N-methyl-N-nitrosourea-induced carcinoma in a localized area of the hamster trachea.

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.

Adenocarcinoma↗
PubMed1980

Inhibition of 1-methyl-1-nitrosourea-induced mammary carcinogenesis in the rat by the retinoid axerophthene.

The hydrocarbon retinoid, axerophthene, and retinyl acetate were compared for their ability to prevent mammary cancer induced in rats by 1-methyl-1-nitrosourea. Chronic feeding of both retinoids delayed the appearance and lessened the incidence of cancers; retinyl acetate was definitely more active. However, axerophthene was significantly better tolerated by the rats and allowed normal weight gain when fed in high doses, in contrast to retinyl acetate.

Animals↗
PubMed1979

N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat.

The synethesis of a new retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide, which has useful biological properties, is described. This retinoid was more potent than retinyl acetate in reversing keratinization caused by retinoid deficiency in tracheal organ culture. It was markedly less toxic than retinyl acetate when fed p.o. to rats over 2-week or 6-month periods. It was an effective agent for inhibition of the development of breast cancer induced in rats by N-nitroso-N-methylurea, although it was not as potent as retinyl acetate in this regard. However, the lesser toxicity of 4-hydroxyphenylretinamide makes it a superior agent for prevention of breast cancer. High-pressure liquid chromatographic analyses of liver and breast extracts from rats treated for 6 months with retinoids show the pharmacokinetic basis for the superiority of 4-hydroxyphenylretinamide; this retinoid and its metabolites were found in high concentrations in breast tissue, without any measurable accumulation in the liver or evident liver toxicity. In contrast, chronic feeding of retinyl acetate caused marked deposition of retinyl esters in the liver and severe hepatotoxicity. Whole mounts of rat mammary glands, made after chronic feeding of 4-hydroxyphenylretinamide, showed that it had a marked antiproliferative effect on mammary epithelium.

Animals↗
PubMed1979

Effect of delay in administration of 13-cis-retinoic acid on the inhibition of urinary bladder carcinogenesis in the rat.

The effect of a delay in starting 13-cis-retinoic acid treatment on the inhibition of urinary bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine was studied in male Fischer 344 rats. Animals received a total p.o. dose of either 1200, 1800 or 2400 mg N-butyl-N-(4-hydroxybutyl)nitrosamine over a period of six weeks. At either one, five, and nine weeks after the last N-butyl-N-(4-hydroxybutyl)nitrosamine intubation, animals were started on a diet supplemented with 13-cis-retinoic acid (240 mg/kg of laboratory chow) or continued on laboratory chow. Animals were killed at one year after the first carcinogen intubation for histological evaluation of the bladder. Feeding of 13-cis-retinoic acid reduced the incidence, average number, and severity of transitional cell carcinomas as well as hyperplasia and cellular atypia. Furthermore, even a nine-week delay in starting the retinoid feeding did not diminish the ability of 13-cis-retinoic acid to inhibit bladder carcinogenesis.

Animals↗
PubMed1979

Effect of the duration of retinyl acetate feeding on inhibition of 1-methyl-1-nitrosourea-induced mammary carcinogenesis in the rat.

The effect of the duration of retinoid treatment on the inhibition of 1-methyl-1-nitrosourea-induced mammary carcinogenesis was studied. Female Sprague-Dawley rats were given i.v. injections of 50 mg 1-methyl-1-nitrosourea per kg body weight at both 50 and 57 days of age. Feeding of a placebo diet or diet supplemented with 323 mg retinyl acetate per kg diet (retinoid treatment) was initiated at 10 days after the first carcinogen injection. Retinoid treatment was either continued or discontinued after 60 days postcarcinogen, and the study was terminated at 182 days postcarcinogen. Retinoid treatment between 10 and 60 days postcarcinogen prolonged the cancer latency and reduced the average number of cancers per rat in comparison to that in placebo-treated rats. Continuation or cessation of retinoid treatment in 60-day tumor-bearing rats had no effect on the time of appearance of additional cancers. In 60-day tumor-free rats, continuation of retinoid treatment prolonged cancer latency in comparison to either 60-day tumor-free rats changed to placebo or rats continuously treated with placebo. The cessation of retinoid treatment in 60-day tumor-free rats resulted in a rapid increase in the appearance of cancers; at the termination of the study, the average number of cancers per rat was similar to that of animals fed only the placebo. The data indicated that some rats are more responsive to the retinoid than are others. Retinoid treatment apparently prevented the progression of early neoplastic lesions, and a continuous daily intake of the retinoid appears necessary to sustain the chemopreventive effect under the experimental conditions imposed.

Adenocarcinoma↗
PubMed1978

Inhibitory effect of 13-cis-retinoic acid on urinary bladder carcinogenesis induced in C57BL/6 mice by N-butyl-N-(4-hydroxybutyl)-nitrosamine.

The effect of 13-cis-retinoic acid on the induction of urinary bladder carcinoma by N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) was studied in male C57BL/6 mice. Animals received a total dose of either 90 or 140 mg of OH-BBN via gastric intubations of 7.5 or 10.0 mg of OH-BBN 2 times each week for 6 or 7 weeks, respectively. Seven days after the last OH-BBN intubation, animals were fed laboratory chow diet supplemented with either 200 mg of 13-cis-retinoic acid per kg or its placebo. Animals were killed at 6 months after the first carcinogen intubation. Highly invasive squamous and transitional cell carcinomas of the urothelium were found at autopsy. In the majority of these carcinomas, invasion of the bladder muscle wall by tumor cells had occurred. At the two dose levels of OH-BBN, feeding of 13-cis-retinoic acid reduced the incidence of both carcinomas and noninvasive papillomas, as well as the extent of neoplastic development in the urinary bladder. In mice receiving the lower dose of OH-BBN, the feeding of 13-cis-retinoic acid prevented the appearance of both squamous and transitional cell carcinomas with a reduction in incidence from 33 to 0% (p less than 0.01). The results of this study indicate that 13-cis-retinoic acid reduced not only the severity of highly invasive urinary bladder carcinomas but also the incidence of such cancers.

Animals↗
PubMed1977

Influence of gonadal hormones and age on 1,2-dimethylhydrazine-induced colon carcinogenesis.

BD-II and BD-IX male and female rats received weekly subcutaneous (s.c.) injections of 15 mg/kg 1,2-dimethylhydrazine dihydrochloride (DMH) beginning at either 35, 120 or 210 days of age and continuing for 20 weeks. Control animals received only the DMH vehicle. Additional BD-II and BD-IX male and female rats of the three age groups were gonadectomized at 21, 106 and 196 days. Beginning 14 days after gonadectomy, the rats received 15 mg/kg of DMH by s.c. injection once a week for 20 weeks. Animals were sacrificed 35 weeks after the initial DMH injection. Control rats of the appropriate age and sex did not develop colon tumors. BD-IX rats are apparently more sensitive to DMH than BD-II rats. The incidence of DMH-induced cancer is less in females than in males in both the BD-II and BD-IX animals. Gonadectomy does not affect cancer incidence in either BD-II males or females nor in the BD-IX females but reduced the incidence in BD-IX males exposed initially at either 120 or 210 days. Administration of androgen to castrate BD-IX males (120-day-old group) increases the incidence of colon cancer to that approaching the intact animal but has little effect in the BD-II castrate male. These data suggest a genetically influenced susceptibility to DMH-induced colon carcinogenesis between BD-II and BD-IX rats. Furthermore, a sex difference is evident in both BD lines but age appears to be a factor only in older BD-IX females. Apparently, androgens influence DMH-induced tumorigenesis in BD-IX males only if the initial exposure of DMH occurs after sexual maturity.

Adenocarcinoma↗