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B S Reddy

Publications and source records attributed to B S Reddy.

At least 127 records · Page 7Linked to original sources

Protective mechanisms of dietary fibers in nutritional carcinogenesis.

Fibers in foods are complex carbohydrates. There are several types of fiber, but, for the purpose of mechanistic insight into their mode of protective action in carcinogenesis, classification into two broad types, soluble and insoluble fibers, is warranted. Soluble fibers are present in fruits, vegetables, and certain grains like oats. This type of fiber undergoes metabolism in the small intestine and especially in the large intestine through bacterial enzymes, converting it to products that increase stool size only moderately. But, they have appreciable effects in modifying the metabolism of colon carcinogens like azoxymethane to yield detoxified products and, thus, reducing colon carcinogenesis. In contrast, insoluble fibers present in sizeable amounts in bran cereals, like wheat or rice, are not significantly metabolized by enzymes in the intestinal flora. Such fibers increase stool size substantially through several mechanisms, including higher water retention. The larger bulk dilutes carcinogens, especially tumor promoters such as secondary bile acids, resulting in lower risk of colon cancer in animals and in humans. Evidence in animal models and in humans also indicates that fiber may lower the risk of breast cancer, possibly via an endocrine mechanism. Based on these concepts, increased intake of total fiber, but especially of wheat bran cereal fiber, to yield a daily stool in adults of about 200 grams can significantly reduce the risk of colon cancer and, to a lesser but definite extent, of breast cancer. Thus, adequate fiber intake from cereals, fruits, and vegetables can help prevent important types of human cancer.

Animals↗

Effect of high fat corn oil, olive oil and fish oil on phospholipid fatty acid composition in male F344 rats.

Epidemiological and laboratory animal model studies have provided evidence that the effect of dietary fat on colon tumorigenesis depends on the amount of fat and its composition. Because of the importance of the composition of dietary fat and of tissue membrane fatty acid composition in tumor promotion, experiments were designed to investigate the relative effects of high fat diets rich in omega 3, omega 6 and omega 9 fatty acids and colon carcinogen on the phospholipid fatty acid composition of liver, colon, small intestine, erythrocytes and blood plasma. At 6 wk of age, groups of animals were fed diets containing 5% corn oil (LFCO), 23.5% corn oil (HFCO), 23.5% olive oil (HFOO), and 20.5% fish oil plus 3% corn oil (HFFO). Two weeks later all the animals except the vehicle-treated animals received azoxymethane s.c. once weekly for 2 wk at a dose rate of 15 mg/kg body weight. Animals were sacrificed 5 d later and liver, colon, small intestine and erythrocytes and blood plasma were analyzed for phospholipid fatty acids. The results indicate that the phospholipid fatty acid composition of liver, colon and small intestine of HFCO diet fed animals, were not significantly different from those fed the LFCO diet. The levels of palmitoleic acid and linoleic acid were increased in erythrocytes and blood plasma of the animals fed the HFCO diet compared to those fed the LFCO diet. Feeding the HFOO diet significantly increased the oleic acid content and decreased the linoleic acid and arachidonic acid levels in various organs when compared to the HFCO diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effects of fish oil on rectal cell proliferation, mucosal fatty acids, and prostaglandin E2 release in healthy subjects.

BACKGROUND: Experimental studies have indicated dietary fish oil as a protective agent in colon carcinogenesis. Prostaglandins have been suggested to be involved in this process. In the present study, the effects of fish oil on rectal cell proliferation (i.e., intermediate biomarker of cancer risk), mucosal membrane fatty acids, and prostaglandin E2 (PGE2) release were investigated in 12 healthy volunteers. METHODS: In addition to a controlled basal diet, the test subjects received either fish oil (4.4 g omega-3 fatty acids/day) or corn oil supplements for two 4-week periods in a double-blind, crossover trial. Rectal cell proliferation was determined by bromodeoxyuridine immunohistochemistry and ornithine decarboxylase activity. After 2-hour incubation with bromodeoxyuridine, PGE2 concentration in the incubation medium was measured by radioimmunoassay. Mucosal membrane fatty acids were analyzed by gas chromatography. RESULTS: Bromodeoxyuridine labeling index (9.2% vs. 10.9%; P < 0.05), ornithine decarboxylase activity (19.7 vs. 36.4 pmol.mg protein-1.h-1; P < 0.005), and PGE2 release from rectal biopsy specimens (435.5 vs. 671.5 pg/mg wet tissue; P < 0.05) were significantly lower during the fish oil than the corn oil period, whereas membrane fatty acids were not statistically different. CONCLUSIONS: The results support the hypothesis that dietary fish oil may protect against colon cancer.

Adult↗

Inhibition by dietary curcumin of azoxymethane-induced ornithine decarboxylase, tyrosine protein kinase, arachidonic acid metabolism and aberrant crypt foci formation in the rat colon.

The present study was designed to investigate the modulatory role of dietary curcumin on (i) azoxymethane (AOM)-induced ornithine decarboxylase (ODC), tyrosine protein kinase (TPK) and arachidonic acid metabolism in liver and colonic mucosa of male F344 rats, (ii) in vitro arachidonic acid metabolism in the liver and colonic mucosa and (iii) AOM-induced aberrant crypt foci (ACF) formation in the colon of F344 rats. At 5 weeks of age groups of animals were fed one of the experimental diets containing 0 or 2000 p.p.m. curcumin. Two weeks later all the animals except the vehicle-treated groups were given s.c. injections of AOM, 15 mg/kg body wt, once weekly for 2 weeks. The animals intended for biochemical study were killed 5 days later and the colonic mucosa and liver were analyzed for ODC, TPK, lipoxygenase and cyclo-oxygenase metabolites. The animals intended for ACF study were killed 9 weeks later and analyzed for ACF in the colon. The results indicated that in saline-treated animals dietary curcumin significantly inhibited the ODC (P < 0.001) and TPK (P < 0.05) activities in the liver and colonic mucosa. Dietary curcumin significantly decreased the levels of AOM-induced ODC activity in the liver and colon (P < 0.0001) and TPK activity in the liver and colon (P < 0.01-0.0001) and the formation of 5(S)-, 8(S)-, 12(S)- and 15(S)-hydroxyeicosatetraenoic acids (HETEs) in the liver and colon (P < 0.0001). Also, curcumin suppressed AOM-induced prostaglandin (PG) and thromboxane (Tx) formation in the liver (PGE2, PGF2 alpha, PGD2, 6-keto-PGF1 alpha and TxB2 to 40, 59, 55, 53 and 39% respectively) and in the colon (PGE2 and PGF2 alpha to 39 and 41% respectively). Further, dietary curcumin reduced the in vitro formation of HETEs, PGs and Tx in a dose-dependent manner. AOM-induced colonic ACF were significantly (P < 0.001) inhibited in the animals fed the curcumin diet. The results of the present study indicate that curcumin, present in turmeric, inhibits AOM-induced colonic preneoplastic lesions and other cellular events relevant to colon carcinogenesis.

Animals↗

Intermediate biomarkers of colon cancer: modulation of expression of ras oncogene by chemopreventive agents during azoxymethane induced colon carcinogenesis.

In our attempts to evaluate the influence of chemopreventive agents on intermediate biomarkers of colon cancer, we have investigated the effect of D,L-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase and piroxicam, a non-steroidal anti-inflammatory drug (NSAID) on the expression levels of biochemically active p21ras, the protein product of cellular ras protooncogenes during the development of azoxymethane (AOM) induced colon carcinogenesis in male F344 rats in order to explore the plausibility of using p21ras as an intermediate biochemical marker of colon cancer. Groups of male F344 rats were fed the modified AIN-76A diets containing 0 or 150 p.p.m. piroxicam or 4000 p.p.m. DFMO and administered s.c. AOM dissolved in normal saline at a dose of 15 mg/kg body wt/week, once weekly, for 4 weeks. Vehicle control groups received s.c. equal vol of normal saline. Groups of animals were then killed at 0, 4, 16, 24 and 32 weeks after the last injection of AOM or saline and their colonic mucosa and tumors analyzed for biochemically active p21ras levels. AOM treatment significantly increased the expression of biochemically active p21ras. The AOM-induced expression of biochemically active p21ras was significantly suppressed by dietary DFMO and piroxicam. DFMO exerted a more pronounced inhibitory effect on AOM-induced colon tumor development as well as the expression of biochemically active p21ras. These results indicate that the determination of biochemically active p21ras may be effectively used in clinical chemoprevention trials as an intermediate end-point to monitor the colon carcinogenesis.

Affinity Labels↗

Modulating effect of amount and types of dietary fat on ornithine decarboxylase, tyrosine protein kinase and prostaglandins production during colon carcinogenesis in male F344 rats.

Epidemiological and laboratory animal model studies suggest that the effect of dietary fat on colon carcinogenesis depends on the amount and its type. In the present study, we investigated the modulating effect of high-fat diets rich in omega-3, omega-6 and omega-9 fatty acids on liver, colon and small intestine mucosal ornithine decarboxylase (ODC) and tyrosine-specific protein kinase (TPK) activities and plasma, liver and colon mucosal prostaglandin E2 (PGE2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) levels in male F344 rats. At 6 weeks of age, groups of animals were fed the low-fat diet containing 5% corn oil (LFCO), or high-fat diets containing 23.5% corn oil (HFCO), 23.5% olive oil (HFOO) and 20.5% fish oil + 3% corn oil (HFFO). Two weeks later, all animals except the vehicle-treated groups received azoxymethane (AOM) s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body wt. All animals were killed 5 days later and liver, colon and small intestine mucosa were analyzed for ODC, TPK and PGs and plasma for PGs. Carcinogen treatment enhanced the ODC and TPK activities (P < 0.0001) in the liver and colon of animals, irrespective of dietary treatment. Dietary HFCO compared with LFCO significantly increased the ODC (P < 0.01) and membrane TPK (P < 0.05) activities in the liver and colon of carcinogen-treated animals, whereas the HFOO and HFFO diets significantly (P < 0.002) suppressed the ODC and membrane TPK (P < 0.05) activities in the liver and colon mucosa compared with the HFCO diet. Carcinogen treatment also significantly (P < 0.01) increased the PG levels in plasma, liver and colon. Feeding of the HFFO diet significantly suppressed both the basal levels and ex vivo production of PGE2 and 6-keto PGF1 alpha levels compared with the HFCO diet, whereas the HFOO diet only decreased PGE2 in liver and colon. These results thus demonstrate that high levels of corn oil in the diet increase colon and liver ODC, TPK and PGs whereas high dietary levels of fish oil and olive oil suppress these activities.

6-Ketoprostaglandin F1 alpha↗

Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats.

Epidemiologic studies suggest that sustained use of aspirin may reduce the risk of development of and mortality due to colon cancer. Previous preclinical studies have shown that several non-steroidal anti-inflammatory drugs act as potential chemopreventive agents in experimentally induced colon cancer models. The present study was designed to investigate the chemopreventive effect of 40 and 80% maximum tolerated dose (MTD) levels of aspirin administered in the diet on azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. The MTD of aspirin as determined in male F344 rats was 500 p.p.m. Beginning at 5 weeks of age, all animals were randomly divided into various experimental groups (48 rats/group) and fed one of the semipurified diets containing 0, 200 p.p.m. (40% MTD), or 400 ppm (80% MTD) of aspirin. Two weeks later, all animals (36 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM at a dose level of 15 mg/kg body wt, once weekly for 2 weeks. All animals were continued on their respective dietary regimen for additional 52 weeks and necropsied. Histopathologic evaluation of colon tumors was performed by routine procedures. Basal levels and ex vivo production of colonic mucosal and tumor prostaglandin E2 (PGE2) were measured in all groups. The results indicate that daily oral administration of 200 and 400 p.p.m. aspirin significantly inhibited the incidence (% animals with tumors) and multiplicity (tumors/animal) of invasive adenocarcinomas of the colon as well as the size of adenocarcinomas. Colonic mucosal and tumor PGE2 levels (basal and ex vivo production) were significantly reduced in animals administered 200 and 400 p.p.m. aspirin. The results of this study support the epidemiologic evidence that ingestion of aspirin inhibits colon carcinogenesis. Although the precise mechanisms of aspirin-induced colon tumor inhibition remain to be determined, it is likely that the effect may be mediated through the modulation of prostaglandin synthesis.

Adenocarcinoma↗

Effect of caffeic acid esters on carcinogen-induced mutagenicity and human colon adenocarcinoma cell growth.

Propolis, a honey bee hive product, is thought to exhibit a broad spectrum of activities including antibiotic, antiviral, anti-inflammatory and tumor growth inhibition; some of the observed biological activities may be due to caffeic acid (cinnamic acid) esters that are present in propolis. In the present study we synthesized three caffeic acid esters, namely methyl caffeate (MC), phenylethyl caffeate (PEC) and phenylethyl dimethylcaffeate (PEDMC) and tested them against the 3,2'-dimethyl-4-aminobiphenyl, (DMAB, a colon and mammary carcinogen)-induced mutagenicity in Salmonella typhimurium strains TA 98 and TA 100. Also, the effect of these agents on the growth of human colon adenocarcinoma, HT-29 cells and activities of ornithine decarboxylase (ODC) and protein tyrosine kinase (PTK) was studied. Mutagenicity was induced in Salmonella typhimurium strains TA 98 and TA 100 plus S9 activation using 5 and 10 micrograms DMAB and antimutagenic activities of 0-150 microM MC, 0-60 microM PEC and 0-80 microM PEDMC were determined. The results indicate that MC, PEC and PEDMC were not mutagenic in the Salmonella tester system. DMAB-induced mutagenicity was significantly inhibited with 150 microM MC, 40-60 microM PEC and 40-80 microM PEDMC in both tester systems. Treatment of HT-29 colon adenocarcinoma cells with > 150 microM MC, 30 microM PEC and 20 microM PEDMC significantly inhibited the cell growth and syntheses of RNA, DNA and protein. ODC and PTK activities were also inhibited in HT-29 cells treated with different concentrations of MC, PEC and PEDMC. These results demonstrate that caffeic acid esters which are present in Propolis possess chemopreventive properties when tested in short-term assay systems.

Caffeic Acids↗

Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

The chemopreventive effect of 40% and 80% maximum tolerated dose (MTD) levels of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) administered in the diet during the initiation phase (2 weeks before, during, and up to 3 days after carcinogen administration) and the post-initiation phase (3 days after carcinogen treatment until termination) of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD of p-XSC was determined in male F344 rats and found to be 50 ppm. Beginning at 5 weeks of age, all animals were divided into various experimental groups (42 rats/group) and fed the high-fat semipurified diet or diets containing 20 (40% MTD) and 40 (80% MTD) ppm p-XSC. At 7 weeks of age, all animals (30 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM (15 mg/kg body weight/week for 2 weeks). Three days after the second injection of AOM or vehicle (normal saline), groups of animals fed the p-XSC diets and control diet were transferred, respectively, to control diet and p-XSC diets and continued on these diets until the termination of the study. All animals were necropsied during the 36th week after AOM treatment. Colonic mucosal prostaglandin E2 and selenium-dependent glutathione peroxidase were measured in animals fed the control and p-XSC diets at the termination of the study. The results indicate that 40 ppm p-XSC administered during the initiation phase significantly inhibited the colon tumor incidence (percentage of animals with tumors). Dietary p-XSC administered at 20 and 40 ppm levels during the initiation phase significantly inhibited colon tumor multiplicity (tumors/animal and tumors/tumor-bearing animal). Colon tumor incidence and multiplicity were significantly reduced in groups fed 20 and 40 ppm p-XSC diets at the postinitiation phase of carcinogenesis. Colonic mucosal selenium-dependent glutathione peroxidase activity was increased, and prostaglandin E2 was reduced in animals fed the p-XSC diet compared to animals fed the control diet. Whereas the precise mechanisms of p-XSC-induced inhibition of colon carcinogenesis remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis and selenium-dependent glutathione peroxidase activity.

Adenocarcinoma↗

Environmental dietary factors in colorectal cancer. Some unresolved issues.

BACKGROUND: Unresolved epidemiologic issues in large bowel cancer include reasons for changes in incidence rates, differences in epidemiology of cancer in the distal and proximal colon and rectal cancer, and the optimal fat and fiber levels for low rates. METHODS: The authors examined questions of suitable procedures for the assessment of intake of specific key nutrients and mode of cooking. International data by site and nutritional factors were compared. RESULTS: Fat and fiber intake in the United States, Japan, and Finland related to differences in rates. Laboratory animal model studies indicated that type of fat affected carcinogenesis. Colon cancer rates in men in the United States increased slightly, but started to decline slightly, as in women. CONCLUSIONS: Dietary factors play a key role in causation and prevention of large bowel cancer, with a diet of 25% fat and 25 g fiber recommended. Comprehensive school health education should be used to modify the nutritional habits of children.

Animals↗

Inhibition of 7,12-dimethylbenz(a)anthracene-induced tumors and DNA adduct formation in the mammary glands of female Sprague-Dawley rats by the synthetic organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate.

We synthesized a novel organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (XSC), possessing low toxicity by comparison with inorganic Na2SeO3, and several other synthetic organoselenium compounds (K. El-Bayoumy, Cancer Res., 45: 3631-3636, 1985). We tested the effect of XSC treatment during the initiation phase on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma formation. A semipurified high-fat diet containing 80 ppm of XSC (40 ppm as selenium) was fed to 6-wk-old virgin female Sprague-Dawley rats for 2 wk, starting 1 wk before and ending 1 wk after carcinogen treatment. At 7 wk of age, rats were given a single dose of DMBA (5 mg) in 0.2 ml of olive oil by gastric intubation; the experiment was terminated 16 wk later. The development of mammary tumors in those rats that received XSC-supplemented diets was significantly inhibited when compared with the control group (fed the same diet without XSC supplements). This was evident from tumor incidence (percentage of tumor-bearing rats, 88 versus 20) and multiplicity of tumors (mean number of tumors/rats, 3.96 versus 0.28). The finding that XSC acts as a chemopreventive agent in the DMBA mammary tumor model prompted us to examine the effect of dietary XSC on DMBA-DNA binding in both the liver and mammary tissue under conditions identical to those described above for the bioassay. Rats (four/group) were killed 6, 24, 48, and 168 h after [3H]DMBA (5 mg/rat; specific activity, 51.2 mCi/mM) administration. Liver and mammary tissue were obtained and DNA was isolated. Dietary XSC was found to inhibit total DMBA-DNA binding in the mammary tissue, but not in the liver. The most profound effect was observed at early time points, i.e., 24 to 48 h after [3H]DMBA administration. The inhibition in total binding was attributed to a reduction in the formation of the three major adducts derived from bay-region diol-epoxides of DMBA; these were identified as anti-diol-epoxide:deoxyguanosine, syn-diol-epoxide:deoxyadenosine, and anti-diol-epoxide:deoxyadenosine adducts on the basis of their chromatographic characteristics on high-pressure liquid chromatography and on a boronate affinity column. The inhibition of the DMBA-DNA binding in the target tissue provides a plausible explanation for the chemopreventive effect of XSC during the initiation stage of carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

Effect of voluntary exercise on azoxymethane-induced hepatocarcinogenesis in male F344 rats.

The effect of voluntary exercise on azoxymethane-induced hepatocarcinogenesis was investigated in male F344 rats. Beginning at 5 weeks of age, all animals were divided into two groups (sedentary and exercise) and fed AIN-76A semipurified diet ad libitum. At 7 weeks of age, animals were given azoxymethane (AOM) s.c. at a dose level of 15 mg/kg of body weight, once weekly for 2 weeks. Four days after the second dose of AOM, all animals in the exercise group were housed in individual wheel-cage units and the animals in the sedentary group were housed in plastic cages. The experiment was terminated at 38 weeks post-AOM treatment. Body weights of animals in the exercise and sedentary groups were comparable. Immunohistochemical staining of glutathione S-transferase placental form (GST-P) was performed in the liver and measured GST-P positive foci. Density (number of GST-P positive foci/cm2 area of liver section), average area of foci and unit area of foci were significantly inhibited in the exercise group, although the incidence of neoplastic nodules and GST-P positive foci were unaffected by the exercise. Thus, energy expenditure due to exercise may reduce hepatocarcinogenesis in a laboratory animal model.

Animals↗

Dietary fat and colon cancer: animal model studies.

Since it was first suggested that high dietary fat is a risk factor in colon cancer, there have been several studies to test this hypothesis. Epidemiologic studies suggested a positive association between dietary fat and colon cancer. Laboratory animal model studies demonstrated that not only the amount of fat, but also types of fat differing in fatty acid composition are important determining factors in colon tumor development. Chemically-induced colon tumor incidence was increased in rats fed the semipurified diets containing 23% corn oil, safflower oil, lard or beef tallow (high-fat) as compared to those fed 5% corn oil, safflower oil, lard or beef tallow diets (low-fat). Diets containing 23% coconut oil, olive oil or fish oil, or high-fat diets containing varying levels of trans fat, had no colon tumor-enhancing effect compared to their respective low fat diets. The stage at which the effect of dietary fat is exerted appears to be mostly during the post-initiation phase of colon carcinogenesis. Lack of a colon tumor enhancing effect of dietary fish oil is observed both during the initiation and postinitiation phases. The mechanisms by which various dietary fats increase colon carcinogenesis are not fully understood. In most instances, however, the high-fat diet appears to enhance tumorigenesis through elevation of agents, such as secondary bile acids, that act as promoters of tumor development. Lack of colon tumor promotion by dietary fish oil and trans fat appears to be mediated through their effect on mucosal ornithine decarboxylase activity, colonic secondary bile acids and/or prostaglandin synthesis.

Animals↗

Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer.

Because of the potential significance of colonic bacteria and secondary bile acids in the pathogenesis of colon cancer, the present study investigated the effect of different types of dietary fiber on fecal bacterial enzymes, namely, beta-glucuronidase, 7 alpha-dehydroxylase, nitroreductase, and azoreductase, and on bile acids and neutral sterols in premenopausal women. The subjects consumed 13-15 g of wheat, oat, or corn bran daily for 8 weeks in addition to their normal diet. Stools collected during the normal and fiber diet periods were analyzed for the above constituents. Dietary wheat bran decreased the concentrations of fecal deoxycholic acid, lithocholic acid, 12-ketolithocholic acid, and neutral sterols and the activities of all bacterial enzymes. Oat bran had no effect on secondary bile acids and 7 alpha-dehydroxylase but decreased beta-glucuronidase, nitroreductase, and azoreductase levels. Dietary corn bran increased 7 alpha-dehydroxylase, lithocholic acid, and cholesterol levels and decreased deoxycholic acid coprostanol, cholestenone, nitroreductase, and azoreductase levels. These results show that the modifying effect of dietary fiber on secondary bile acids and bacterial enzymes that may play a role in carcinogenesis depends on the type of fiber consumed.

Adult↗

Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds.

The inhibitory effect of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid on colon carcinogenesis was investigated in male F344 rats. The MTD levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid as determined in male F344 rats were 500, 500, 250 and 3000 p.p.m. respectively. At 5 weeks of age, groups of male F344 rats were fed the control (AIN-76A) diet and 40 and 80% MTD levels of each test agent in AIN-76A diet. At 7 weeks of age, all animals except the vehicle (saline)-treated controls received azoxymethane (AOM) at a dose rate of 15 mg/kg body wt, once weekly for 2 weeks. All animals were necropsied 50 weeks after the second AOM injection and colon tumor incidences were compared among the groups fed the control diet and chemopreventive agents. Animals fed 400 (80% MTD) and 200 p.p.m. (40% MTD) of piroxicam, 400 p.p.m. (80% MTD) of ibuprofen and 200 p.p.m. (80% MTD) of ketoprofen showed a significant inhibition of colon tumorigenesis as compared to those fed the control diet. Results analyzed by the linear regression method suggested a dose-dependent inhibition of colon carcinogenesis with increasing levels of piroxicam or ibuprofen. In contrast, glycyrrhetinic acid had no measurable chemopreventive effect on colon carcinogenesis.

Animals↗

Effect of the chemopreventive agents piroxicam and D,L-alpha-difluoromethylornithine on intermediate biomarkers of colon carcinogenesis.

Our previous studies have shown that dietary piroxicam, a non-steroidal anti-inflammatory drug (NSAID), and D,L-alpha-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, act as potential chemopreventive agents in inhibiting azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. The present study was designed to determine the effect of these chemopreventive agents on intermediate biomarkers, namely colonic epithelial cell proliferation and levels of prostaglandins, which can be used as effective predictors of colon cancer. Starting at 6 weeks of age, groups of animals were fed the control diet and experimental diets containing piroxicam or DFMO. At 7 weeks of age, all animals, except the vehicle controls, were injected s.c. with AOM at a dose level of 15 mg/kg body wt/week for 4 weeks. Vehicle controls received an equal volume of normal saline. Groups of animals were then killed at the end of last AOM or saline injection (baseline) and at week 4, 16, 24 and 32 following the last AOM or saline treatment. Animals intended for cell proliferation study were injected with bromodeoxyuridine (BrdU) at a dose level of 20 mg/kg body wt 1 h prior to being killed. The rate of colonic cell proliferation at all time points was assessed immunohistochemically using anti-BrdU. The levels of colonic mucosal prostaglandins were estimated by radioimmunoassay. The results indicate that carcinogen treatment increased the colonic cell proliferation measured as the crypt labeling index in proximal and distal colons and the concentrations of colonic prostaglandin E2 (PGE2) and 6-keto PGF1 alpha. The data demonstrate that DFMO significantly inhibited the AOM-induced labeling index in the distal and proximal colon at all time points, whereas piroxicam slightly decreased the labeling index. On the other hand, piroxicam exerted a pronounced inhibitory effect on the levels of both PGE2 and 6-keto PGF1 alpha. DFMO suppressed the colonic PGE2 levels to a lesser degree than piroxicam. The results demonstrate that DFMO, an inhibitor of ODC, suppresses cell proliferation, whereas piroxicam, a NSAID, inhibits prostaglandins, and emphasize the need to develop agent-dependent intermediate biomarker(s) to validate the efficacy of chemopreventive agent(s) in colon carcinogenesis.

6-Ketoprostaglandin F1 alpha↗

A rare association of localized gigantism with tuberous sclerosis.

An unusual association of localized gigantism with hypertrophy of the long bones and soft tissues in the left lower limb in an 18-year-old male with tuberous sclerosis (TS) is reported. The significance of this association is discussed from the point of view of its common neural crest origin during embryogenesis.

Adolescent↗