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Biomedical subjects

C Ip

Publications and source records attributed to C Ip.

At least 91 records · Page 5Linked to original sources
PubMed1989

New approaches to cancer chemoprevention with difluoromethylornithine and selenite.

New approaches to enhancing D,L-alpha-difluoromethylornithine (DFMO) inhibition of DMBA-induced mammary tumorigenesis were investigated. It is reasoned that perturbation of a second regulatory element in polyamine biosynthesis, i.e., the generation of propylamine groups from S-adenosylmethionine (AdoMet), would potentiate the effectiveness of DFMO. Precursor availability for AdoMet was limited when rats were fed a low methionine diet. The diet of control rats was supplemented with 0.3% methionine. DFMO, when added to the diet at 0.1%, suppressed tumorigenesis, regardless of methionine levels, although its efficacy was significantly enhanced by the low methionine diet. Selenite, another effective chemopreventive agent in this tumor model, also requires AdoMet for its metabolism. However, the anticarcinogenic action of selenite is not compromised by low dietary methionine. The differential sensitivity of DFMO and selenium chemoprevention to low dietary methionine, therefore, provides an opportunity to test for an additive effect. Results of the combination regimen study showed that the incidence and yield of DMBA-induced mammary tumors were significantly lower in the two-agent protocol compared to either DFMO or selenite alone. The mechanism(s) that accounts for the heightened efficacy of combined DFMO and selenite chemoprevention will be discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Tissue selenium levels in selenium-supplemented rats and their relevance in mammary cancer protection.

The present study was designed to investigate whether there is any correlation between the anticarcinogenic efficacy of selenium (Se) compounds and tissue Se retention under high levels of supplementation. With the use of the dimethylbenz[a]anthracene-induced mammary tumor model in chemoprevention experiments, our data showed that selenomethionine was not as active as selenite over a graded dose range from 1 to 5 p.p.m. Se. Tissue Se concentrations in blood, liver, kidney and skeletal muscle were always higher in rats given selenomethionine compared with those given selenite at each of the three levels tested (1, 3 and 5 p.p.m. Se). The difference was only minimal in blood, but became more pronounced in the liver and kidney, and was quite dramatic in the skeletal muscle. Thus a high tissue concentration or total body burden of Se is not necessarily an indicator of reduced susceptibility to carcinogenesis. The bioavailability of the Se pool in maintaining liver glutathione peroxidase activity during a period of Se deprivation, following excess selenite or selenomethionine loading, was also assessed. The half-life of decay of the enzyme was calculated to be 4.2 and 9.1 days respectively, in those rats that had already been exposed to 3 p.p.m. Se as either selenite or selenomethionine. From a nutritional viewpoint, selenomethionine may be superior to selenite, especially with respect to maintenance of glutathione peroxidase during periods of Se inadequacy, but the reverse seems to be true in terms of anticarcinogenic potency under high levels of Se supplementation. These results suggest that the nutritional and anticarcinogenic efficacies of a given Se compound may not be parallel to each other.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

A comparison of the effects of the prostaglandin synthesis inhibitors indomethacin and carprofen on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats fed different amounts of essential fatty acid.

The effects of the cyclooxygenase inhibitors indomethacin and carprofen on the enhancement of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis by dietary linoleate have been compared in female Sprague-Dawley rats. Indomethacin and carprofen, 0.004% and 0.02% (w/w) in the diet, respectively, were fed to rats receiving 20% fat diets containing 0.5, 4 or 12% linoleate starting 7 days after administration of 5 mg DMBA i.g. Indomethacin was shown to have a marked inhibitory effect on mammary tumorigenesis in rats fed the 4 and 12% linoleate diets, but did not alter tumorigenesis in rats fed the 0.5% linoleate diet. In contrast, carprofen was not inhibitory in any of these dietary groups, or in a separate experiment in which a 5% fat--3% linoleate diet was fed. The effect of each drug on prostaglandin E2 (PGE2) levels in normal mammary glands enriched in epithelial cells after a 3-week pretreatment with 17 beta-estradiol and progesterone was also investigated. Carprofen was shown to reduce PGE2 levels to a similar or greater extent than indomethacin at each level of linoleate in the diet. These data demonstrate that a reduction in PGE2 synthesis in the mammary epithelium does not correlate with inhibition of mammary tumorigenesis, and that other factors, including possible alterations in other products of the arachidonic acid cascade, are responsible for this inhibitory effect.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Exercise training and the differential prolactin response in male and female rats.

Adult male and female Sprague-Dawley rats were trained on a horizontal treadmill for 0, 1, 3, 5, or 7 days/wk for 10 wk. Speed and duration were progressively increased over 5 wk to a maximum of 20 m/min for 1 h. Between weeks 9 and 10 of training, animals were placed on the nonmoving treadmill, and blood (500 microliters) was sampled via chronic venous cannulas 30 min before, 0, 10, 20, 30, 45, and 60 min during exercise, and 15, 30, 60, 90, and 120 min after exercise. In another study, resting animals in the various groups were injected with thyrotropin-releasing hormone (TRH; 2 micrograms/kg for males and 0.4 microgram/kg for females) to determine pituitary prolactin responsiveness. In males, exercise induced a significant increase in plasma prolactin levels, with the greatest increase observed in the least trained and the smallest increase in the most highly trained animals. Female rats displayed the opposite trend with the greatest increase in prolactin secretion observed in the highest trained and the smallest increase observed in the least trained animals. TRH induced similar increases in plasma prolactin in all male groups, whereas TRH-induced prolactin release was greatest in the highest trained and smallest in the least trained females. The reduced prolactin response in highly trained males may reflect their acclimation to repetitive exercise stress, whereas the enhanced response in the highly trained female rats appears to result from increased pituitary sensitivity to prolactin-releasing factors.

Animals↗
PubMed1988

Differential effect of dietary methionine on the biopotency of selenomethionine and selenite in cancer chemoprevention.

The influence of a low methionine intake on the chemopreventive efficacy of selenomethionine versus selenite was compared in the 7,12-dimethylbenz[a]anthracene-induced mammary tumor model in rats. Animals were fed from weaning a purified 20% casein diet with or without 0.3% methionine supplementation. Selenomethionine or selenite, at a final concentration of 3 ppm of selenium (Se), was added to the diet starting 5 days after DMBA administration. Control rats continued to receive the basal diets which contained 0.1 ppm of Se. Results of the carcinogenesis experiment indicated that suboptimal dietary methionine significantly reduced the protective effect of selenomethionine in cancer prevention. In contrast, the efficacy of selenite was not affected. In rats given 3 ppm of selenomethionine, tissue Se was actually higher in those fed a diet with a suboptimal amount of methionine than in those with an adequate intake of methionine. On the other hand, dietary methionine did not influence the level of tissue Se in animals given selenite. An increase of dietary methionine to 0.6% did not enhance the efficacy of selenomethionine in cancer protection but would allow the use of a higher level of selenite without the accompanying adverse effects. The biological significance of Se utilization under suboptimal or adequate methionine intake was also assessed using the glutathione peroxidase assay in the liver of Se-deficient rats given graded levels of Se as either selenite or selenomethionine. The enzyme study demonstrated that low dietary methionine decreased the nutritional biopotency of selenomethionine in restoring glutathione peroxidase activity but not that of selenite. These experiments suggest that adequate methionine intake is required for the utilization of selenomethionine for nutritional and anticarcinogenic purposes.

Animals↗
PubMed1988

Feasibility of using lower doses of chemopreventive agents in a combination regimen for cancer protection.

In experimental cancer chemoprevention studies, the doses of the agent used to produce an inhibitory response are generally very high, sometimes bordering on levels that will result in toxicity to the test animals. The present study was designed to test the hypothesis that low doses of two or more agents may be just as effective as high doses of a single agent. An earlier report from our laboratory showed that vitamin E, although ineffective by itself, potentiates the anti-carcinogenic potency of selenite. Our objective was to complete a comprehensive set of dose titration experiments in the quantitative analysis of the synergism between selenium (Se) and vitamin E. Results indicated that the minimal amount of vitamin E required was around 500 ppm, which when combined with as little as 1 ppm Se, produced a significant protective effect in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor model. This level of Se is 5 times below the marginal toxicity level of 5 ppm observed in our previous experience. With a 3-agent combination protocol involving Se (1 ppm), vitamin E (500 ppm) and vitamin A (66 ppm), it was found that vitamin A at this particular dose did not contribute any further chemoprevention than that provided by the Se/vitamin E duo. Both Se and vitamin E were present at a concentration 10 times, while vitamin A was present at 30 times their respective nutritional requirement. Our findings thus suggest that the minimum effective dose has to be systematically established for each micronutrient, and that it is feasible to use lower doses of a combination of agents if the threshold level of each agent can be determined under a prescribed set of conditions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Efficacy of trimethylselenonium versus selenite in cancer chemoprevention and its modulation by arsenite.

Selenite, which has been demonstrated to be an effective prophylactic agent in experimental carcinogenesis, is metabolized to trimethylselenonium as an excretory product. Previous reports in the literature have shown that arsenite decreases the toxicity of selenite but increases that of trimethylselenonium. The present study was designed to compare the anti-carcinogenic efficacy of selenite and trimethylselenonium and their interactions with arsenite in chemoprevention, using the dimethylbenz[a]anthracene-induced mammary tumor model in rats. The results of this experiment indicated that supplementation of selenite (3 p.p.m. Se) alone produced approximately 50% reduction in tumor yield, and arsenite (5 p.p.m. As) reduced the response to selenite. In contrast, arsenite greatly enhanced the protective effect of trimethylselenonium (40 p.p.m. Se); this combination was nearly as effective as selenite, although either trimethylselenonium or arsenite alone was inactive. Thus, arsenite has the capacity to influence the anti-carcinogenic action of selenium, and can either potentiate or attenuate the protective effect depending on the methylation state of the selenium compound. The metabolism of selenium and its perturbation by arsenite are discussed in relation to the above findings.

Animals↗
PubMed1987

Mammary cancer chemoprevention by inorganic and organic selenium: single agent treatment or in combination with vitamin E and their effects on in vitro immune functions.

The chemopreventive efficacies of selenate, selenite, selenium dioxide, selenomethionine and selenocystine were examined during the promotion phase of carcinogenesis in the 7,12-dimethylbenz[a]anthracene-induced mammary tumor model in rats. Each agent was added to the diet at a final concentration of 3 p.p.m. selenium. In general there was no significant difference in the potency of these five selenium compounds in inhibiting the development of mammary tumors. The interaction of vitamin E (500 p.p.m.) with either selenite or selenomethionine was further characterized in a second carcinogenesis study. Results of this experiment suggested that vitamin E enhanced the protective effect of selenite but not that of selenomethionine. In an attempt to explore the synergistic mechanism of selenium and vitamin E, the effects of these two agents on mitogen-induced blastogenesis and natural killer cytotoxic activity were also investigated. No consistent changes in these in vitro immune functions were detected resulting from supranutritional feeding of either selenite or vitamin E or both. The metabolism of inorganic versus organic selenium was discussed in relation to their role in the control of neoplastic growth as well as to their selective modulation by vitamin E.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

The chemopreventive role of selenium in carcinogenesis.

This review discusses the effect of selenium intake on chemical carcinogenesis in animal models. Specifically, the available information in the following areas is summarized: the dose response of selenium intake ranging from deficiency to supranutritional levels of supplementation, the stage specificity of selenium-mediated inhibition of chemical carcinogenesis, the effect of selenium on carcinogen metabolism and DNA adduct formation, and dietary factors (vitamins A, C, and E) that influence the anticarcinogenic efficacy of selenium.

Animals↗
PubMed1986

BCG-modulated mammary carcinogenesis is dependent on the schedule of immunization but is not affected by dietary fat.

The present study was designed to study the effect of dietary fat intake on the modulation of dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in rats injected with the methanol extract residue of Bacillus Calmette-Guerin (MER-BCG). Rats were maintained on either a 5% or a 20% corn oil diet for the entire duration of the experiment. When MER-BCG was administered 2 and 3 weeks before DMBA, mammary tumorigenesis was suppressed in the 2 dietary groups with different levels of fat intake. This was in contrast to when MER-BCG was administered 3 and 5 weeks after DMBA; in this case the development of mammary tumors was noticeably enhanced regardless of the fat intake of the host. The magnitude of inhibition or increase by MER-BCG was similar in animals fed either fat level, although a high fat diet consistently stimulated mammary tumorigenesis in the 2 experiments. In vitro assays on T cell mitogen-induced blastogenesis and natural killer cell activity in splenocytes isolated from the untreated rats showed that dietary fat failed to elicit any differential response in these immune functions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Effects of high dietary fat on the growth and development of ovarian-independent carcinogen-induced mammary tumors in rats.

This study examined the influence of high dietary fat intake on the development of ovarian-independent mammary tumors in both vehicle-treated controls and rats made deficient in estrogen and prolactin during tumor induction. The majority of 7,12-dimethylbenz(a) anthracene (DMBA)-induced mammary tumors in rats are dependent on estrogen and prolactin for growth, and suppression of prolactin and estrogen at the time of tumor initiation causes a reduction in tumor incidence and increase in tumor latency. However, the majority of mammary tumors which do develop in these animals exhibit ovarian-independent growth. Sprague-Dawley rats were given 7.5 mg DMBA p.o. at 57 days of age. Starting 1 day prior to and continuing for 7 days after DMBA administration, rats were given daily injection of vehicle or the combination of tamoxifen (20 micrograms/rat) plus bromocryptine (5 mg/kg). At the end of drug treatment, rats in each treatment group were equally divided and placed on normal fat (5% corn oil) or high fat (20% corn oil) diets for the duration of the experiment. Vehicle-treated rats were ovariectomized 27 wk and drug-treated rats 47 wk after DMBA administration to determine tumor ovarian dependency. Vehicle-treated rats fed high fat diets showed significant increases in mammary tumor incidence and number as compared to similarly treated rats fed a normal fat diet, with approximately 80% of the tumors in each group being ovarian dependent. Likewise, tamoxifen-bromocryptine-treated rats fed a high fat diet showed a significant enhancement in mammary tumor number, although not incidence, as compared to similarly treated rats fed a normal diet. Tumors in these drug-treated groups displayed essentially the same incidence of ovarian dependence (23%). Tamoxifen-bromocryptine-treated groups displayed a 2-fold increase in latency of tumor appearance as compared to vehicle-treated controls; however, this long latency was not reduced when these rats were fed a high fat diet. These results demonstrate that high dietary fat stimulates ovarian-dependent and -independent mammary tumorigenesis in rats but does not influence the hormonal responsiveness of these tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Interaction of vitamin C and selenium supplementation in the modification of mammary carcinogenesis in rats.

The objectives of this study were a) to compare the efficacy of inorganic and organic selenium compounds in protecting against mammary tumorigenesis induced by 7,12-dimethylbenz[a]anthracene [(DMBA); CAS: 57-97-6] in rats and b) to study the interaction of vitamin C with either selenite (inorganic) or seleno-DL-methionine (organic) in chemoprevention. Control Sprague-Dawley rats were fed a purified 5% corn oil diet containing 0.1 ppm selenium. Selenite or seleno-DL-methionine was added to the basal diet in concentrations of 2, 3, or 4 ppm starting 1 week after DMBA administration. The inhibitory response in mammary tumorigenesis with selenium supplementation was dose dependent. Both selenium compounds were found to be equally efficacious in prophylaxis, although at the 4-ppm level a slight reduction in growth was observed. In the second experiment, different concentrations of vitamin C (0.2, 0.5, and 1%) were tested. In general, there was no change with the two lower levels; but a slight, although insignificant, increase in tumor yield was detected in rats supplemented with 1% vitamin C in the diet. The interaction of 0.5% vitamin C with either selenite or seleno-DL-methionine (3 ppm) was studied in the third experiment. Results showed that the protective effect of selenite in tumorigenesis was nullified by vitamin C, whereas the chemopreventive action of seleno-DL-methionine was not affected. It is possible that selenite is reduced by vitamin C to elemental selenium and is therefore not available for uptake by tissues. This hypothesis was indirectly supported by tissue selenium measurements showing that 0.5 or 0.25% of vitamin C in the diet completely negated in blood, liver, and mammary gland the accumulation of selenium induced by 3 ppm of selenite supplementation. Lower levels of vitamin C (less than or equal to 0.1%) were found to have no effect on tissue selenium concentrations. Furthermore, the presence of 0.1% vitamin C in the diet no longer abolished the anticarcinogenic effect of selenite. This study suggests that high levels of vitamin C can interfere with the accumulation of tissue selenium and that an increased titer of this trace element in cells is essential for retarding tumor development.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Comparative effects of different animal and vegetable fats fed before and during carcinogen administration on mammary tumorigenesis, sexual maturation, and endocrine function in rats.

The purpose of this investigation was to determine whether diets high in animal or vegetable fat affected mammary tumorigenesis when fed to rats only prior to and during the initiation phase of carcinogenesis. Weanling 21-day-old female Sprague-Dawley rats were divided into different dietary treatment groups and were allowed to feed and libitum on one of the following diets: 5% (normal fat) corn oil; 20% (high fat) corn oil; 20% palm oil; 20% beef tallow; or 20% lard. At 52 days of age, all rats were given p.o. 7.5 mg 7,12-dimethylbenz(a)anthracene (DMBA). One week following DMBA administration, all rats were switched to the 5% corn oil control diet and were maintained on this diet for the duration of the experiment. Rats fed a 20% lard diet during the treatment period showed a significant increase in mammary tumor incidence and number 19 weeks after DMBA administration, when compared to all other dietary treatment groups. Rats fed a 20% beef tallow diet during this same time period also demonstrated enhanced mammary tumor development, during the 10- to 19-week time period after DMBA. Mammary tumor development in rats fed 20% corn oil or palm oil diets during this treatment period was similar to that of normal fat controls. Estrogens are potent stimulators of mammary tumor growth and development in rats. Because mammary tumorigenesis was enhanced in rats fed high animal, but not vegetable fat diets, it was possible that estrogens present in animal fat might be responsible for this stimulation. Further studies demonstrated however, that increased mammary tumorigenesis in rats fed diets high in animal fat could not be explained on the basis of endocrine stimulation. Average day of vaginal opening for all groups fed 20% fat diets was similar and occurred earlier than in normal fat controls. In addition, 50- to 65-day-old rats in the different dietary treatment groups showed no differences in basal or surge levels of serum prolactin, luteinizing hormone, or estradiol. Rat diestrus uterine weight also showed no significant differences among dietary treatment groups. Thus diets containing high levels of animal fat caused little if any increased estrogenic activity in rats. In conclusion, high dietary intake of lard and beef tallow, but not vegetable fat, fed from weaning until only 1 week after DMBA administration, significantly enhances mammary tumorigenesis in rats. The mechanism(s) by which animal fat induces this stimulation is not clear, but it does not appear to result from endogenous or exogenous endocrine stimulation.

Animals↗
PubMed1985

Attenuation of the anticarcinogenic action of selenium by vitamin E deficiency.

The present study showed that in the dimethylbenz[a]anthracene-induced mammary tumor model in rats, the anticarcinogenic efficacy of selenium was much attenuated when the intake of vitamin E was deficient. Selenium supplementation at 2.5 mg/kg in the diet reduced the total tumor yield by 45% and 25%, respectively, in rats with an adequate or low vitamin E intake. Measurements of selected hepatic phase I and phase II detoxifying enzymes indicated that they were not responsive to changes in dietary vitamin E or selenium levels. However, a low vitamin E intake significantly increased lipid peroxidation in the mammary fat pad regardless of selenium status, suggesting that selenium supplementation was less effective under this nutritional condition and might be associated with the higher degree of oxidant stress in the cellular environment.

9,10-Dimethyl-1,2-benzanthracene↗