Hormones influencing postpartum growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors.
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Adenocarcinoma↗
Biomedical subjects
R C Moon
Publications and source records attributed to R C Moon.
Effect of 3-methylcholanthrene on thyroid function in Sprague-Dawley rats.
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Animals↗
Effect of all-trans-retinoic acid on nuclear RNA polymerase activity in chemically-induced rat mammary tumors.
In the present study the effect of all-trans-retinoic acid (RA) on nuclear RNA polymerase activity in N-methyl-N-nitrosourea (MNU)-induced mammary tumors was investigated. Three experimental protocols were used. (1) The tumor mince was incubated with 1 microM RA for 30 min at 30 degrees C; the RNA polymerase activity was measured in the purified nuclei and compared with control nuclei. (2) In order to evaluate the influence of retinoic binding protein on enzyme activity, mammary tumor nuclei were incubated with RA bound cytosolic retinoic acid binding protein complex (RA-CRABP) at 25 degrees C for 30 min. This step allows the complex to translocate into the nuclei. The enzyme activity in these nuclei was compared with the nuclei pre-incubated with buffer or cytosol. (3) Finally, the influence of the addition of RA-CRABP complex directly into the RNA polymerase reaction mixture was determined and compared with appropriate controls. Results indicated that the RNA polymerase activity in the nuclei of RA treated tissue as well as in the nuclei subsequent to the translocation step was significantly reduced. However, the addition of RA-CRABP into the reaction mixture did not alter the enzyme activity. These results suggest that alteration of RNA polymerase activity may be an essential step in the retinoid action in mammary tissues.
Animals↗
Dietary retinoids and carotenoids in rodent models of mammary tumorigenesis.
In this review of the scientific literature the relationship between retinoids, carotenoids, and mammary carcinogenesis is examined. Several retinoids have shown promise as chemopreventive agents against chemically induced mammary carcinogenesis in mice and especially in rats. The most promising retinoids are retinyl acetate (RA) and N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide). In rats, dietary administration of these retinoids reduced tumor incidence and multiplicity, and increased the latency of DMBA or MNU-induced mammary cancers. In mice, 4-HPR reduced the number of hyperplastic alveolar nodules and the number of tumors in MTV- and MTV+ mice, respectively. Among retinoids, 4-HPR is at present the most promising analogue, due to its ability to concentrate in the mammary gland. The combination of 4-HPR with tamoxifen not only is more effective in suppressing breast cancer than either agent alone, but also inhibits the appearance of subsequent cancers following the surgical removal of the first tumor. These studies suggest that retinoids, like tamoxifen, may be applicable to the prevention of contralateral breast cancer in women who underwent breast cancer surgery. It is also becoming evident that differentiation therapy and chemoprevention can become attractive alternative approaches to intensive cytotoxic chemotherapy. The role of carotenoids in the prevention of mammary carcinogenesis, however, is ambiguous. Poor absorption and low levels of carotenoids that reach the target tissues complicate interpretation of data in rodent models of mammary carcinogenesis. Very few animal studies are presently available in which purified carotenoids were found effective against mammary carcinogenesis. These results do not justify undertaking clinical evaluation of individual carotenoids against breast cancer at this time.
Animals↗
Chemoprevention of MNU-induced mammary tumors in the mature rat by 4-HPR and tamoxifen.
The chemopreventive efficacies of the retinoid all-trans-N-(4-hydroxyphenyl)-retinamide (4-HPR) and the anti-estrogen tamoxifen citrate were evaluated against N-methyl-N'-nitrosourea (MNU) induced mammary cancer in 120-day old female Sprague-Dawley rats. The agents were tested alone and in combination. They were administered in a modified AIN-76A diet, beginning 60 days prior to a single i.v. dose of 50 mg MNU/kg-bw and continuing until the end of the study, 180 days post-carcinogen treatment. At 782 mg/kg diet, 4-HPR alone significantly inhibited the induction of mammary adenocarcinomas compared with carcinogen controls. At 0.250 mg/kg diet, tamoxifen alone reduced tumor incidence compared with carcinogen controls. At 0.125 mg/kg diet, tamoxifen was ineffective. Combinations of 782 mg 4-HPR/kg diet with either 0.250 or 0.125 mg tamoxifen/kg diet were effective in inhibiting MNU-induced adenocarcinomas. The reductions in tumor incidence were greater for these combinations than for either agent alone. 4-HPR and 0.250 mg tamoxifen/kg diet decreased tumor incidence 81% (p less than 0.005), whereas 4-HPR and 0.125 mg tamoxifen/kg diet decreased tumor incidence 72% (p less than 0.005) compared with carcinogen controls. The combination of 391 mg 4-HPR/kg diet and 0.500 mg tamoxifen/kg diet was also tested and was effective in reducing tumor incidence.
Administration, Oral↗
Influence of thiols and inhibitors of prostaglandin biosynthesis on the carcinogen-induced development of mammary lesions in vitro.
Mouse mammary gland undergoes physiological changes, comparable to that in the animal, under appropriate hormonal conditions in organ culture. Moreover, they form mammary lesions when exposed to the carcinogen, dimethylbenz(a)anthracene (DMBA) for a short duration. This organ culture system was utilized in the present of study to evaluate activity of two groups of potential chemopreventive agents. Activity of inhibitors of prostaglandin synthesis and thiols was determined at five concentrations. The average incidence of mammary lesions induced by DMBA was 60%, oltipraz oxithiazolidine, thioctic acid and N-acetylcysteine were effective at different concentrations, whereas diallyldisulfide, sulfasalazine and ajoene were marginally effective. Within the inhibitors of prostaglandin synthesis category, aspirin, ibuprofen and indomethacin were effective, whereas dipyridamol, piroxicam and pentoxyphyllin were ineffective. The results correlated well with the known in vivo effects of these agents on chemically induced carcinogenesis of mammary gland. The study provides evidence for the use of mammary gland organ culture as a screening total system for prediction of effective chemopreventive agents against mammary carcinogenesis.
9,10-Dimethyl-1,2-benzanthracene↗
Characterization of effective chemopreventive agents in mammary gland in vitro using an initiation-promotion protocol.
Mouse mammary glands respond to carcinogen stimulus to form mammary lesions in organ culture. Prevention of the formation of mammary lesion has been utilized as a test to evaluate the effectiveness of a variety of classes of agents. In the present study we determined whether the effective chemopreventive agents are active against initiation or the promotion phase of lesion development. Mammary glands were subjected to 24 hours exposure to 2 mg/ml dimethylbenz (a) anthracene (DMBA) followed by a 5 day exposure to 7,12-tetradecanoyl phorbol - 13 - acetate (TPA). This treatment protocol allows one to study initiation and promotion aspects of lesion development. Chemopreventive agents effective when present prior to the carcinogen were considered as anti-initiators, whereas agents effective when present after the DMBA treatment along with TPA were considered as anti-promoters. Within the chemopreventive agents evaluated, limonene, oltipraz, aspirin, curcumin and b-sitosterol were anti-initiators. Esculatin, thiolutin, silymarin, DHEA and a few others were found to be anti-promoters. Results presented in this report can be utilized to study the efficacy of these agents in vivo.
9,10-Dimethyl-1,2-benzanthracene↗
Interspecies analysis of the chemopreventive efficacy of dietary alpha-difluoromethylornithine.
The anticarcinogenic efficacy of the polyamine biosynthesis inhibitor, alpha-difluoromethylornithine (DFMO), was assessed in three rodent models of human epithelial cancer. In DMBA-induced female, Sprague-Dawley rats, DMFO treatment (3.2 or 6.4 g/kg diet) for 180 days significantly inhibited mammary carcinogenesis and reduced tumor-related intercurrent mortality compared to untreated controls. In male, C57BL/6x DBA/2F1 mice induced with N-butyl-N(4-hydroxybutyl)nitrosamine (OH-BBN), DFMO treatment (2 or 4 g/kg diet) concurrent with the period of carcinogen administration significantly reduced the incidence and severity of urinary bladder carcinomas. In methylnitrosourea (MNU)-induced male Syrian golden hamsters, DFMO (3.2 g/kg diet) numerically reduced the incidence and size of tracheal carcinoma relative to untreated controls. DFMO-mediated toxicity was not evident in any of the animals on study, although a slight reduction in mean body weight gain was evident in rats and mice.
Animals↗
N-(4-hydroxyphenyl)-all-trans-retinamide pharmacokinetics in female rats and mice.
The distribution of N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR) and its metabolites was investigated in the liver, serum, mammary gland, and urinary bladder of female rats and mice. Following an iv dose of 5 mg/kg to rats, 4-HPR distributed to all tissues examined with the highest levels reached in the liver. The distribution period was completed in about 4 hr and was followed by first order elimination kinetics. The t1/2 for 4-HPR elimination from the liver was 9.4 hr, from the serum was 12.0 hr (not significantly different from liver), from the mammary gland was 43.6 hr, and from the urinary bladder was 9.3 hr. A 5-day ip dosing study (5 mg/kg/day of 4-HPR) in both rats and mice revealed that 4-HPR distributed to all tissues examined with the highest levels reached in the urinary bladder. 4-HPR and four metabolites were detected in the tissues. One coeluted with a cis isomer of 4-HPR (M2), another with N-(4-methoxyphenyl)-all-trans-retinamide (4-MPR) (M3), a third appeared to be a 4-HPR-ester (M4), and the fourth remains unidentified (M1). However, the amount of each metabolite varied between tissues and between species. The concentration of 4-HPR was significantly 2-4 times lower and the percentage of M3 (4-MPR) was 3 times higher in the mouse tissues than in the corresponding tissues of the rat. M2 (cis-4-HPR) and M4 (4-HPR-ester) were present in rat liver but not in mouse liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of pretreatment with the retinoid N-(4-hydroxyphenyl)-all-trans-retinamide and phenobarbital on the disposition and metabolism of N-(4-hydroxyphenyl)-all-trans-retinamide in mice.
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.
Animals↗
A correlative approach for the identification of antimutagens that demonstrate chemopreventive activity.
Seventy natural and synthetic compounds were tested for potential to inhibit mutation induced by 7,12-dimethylbenz(a)anthracene (DMBA) in Salmonella typhimurium strain TM677. Results were compared with their ability to inhibit DMBA-induced preneoplastic lesions in a mouse mammary gland organ culture system. The response mediated by fifty-five of the test compounds was either positive or negative in both test systems, indicating that the combined use of these assays should aid in the discovery of antimutagenic agents that have cancer chemopreventive potential.
9,10-Dimethyl-1,2-benzanthracene↗
Structure-activity relationships of brassinin in preventing the development of carcinogen-induced mammary lesions in organ culture.
Brassinin, a phytoalexin, is found in Chinese cabbage. Previously, we showed that brassinin significantly inhibited dimethylbenz(a)anthracene (DMBA)-induced mammary lesions in organ culture. Moreover, it was an effective inhibitor against two stage skin carcinogenesis. In the present study, we synthesized several analogs of brassinin and evaluated their effectiveness in the mouse mammary gland organ culture model. Results showed that cyclobrassinin, also a naturally occurring brassinin analog, was more effective than brassinin. Spirobrassinin and N-ethyl-2,3-dihydrobrassinin also significantly inhibited mammary lesion formation. However, none of the methyl substituted analogs were effective. The effects of brassinin may, in part, be mediated by induction of phase II detoxifying enzymes such as quinone reductase.
9,10-Dimethyl-1,2-benzanthracene↗
Chemoprevention of MNU-induced mammary tumorigenesis by hormone response modifiers: toremifene, RU 16117, tamoxifen, aminoglutethimide and progesterone.
The effects of structurally different antiestrogens, progesterone and the aromatase inhibitor aminoglutethimide, were evaluated for chemopreventive activity in the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model. Treatment with either RU 16117, progesterone or aminoglutethimide resulted in a significant decrease in cancer multiplicity [> or = 50%; P < .05] when administered individually at doses 80% of the maximally tolerated dose [MID]. Toremifene was also remarkably effective in inhibiting MNU-induced mammary tumorigenesis although this inhibition was achieved at a dose which caused a significant decrease in body weight gain. Aminoglutethimide, RU 16117 and toremifene citrate, in addition to their effects on tumor multiplicity, caused significant increases in the latency period for tumor development. Combinations of aminoglutethimide, progesterone and/or a suboptimal dose of tamoxifen citrate also proved to be effective in inhibiting the development of MNU-induced mammary cancers; however, the combination regimen was no more effective than either aminoglutethimide or progesterone administered alone. These results suggested that agents altering the hormonal environment, regardless of their mechanism of action, may provide protection against the development of hormone responsive mammary cancer.
Aminoglutethimide↗
Chemoprevention of OH-BBN-induced bladder cancer in mice by oltipraz, alone and in combination with 4-HPR and DFMO.
The chemopreventive efficacy of the schistosomicidal drug oltipraz (5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione) was evaluated against urinary bladder transitional cell carcinoma (TCC) induced in male C57BL/6 x DBA/2FI (BDF) mice by N-butyl-N(4-hydroxybutyl)nitrosamine (OH-BBN). Oltipraz was fed in the diet from one week prior to OH-BBN dosing until sacrifice, six months later. The agent at 250 mg/kg diet significantly reduced the incidence of TCC compared with that in carcinogen controls. Oltipraz also significantly reduced TCC incidence when fed at 500 mg/kg diet for 76 days, then at 125 mg/kg diet until the end of the test period. Treatment with this higher dose level of oltipraz also appeared to decreases the depth of tumor invasion. At lower dose levels of 100 and 200 mg/kg diet, oltipraz alone had no effect on tumor incidence. It also was tested at these dose levels in combinations with 2-difluoromethylornithine (DFMO) and with all-trans-N-(4-hydroxyphenyl)retinamide (4-HPR). Treatment with the combination of 640 mg DFMO/kg and 100 mg oltipraz/kg diet was efficacious, although DFMO alone at 640 mg/kg diet was inactive. The combination of 1280 mg DFMO/kg and 200 mg oltipraz/kg diet reduced TCC incidence significantly compared with carcinogen controls, but the effect was no greater than that of DFMO alone at 1280 mg/kg, and weight gain was suppressed compared with carcinogen controls. The depth of tumor invasion was decreased with this combination treatment. Combinations of oltipraz at 100 and 200 mg/kg diet, 4-HPR at 156 and 313 mg/kg diet, and DFMO at 640 and 1280 mg/kg diet were efficacious and without apparent toxicity. Nonetheless, the three agent combinations cannot be considered more effective than DFMO alone at 1280 mg/kg diet or the lower dose combination of oltipraz and DFMO.
Animals↗