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Biomedical subjects

C C Brown

Publications and source records attributed to C C Brown.

At least 145 records · Page 8Linked to original sources
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

Stroke rehabilitation--is age a determinant?

A retrospective survey was made of the average improvement, length of stay, and discharge placement of 180 stroke patients admitted to a rehabilitation hospital. The patients were divided into four age groups: under 55, 55-65, 66-75, and over 75. A grading system was used for evaluating the patient's ability in ambulation and self-care. No significant differences were found among the four age groups. The patients were then divided into subgroups depending upon the admission functional score: 0-20, 21-40, 41-60, and over 60. In the subgroups, no statistically significant differences were apparent for the average improvement of patients under age 55 as compared to those over 75, except for those whose initial functional score was 21-40. In this subgroup, the average improvement for patients under age 55 was 26.4 points with a length of stay of 31.9 days, whereas for those over age 75 the average improvement was 15.5 points with a length of stay of 25.9 days. Thus, age per se did not seem to be a determinant factor in successful rehabilitation; rather, the poor showing of the oldest group for the 21-40 score in the sub-set may have been due to premature discharge.

Activities of Daily Living↗
PubMed1980

Multistage models and primary prevention of cancer.

Removal of carcinogenic exposures should reduce the subsequent risk for developing cancer. Of interest are the extent of the reduction and the speed with which it takes place. Multistage models with more than two stages for tumor development predict different patterns of chaniging risk following removal of a carcinogenic exposure, depending upon the stage in the process that the carcinogen predominantly affects. The fall in risk following removal of a early-stage carcinogen is only slowly evident, whereas removal of a late-stage carcinogen leads to a more rapid reduction in excess risk. Experimental and epidemiologic data are reviewed, and both early- and late-stage effects are seen. The long-term danger arising from entry into the environment of early-stage carcinogens is discussed, and it is shown that by the time human evidence that a hazard does exist becomes available, those already exposed may well have accumulated their fully effective doses.

Age Factors↗
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↗
PubMed1980

An analysis of comparative carcinogenesis experiments based on multiple times to tumor.

Methods are given for the comparison of two treatment groups in experiments giving rise to multiple tumors. Methods based on the gaps in time between successive tumors are emphasized, but, for comparison, one method based directly on times to tumor is also presented. When applied to the results of an experimental animal carcinogenesis study, these analyses show that a diet supplemented with retinyl acetate reduces the hazard of mammary tumors, compared with controls, in every gap, and they allow one to combine evidence from the several gaps to obtain a powerful test for treatment effect.

Animals↗
PubMed1979

Effects of L-tryptophan on sleep onset insomniacs.

Eighteen female subjects with demonstrated laboratory sleep onset latency greater than 20 minutes for two nights participated in this double blind study of the effectiveness of l-tryptophan as a hypnotic. Standard sleep recordings were made on 10 nights over a 3 month period with lights out occurring 20 minutes after drug administration (placebo, 1 gm. l-tryptophan, 3 gms. l-tryptophan). Neither dose of l-tryptophan differed from placebo as to the amount of REM, SWS or wakefulness, but 3 gms. significantly reduced sleep onset latency on some of the nights. Those subjects with latencies longer than 40 mins. had the greatest reduction in latency with 3 gms. and also evidenced high levels of anxiety on the Taylor Manifest Anxiety Scale initially. Subjects with latency between 20 and 40 minutes appeared to receive the longest lasting hypnotic effect from the higher dose. Adaptation to the sleep lab took place across the entire 10 nights of the study. Therefore, valid comparisons between treatments in a sleep study extending over a number of nights should be made between temporally adjacent samples.

Clinical Trials as Topic↗
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

Statistical aspects of extrapolation of dichotomous dose-response data.

A mathematical model based on the hypothesis that carcinogenesis is a multistage process was proposed for the statistical problem of extrapolating the results of bioassay experiments performed at high dose levels of the carcinogenic risk at lower dose levels. This general multistage model had extrapolation characteristic similar to those of the more specific models that are commonly used; a graphic technique based on statistical likelihood procedures provided a measure of the uncertainty in this extrapolation problem. The examples used were 1) exposure to DES and mammary carcinoma and 2) exposure to DMN and liver carcinoma.

Animals↗
PubMed1978

Estimating cancer risks to a population.

Three important issues impinge on estimating the risk of cancer to a population: (1) How can one use epidemiologic studies on one population to tell us what is likely to happen to other populations? (2) How can one use nonhuman data (i.e., laboratory experiments) to tell us what is likely to happen to humans? (3) What reasonable assumptions can be used to guide the logical extension of information from the laboratory to expectations for man, and what research is needed to support or modify these assumptions? Four principles currently guide our laboratory-to-man extrapolations: effects in animals, properly qualified, are applicable to man; methods do not now exist to establish a threshold for long-delayed effects such as cancer; the exposure of experimental animals to high doses is a necessary and valid method of discovering possible carcinogenic hazards in man; materials should be assessed in terms of human risk rather than as "safe" or "unsafe".

Animals↗
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

13-cis-retinoic acid: inhibition of bladder carcinogenesis in the rat.

Transitional cell and squamous cell cancer of the bladder was induced in Wistar/Lewis female rats by direct instillation of N-methyl-N-nitrosourea into the bladder. Feeding of the synthetic retinoid, 13-cis-retinoid acid, inhibited the incidence and extent of bladder cancer in these rats, even when 13-cis-retinoic acid administration was begun after completion of the carcinogen treatment.

Animals↗
PubMed1977

Comparative epidemiology of carcinoid and oat-cell tumors of the lung.

Oat-cell carcinoma and bronchial carcinoid share histologic features with the Kultschitzky cell, and this argues for a common origin from the Kultschitzky cell for these tumors. In this view, the carcinoid represents the less malignant form and the oat-cell carcinoma the highly malignant adenocarcinoma of the colon, the epidemiologies of the benign and malignant forms of tumor arising from the same precursor are similar. However, the epidemiology of carcinoid tumor and that of oat-cell carcinoma are different. Although the ectopic production of hormones links the two kinds of tumor, it is also seen in other histologic types of lung carcinoma. Lung carcinoids occur in the genetic disorder of multiple endocrine adenomatosis, suggesting a genetic etiology for at least some carcinoids. This contrasts with the exogenous etiologic agents of cigarette smoking, occupational exposure, and urban domicile for oat-cell carcinoma. All these strong differences between lung carcinoid and oat-cell carcinoma indicate a markedly different process of carcinogenesis, which casts doubt on the hypothesis of a common cell precursor.

Age Factors↗