Inhibition of mammary carcinogenesis by flurbiprofen, a non-steroidal antiinflammatory agent.
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Animals↗
Biomedical subjects
R C Moon
Publications and source records attributed to R C Moon.
Retinoids inhibit prolactin-induced development of the mammary gland in vitro.
Mouse mammary gland organ culture technique was utilized to determine the effects of retinoids on the prolactin-induced structural differentiation of the mammary gland. Thoracic glands from BALB/c mice pretreated with steroids differentiate in 6 days into alveolar structures in presence of insulin and prolactin. All-trans-retinoic acid and N-(-4-hydroxyphenyl)retinamide inhibit prolactin-induced structural changes in the glands. Retinyl acetate, which is effective against mammary carcinogenesis in the rat, but is ineffective against mouse mammary carcinogenesis, failed to inhibit such proliferation. These results were correlated with inhibition of [3H]thymidine incorporation into DNA in a dose related manner by retinoids effective in inhibiting mammary development.
Animals↗
Inhibition of mammary tumorigenesis in nulliparous C3H mice by chronic feeding of the synthetic retinoid, N-(4-hydroxyphenyl)-retinamide.
Feeding of N-(hydroxyphenyl)retinamide (4-HPR) (1.0 mM/kg diet) for 39 weeks to 2 month old nulliparous C3H/Crgl mice significantly (p less than 0.01) reduced the incidence of mammary tumors; 98 control mice developed a total of 235 mammary tumors, 100 4-HPR treated mice developed 171 mammary tumors. Feeding the same dietary level of 4-HPR to 4-6 month old multiparous C3H mice for 14 weeks did not significantly influence the development of mammary tumors; 78 control mice developed a total of 115 mammary tumors; 78 4-HPR treated mice developed 130 mammary tumors. Body weight gains were comparable among 4-HPR treated mice and control mice. Significant suppression of mouse mammary gland tumorigenesis in vivo by dietary retinoids (nulliparous C3H mice) has heretofore not been reported.
Animals↗
Effect of N-(4-hydroxyphenyl) retinamide on food intake, growth, and mammary gland development in rats.
Food intake and growth were depressed during the first week of feeding the anticarcinogenic retinoid N-(4-hydroxyphenyl) retinamide (HPR) at a concentration of 782 mg/kg diet to female rats. Food intake was normalized thereafter, but body weight did not reach that of control animals until 40 days later. The use of a pair-fed group demonstrated that weight depression in HPR fed animals was entirely due to reduced food intake. Mammary glands from HPR-fed animals showed decreased ductal branching and decreased end bud proliferation relative to control glands. Total hepatic retinol and retinol concentration were lower (P less than 0.05) for HPR fed animals than for controls. The effects of HPR on mammary development and retinol storage were attributable to dietary HPR per se. HPR was detected in mammary gland and body fat at concentrations of 27 and 53.7 nmol/g, respectively.
Adipose Tissue↗
Inhibition of carcinogenesis by retinoids.
Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits development of additional mammary cancers following surgical removal of the first mammary cancer. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment is delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods.
Adenocarcinoma↗
Nuclear interactions of retinoic acid-binding protein in chemically induced mammary adenocarcinoma.
Cellular retinoic acid-binding protein (CRABP) was detected in the nuclear fraction of N-methyl-N-nitrosourea-induced mammary cancers after the incubation of cytosol containing [3H]retinoic acid (RA)-bound CRABP with isolated nuclei. CRABP extracted from the nuclei in buffer containing 0.4 M-KCl sedimented as a 2 S component when subjected to sucrose-density-gradient analysis. [3H]RA-CRABP was found to be a prerequisite for the detection of nuclear binding, since the incubation of isolated nuclei or 0.4 M-KCl extract of the nuclei with [3H]RA did not result in any significant binding. Incubation of [3H]RA-CRABP at 25 or 30 degrees C before incubation with the nuclei neither altered the sedimentation coefficient nor enhanced the nuclear binding compared with 0 degrees C incubation. The tumour nuclei contained a saturable number of binding sites with a dissociation constant of 1.6 x 10(-9) M. These results indicate that the action of retinoic acid in the target organ may be mediated by its interaction with the nuclei.
Adenocarcinoma↗
Temporal association between arterial cholesterol deposition, thymidine incorporation into DNA, and atherosclerosis in Japanese quail fed an atherogenic diet.
Male Japanese quail (strain SEA) rapidly develop atherosclerotic lesions in the aorta and brachiocephalic arteries when fed an atherogenic diet containing 1.0% cholesterol and 0.5% cholic acid. The present study was conducted to determine the parameters of the atherosclerotic response. Groups of 20 quail fed the atherogenic diet were killed at 0 days, 1 day, 3 days, or weekly from 1 to 12 weeks. Quail fed the atherogenic diet for 1 day showed a significant increase in serum cholesterol; a plateau was reached by 2 weeks. A significant increase in arterial cholesterol was seen after 2 weeks on the atherogenic diet, and arterial cholesterol showed a linear increase with time from 2 to 12 weeks. Increased incorporation of tritiated thymidine into the DNA of arterial cells was first seen at 2 weeks; thymidine incorporation increased to a maximum value at 9 weeks, then declined to 50-60% of the 9-week value at weeks 11 and 12. Grossly visible atherosclerotic lesions were first seen at 3 weeks, and 90% of birds showed gross atherosclerotic lesions by 8 weeks. Atherosclerosis induced in Japanese quail by feeding cholesterol and cholic acid is characterized initially by lipid deposition in the arterial wall, followed by increased incorporation of tritiated thymidine and the appearance of gross lesions.
Animals↗
Retinoic acid binding proteins and steroid receptor levels in human breast cancer.
Samples of 31 human breast cancer tissues were examined for the presence or absence of cytosolic retinoic acid binding proteins (cRABP), estrogen receptors (ER) and progesterone receptors (PR). cRABP were detected as specifically sedimenting 2S components on sucrose density gradient. Specific binding under the 2S region for cRABP and under the 8S region for ERR and PR were determined. The levels of cRABP ranged from less than 1 pmol to 14 pmol per mg of cytosol protein. Tumors containing less than 3 pmol cRABP were designed as low cRABP; tissues were considered ER- and PR- when the receptor levels were less than 10 fmol/mg protein. Approximately 60% of primary and metastatic tumors examined contained high cRABP. Tumors with well differentiated histopathology exhibited increased levels of cRABP. There was no significant correlation between the presence or absence of steroid receptors and cRABP in human mammary tumors.
Breast Neoplasms↗
Inhibition of chemical carcinogenesis by retinoids.
Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland, esophagus, and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits mammary tumor recurrence following surgical removal of the first mammary tumor. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment if delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods. Current research focuses on the identification of new retinoids with increased chemopreventive activity and decreased toxicity, and combination studies which will provide treatment regimens with increased anticancer activity as well as information pertaining to mechanisms of retinoid action.
Animals↗
Correlation between retinoid inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis and levels of retinoic acid binding proteins.
A correlation was made between the ability of retinoids to suppress N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis and the levels of cytosolic retinoic acid binding proteins (cRABP) in the cytosol of MNU-induced mammary tumors. Although retinyl acetate and N-(4-hydroxyphenyl)-retinamide were found to be effective inhibitors of mammary carcinogenesis in intact hosts, both retinoids were significantly more active in ovariectomized rats than in intact animals. Quantitative analysis of cRABP in the tumors indicated that mammary cancers arising in animals which were ovariectomized one week after MNU administration contained significantly increased concentrations of cRABP compared to cancers appearing in intact rats. In addition, when animals bearing palpable mammary tumors were ovariectomized, the tumors which continued to grow contained significantly higher levels of cRABP than did tumors which stopped growing or regressed. These data suggest that the selective inhibition of ovarian hormone-independent mammary cancer by retinyl acetate and N-(4-hydroxyphenyl)retinamide may be mediated through an increased level of cRABP in tumor cells of ovariectomized hosts.
Animals↗
Influence of 15 retinoic acid amides on urinary bladder carcinogenesis in the mouse.
A series of experiments was conducted to determine the efficacy of 15 synthetic retinoic acid amides (retinamides) as inhibitors of chemical carcinogenesis of the urinary bladder in C57BL/6 x DBA/2F1 mice. Eight of the retinamides tested had significant protective activity when administered at nontoxic levels in the diet. Minor structural alterations, such as the addition of a methyl or hydroxyl group to the terminal amide moiety had a major influence on the anticarcinogenic activity of the retinamides. Although 13-cis retinamides generally were less toxic on a molar basis than were their all-trans isomers, no consistent pattern of differential anticarcinogenic activity was noted among the six pairs of all-trans and 13-cis isomers tested. All-trans-4-hydroxyphenyl retinamide was among the most active and least toxic of the retinoids tested, and appears to be the compound of choice for further study.
Animals↗
Inhibition of mammary and urinary bladder carcinogenesis by a retinoid and a maleic anhydride-divinyl ether copolymer (MVE-2).
N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid, and MVE-2, a maleic anhydride-divinyl ether copolymer, were both effective inhibitors of mammary carcinogenesis induced in Sprague-Dawley rats by N-methyl-N-nitrosourea and of urinary bladder carcinogenesis induced in C57BL/6 x DBA/2F1 mice by N-butyl-N-(4-hydroxybutyl)-nitrosamine. However, combined administration of 4-HPR and MVE-2 was no more effective in cancer inhibition than was either agent alone. Retinoids and maleic anhydridedivinyl ethers may exhibit a mechanistic or metabolic antagonism which precludes an additive or synergistic interaction in inhibiting chemical carcinogenesis.
Animals↗
Enhanced inhibition of mammary carcinogenesis by combined treatment with N-(4-hydroxyphenyl)retinamide and ovariectomy.
Bilateral ovariectomy and dietary administration of the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) are both effective inhibitors of chemical carcinogenesis in the rat mammary gland. The present study was designed to determine whether an enhanced inhibitory effect is obtained with combined ovariectomy and 4-HPR administration, compared to either treatment alone. In separate experiments, 50-day-old virgin female Sprague-Dawley rats received either a single i.v. injection of 50 mg N-methyl-N-nitrosourea per kg body weight or a single intragastric dose of 20 mg 7,12-dimethylbenz(a)anthracene. The experimental design was the same in both the N-methyl-N-nitrosourea and 7,12-dimethylbenz(a)anthracene experiments: Group 1, 25 intact rats, placebo diet; Group 2, 25 intact rats, supplement of 782 mg 4-HPR per kg diet; Group 3, 50 ovariectomized rats, placebo diet; Group 4, 50 ovariectomized rats, supplement of 782 mg 4-HPR per kg diet. Feeding of the 4-HPR supplement was begun 7 days after carcinogen administration; ovariectomy was performed 7 days post-7,12-dimethylbenz(a)anthracene or 14 days post-N-methyl-N-nitrosourea. In both experiments, combined ovariectomy plus 4-HPR was significantly more active in suppressing mammary cancer induction than was either manipulation alone. 4-HPR was a more effective inhibitor of carcinogenesis in ovariectomized rats than in intact animals. These data indicate that 4-HPR is highly effective in inhibiting ovarian hormone-independent cancers and suggest that retinoid inhibition of mammary carcinogenesis does not involve an influence on ovarian hormone action.
9,10-Dimethyl-1,2-benzanthracene↗
Influence of delayed administration of retinyl acetate on mammary carcinogenesis.
Administration of a dietary retinoid supplement beginning 1 week after carcinogen administration is highly effective in the inhibition of rat mammary carcinogenesis. A study was designed at two carcinogen dose levels to determine to what extent retinoid feeding can be delayed and retain its chemoprotective effect. In the high-dose experiment, groups of 30 virgin female Sprague-Dawley rats received a single i.v. dose of 50 mg N-methyl-N-nitrosourea (MNU) per kg body weight and were fed a dietary supplement of 328 mg retinyl acetate per kg diet beginning at 1, 4, or 8 weeks after MNU administration. In the low-dose experiment, groups of 50 rats received 25 mg MNU per kg, and the retinoid was begun at 1, 4, 8, 12, 16, or 20 weeks post-MNU. Controls at both dose levels received a placebo diet beginning 1 week after carcinogen treatment. At the high MNU dose, retinyl acetate was most effective in inhibition of carcinogenesis when treatment was begun 1 week after MNU administration. Delaying retinyl acetate feeding until 4 weeks post-MNU resulted in slightly reduced chemoprotective efficacy, while an 8-week delay caused a complement loss of anticancer activity. At the low MNU dose, delaying retinyl acetate administration for up to 12 weeks after MNU administration caused no loss of chemopreventive efficacy. A 16-week delay resulted in decreased anticancer activity, while retinoid treatment begun 20 weeks post-MNU had no effect on cancer induction. Retinoid administration can be delayed beyond 1 week and retain its activity against rat mammary carcinogenesis; the length of delay allowable without loss of activity is a function of tumor latency.
Animals↗
Hormonal regulation of retinoic acid-binding proteins in the mammary gland.
A cytosolic retinoic acid-binding (RAB) protein that sediments specifically as a 2S component on sucrose density gradients was detected in the mammary glands of virgin, pregnant and lactating rats. Mammary cytosol from pregnant rats contained significantly higher concentrations of cytosolic RAB protein than did cytosol from either virgin or lactating rats. The glands of pregnant animals exhibited increased concentration of cytosolic RAB protein during the first 5 days of pregnancy, and a steady decline was observed thereafter. The concentration of cytosolic RAB protein dropped to the value observed during lactation on the day 20 of pregnancy. Moreover, throughout lactation, low concentrations of cytosolic RAB protein were maintained. Daily treatment of virgin and lactating animals with 5 micrograms of oestradiol-17 beta for 1 week increased cytosolic RAB protein to concentrations comparable with those seen in pregnant rats. Progesterone, however, did not affect the mammary cytosolic RAB protein content of virgin rats. These results suggest hormonal involvement in the regulation of cytosolic RAB protein concentration of mammary gland during differentiation.
Animals↗
Retinoid binding in normal and neoplastic mammary tissue.
The inhibitory effect of dietary supplementation of certain retinoids on mammary carcinogenesis in the rat has been reported from our laboratory. Specific cytosolic retinoic acid binding proteins (cRABP) as well as retinol binding proteins sedimenting as 2S components have been detected in the mammary tissue during normal and neoplastic differentiation. Relatively higher levels of cRABP were observed in the mammary glands from pregnant animals as well as in ovarian hormone independent tumors; whereas in glands obtained from lactating rats and in hormone dependent tumors, lower levels of cRABP were evident. Exogenous treatment of such animals with estradiol-17 beta enhanced the levels of cRABP. The results indicate a possible correlation between endocrine and retinoid function in both normal and neoplastic differentiation of mammary tissue. [3H]retinoic acid-RABP complex, under appropriate conditions, translocates into th nucleus. Unbound [3H]retinoic acid, however, failed to associate with the nuclear sites. Additional studies indicate a possible selective inhibition of ovarian hormones independent tumors by the retinoids.
Animals↗
Influence of total dose and dose schedule on induction of urinary bladder cancer in the mouse by N-butyl-N-(4-hydroxybutyl)nitrosamine.
Dose-response relationships in the induction of urinary bladder cancer in male C57BL/6 x DBA/2-F1 (BDF) mice by intragastric instillation of N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) were studied. Administration of a total dose of 0 to 80 mg OH-BBN in 10 weekly fractions to groups of 25 mice resulted in a linear increase in carcinoma incidence with dose. OH-BBN administration schedule had a significant effect on cancer incidence: administration of a total dose of 30, 20, or 15 mg OH-BBN in 20 weekly fractions was more effective in cancer induction than was the same total dose given in 5 fractions. A 10 dose administration schedule was of intermediate efficacy. The data obtained indicate that OH-BBN induces urinary bladder cancers in BDF mice in a dose-related manner, with high target organ-specificity, little toxicity, and short tumor latency; induced tumors are primarily transitional cell carcinomas which morphologically resemble their human counterpart. Administration of OH-BBN mice provides a useful model for the experimental study of urinary bladder cancer.
Animals↗
Carcinogenicity of N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea when applied to a localized area of the hamster trachea.
The carcinogenicity of N-methyl-N-nitrosourea (MNU) and N-ethyl-N-nitrosourea (ENU) was studied with the use of a hamster tracheal tumor model system. Hamsters received 15 or 10 once-weekly treatments of either a 0.5 or 0.25% solution of MNU and were killed 9 months after the first intratracheal instillation. Other hamsters received 15 once-weekly treatments of a 0.5, 0.25, or 0.125% solution of ENU and were killed at 6 months. Treatment with MNU resulted in a dose-dependent induction of tracheal carcinomas; 94% of the tumors induced were combined epidermoid and adenocarcinomas. Treatment of hamsters with a 0.5, 0.25, 0.125% solution of ENU induced an 83, 64, and 71% incidence of benign tracheal tumors, respectively (papillomas and polyps). No tracheal carcinomas were induced by ENU. The carcinogenicity of MNU and the reproducibility of tumor induction with the use of the localized tracheal washing, tumor model system were confirmed. Furthermore, the sensitivity of the localized tracheal washing technique for the detection of the tumorigenicity of compounds toward respiratory epithelium was demonstrated.
Adenocarcinoma↗