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At least 991 records · Page 55Linked to original sources
PubMed2003

Deguelin suppresses the formation of carcinogen-induced aberrant crypt foci in the colon of CF-1 mice.

Deguelin [(7aS,BaS)-13,13a-dihydro-9,10-dimethoxy-3,3-dimethyl-3H-Bis[1]benzopyrano[3,4-b:6',5'-e]pyran-7(7aH)-one], a naturally occurring rotenone, has shown chemopreventive efficacy in several in vivo and in vitro models. In this report, the effectiveness of deguelin at inhibiting the development of AOM-induced colonic ACF was investigated in CF-1 mice. Loss of hex activity was assessed as a second biomarker. In an initial experiment, animals were given s.c. injections of AOM (10 mg/kg body weight) once a week for 2 weeks to induce ACF. Deguelin and vehicle (corn oil) were administered i.g. 7 days a week. Treatment was initiated 2 weeks prior to the first dose of carcinogen and continued for the duration of the study. The mean number of ACF for the control group was 29.0 +/- 4.3, whereas the mean numbers of ACF in the deguelin groups were 24.8 +/- 2.7, 7.2 +/- 1.5 and 4.6 +/- 1.4 at doses of 2.5, 5.0 and 10.0 mg/kg body weight, respectively. In a similar manner, treatment with deguelin significantly (p < 0.001) suppressed the appearance of hex(-) crypts in a dose-dependent manner. In a second study, the ability of deguelin to block the initiation and promotion stages of colon carcinogenesis was investigated. Greatest inhibition was observed when deguelin was administered during the promotional stage (73.3%, p < 0.001). These results demonstrate that deguelin is an efficacious chemopreventive agent against colon carcinogenesis.

Animals↗
PubMed2007

Chitosan prevents the development of AOM-induced aberrant crypt foci in mice and suppressed the proliferation of AGS cells by inhibiting DNA synthesis.

We study the effect of fungal-derived chitosan on the development of chemical-induced colonic precancerous lesions in ICR mice and delineate its possible molecular mechanisms. In the 2 weeks preventive experiments, mice fed with a diet containing high molecular weight chitosan (HMWC) had significant fewer aberrant crypt foci formation than those fed with control diet. As the treatment extended to 6 weeks, both low molecular weight chitosan (LMWC)- and HMWC-fed mice contained less aberrant crypt foci when compared to control. However, such effect was not observed in mice in the 6 weeks therapeutic experiments. The anti-tumorigenesis effect of water-soluble chitosan oligomer (WSCO) was tested on four cancer cell lines. WSCO significantly suppressed AGS and to a less extent, COLO 205 cells proliferation. Flow cytometry analysis of cell cycle distribution indicated that the percentage of S phase reduced significantly in AGS cells treated with WSCO together with a decrease in DNA synthesis rate in BrdU incorporation assay. WSCO treatment also upregulated cell cycle-related genes p21/Cip and p27/Kip, whereas downregulated that of PCNA.

Animals↗
PubMed1980

Genetical relationship between resistance to insecticides and procarcinogens in two Drosophila populations.

Two Drosophila populations, one resistant and the other susceptible to several insecticides, were examined for response to several alkaryltriazenes (2,4,6-Cl3-PDMT; 3-PyDMT; 3-PyDET) and to DMN, DEN and AM. Hikone R (HR) males developed relative resistance to both mutation induction and cell killing by the triazenes, whereas Berlin K (BK) males showed increased tolerance to DMN, DEN, and AM. When F1 hybrid males from the two strains were treated with 2,4,6-Cl3-PDMT, the yield of recessive lethal mutations in the heterozygotes was nearly half of that found in homozygotes from the susceptible strain Berlin K. These findings indicate that in Drosophila metabolism of procarcinogens is controlled by multiple-gene systems located on several chromosomes. An extremely divergent response of the two genotypes was found following treatment with 3-PyDET; this triazene acts as a potent mutagen in BK males but is hardly mutagenic when tested in strain HR.

Animals↗
PubMed1996

Dietary fiber and the chemopreventive modelation of colon carcinogenesis.

Comparative international epidemiological data indicate that the difference between the highest and lowest colon cancer incidence is approximately 10-fold. This suggests that the dominant causes of colon cancer are environmental rather than genetic in origin, with the dominant environmental cause being the typical diet of Western industrialized countries. Many epidemiological and experimental studies have suggested an important role for dietary fiber in the prevention of colon cancer. Using the Fischer-344 rat as the experimental model, data clearly demonstrate a strong protective effect of a diet that is low in fat, high in fiber and high in calcium (low-risk diet). Such a diet prevents the development of both preneoplastic aberrant crypt foci (ACF) and colon tumors. Recent experiments have also demonstrated a direct relationship between a ras point mutation in ACF at different stages of rat colon carcinogenesis, and a ras point mutation that is subsequently present in colon tumors. Using wheat bran as the model dietary fiber source, its effects were compared to the effects of psyllium, phytic acid, vitamin E, beta-carotene, folic acid, alone or in combination, for their ability to prevent colon cancer in rats on high-risk Western-style diets. Our studies clearly demonstrated the ability of wheat bran to reduce ACF and colon tumors in rats that consumed high-fat, Western-style diets. Although phytic acid, which is a constituent of wheat bran, alone demonstrated strong cancer-preventive potential, our experiments provided evidence for the cancer-preventive effect of the crude fiber fraction that is independent of the effect of phytic acid. The synergistic combination of wheat bran with the soluble fiber psyllium led to enhanced protection; while the combination of wheat bran with beta-carotene showed only an additive effect. Beta-carotene appeared to show higher protection than wheat bran at an intake level that is nutritionally relevant to humans, suggesting the possibility of using beta-carotene to enhance the effects of dietary fiber in high-risk Western populations. Using ACF as an intermediate endpoint, it was also shown that vitamin E and beta-carotene appear to inhibit progression of ACF to colon cancer, while wheat bran and folic acid appeared to have weak cancer-preventive potential at this late stage of carcinogenesis. In conclusion, wheat bran alone, or in combination with psyllium, appears to have greater potential to inhibit earlier phases of carcinogenesis, while beta-carotene and vitamin E may also inhibit later stages of carcinogenesis. Despite considerable epidemiological and experimental evidence that increasing the fiber and lowering the fat content of the Western diet could substantially reduce the risk of cancer and heart disease, the real challenge is to find effective ways to educate and motivate people to overcome their intrinsic cultural resistance to such changes in their eating habits.

Animals↗
PubMed1990

Dietary butyrate (tributyrin) does not enhance AOM-induced colon tumorigenesis.

Butyrate has induced differentiation in neoplastic cells grown in vitro, among them being colon cancer cell lines. In vivo, only one major study used sodium butyrate in the drinking water and showed an elevation in 1,2-dimethylhydrazine induced colon cancer in rats. Seeking to show that it was the sodium and not the butyrate which was responsible for the enhancement, we fed tributyrin at a 5% level to mice for 48 weeks. Mice experienced normal growth and development at this dose. Analysis of short chain fatty acids in the feces after 6 months in tributyrin feeding showed a 10-fold increase in butyric acid. However no difference in AOM induced focal areas of dysplasia or colonic tumor incidence was observed between tributyrin fed and control mice. At least two conclusions have been reached by this study, (1) that the dietary use of a sodium salt can contribute to the enhancement of chemically induced colon neoplasia and (2) butyrate may be discounted as providing any major therapeutic benefit against colonic tumorigenesis.

Animals↗
PubMed1991

The thalidomide analog, EM 12, enhances 1,2-dimethylhydrazine-induction of rat colon adenocarcinomas.

Young male Sprague-Dawley rats in 3 groups were fed a basal diet supplemented with 0.10 wt. % each of thalidomide and its imide-analog of much higher teratogenicity, EM 12. Following an induction period of 17 days on the diets, all animals were injected subcutaneously with 1,2-dimethylhydrazine at 20 mg/kg for a total of 20 weekly doses and killed on week 18 after the 20th injection. The total number of colon adenocarcinomas and their occurrence in the proximal and distal portions for the thalidomide-treated rats were similar to those of the respective controls. However, the EM 12-fed group elicited statistically significant increases both in the total and ascending colon-based adenocarcinomas as compared with the control findings, in keeping with its greater teratogenicity and embryotoxicity. The numbers of small intestinal adenocarcinomas were equally higher in the imide-fed groups in contrast to the control frequency.

1,2-Dimethylhydrazine↗
PubMed1995

Role of aberrant crypt foci in understanding the pathogenesis of colon cancer.

Aberrant crypt foci (ACF) are present in carcinogen treated rodent colons and in the colons of humans with a high risk for developing the disease. It is proposed that ACF are preneoplastic lesions. Quantification of the number and growth features of ACF has been employed to study modulators of colon carcinogenesis. In this review, examples are presented to support the concept that ACF are preneoplastic lesions and that sequential quantification of their number and growth features (crypt multiplicity) in animal colons may provide further insight into the pathogenesis of colon cancer. It is proposed that cellular and molecular heterogeneity among ACF with different growth and morphologic features will be invaluable in the identification of events critically associated with cancer development.

1,2-Dimethylhydrazine↗
PubMed2005

In vivo measurement of DNA synthesis rates of colon epithelial cells in carcinogenesis.

We describe here a highly sensitive technique for measuring DNA synthesis rates of colon epithelial cells in vivo. Male SD rats were given (2)H(2)O (heavy water). Colon epithelial cells were isolated, DNA was extracted, hydrolyzed to deoxyribonucleosides, and the deuterium enrichment of the deoxyribose moiety was determined by gas chromatographic/mass spectrometry. Turnover time of colon crypts and the time for migration of cells from basal to top fraction of the crypts were measured. These data were consistent with cell cycle analysis and bromodeoxyuridine labeling. By giving different concentrations of a promoter, dose-dependent increases in DNA synthesis rates were detected, demonstrating the sensitivity of the method. Administration of a carcinogen increased DNA synthesis rates cell proliferation in all fractions of the crypt. In conclusion, DNA synthesis rates of colon epithelial cells can be measured directly in vivo using stable-isotope labeling. Potential applications in humans include use as a biomarker for cancer chemoprevention studies.

Animals↗
PubMed2004

Polyethylene glycol inhibits intestinal neoplasia and induces epithelial apoptosis in Apc(min) mice.

Efficacy of a safe and clinically utilized polyethylene glycol formulation (PEG-3350) to suppress intestinal tumors was investigated in the Apc(min) mouse-model of experimental carcinogenesis. Furthermore, based on our previous finding on the induction of apoptosis in HT-29 cells by PEG, we evaluated its ability to stimulate epithelial cell apoptosis in both Apc(min) mouse as well as AOM-treated rat as a potential molecular mechanism of chemoprevention. Twenty-two Apc(min) mice were randomized equally to PEG or vehicle (control) supplementation. Tumors were scored and uninvolved intestinal mucosal apoptosis was assayed using a modified terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) assay and by immunohistochemical detection of cleaved caspase-3. Supplementation of Apc(min) mice with 10% PEG 3350 (in drinking water) resulted in a 48% (P<0.05) reduction in intestinal tumor burden and induced 2-3 fold increase in mucosal apoptosis. Dietary supplementation of polyethylene glycol (5%) also stimulated colonic mucosal apoptosis 4-5 fold in AOM-treated rats, the regimen that we previously reported to reduce tumor burden by 76% (P<0.05). In summary, we demonstrate, for the first time, that PEG does protect against Apc(min) mouse tumorigenesis. The correlation between pro-apoptotic actions and chemopreventive efficacy of PEG in these models strongly implicates induction of apoptosis as one of the impending mechanisms of chemoprevention.

Animals↗
PubMedDate not supplied

Thermospray liquid chromatography/mass spectrometry studies on mechanisms of nucleic acid alkylation by some deuterated carcinogens.

Alkylation of liver nucleic acids of rats treated with nitrosobis(2-oxopropyl)amine (BOP), nitrosomethyl(2-oxopropyl)amine (NMOP), and (methylazoxy)methane (AOM) was studied by using deuterium-labeled compounds. Six hours after treatment of each rat with 5-10 mg of compound, nucleic acids were isolated from the liver of two rats and hydrolyzed in dilute acid, and the fraction containing 7-methylguanine (7-MeG) was separated by ion-exchange high-pressure liquid chromatography. After purification by repeated chromatography, the sample was analyzed by liquid chromatography in ammonium acetate coupled with thermospray positive ion mass spectrometry. AOM containing a deuterated methyl group proximal to the oxygen-bearing nitrogen gave 7-MeG containing three deuterium atoms (169 amu), whereas AOM having the methyl group distal to oxygen deuterated produced 7-MeG without deuterium (166 amu). This indicates that methylation of nucleic acids is through oxidation of AOM to (methylazoxy)methanol and the corresponding aldehyde. BOP-d4, in which both alpha-methylenes contained deuterium, gave rise to 7-MeG containing two atoms of deuterium (168 amu). NMOP-d5, with deuterium in the N-methyl and in the alpha-methylene, gave rise only to 7-MeG containing three deuterium atoms. The methyl-d3 group must originate from the N-methyl of NMOP, probably through formation of a methyldiazonium ion. This result lends support to a mechanism involving a Baeyer-Villiger oxidation of the ketone, rather than oxidation of the N-methyl and formation of an (oxopropyl)diazonium ion, which could give rise to a methylating agent following cyclization.

Alkylation↗
PubMed2000

Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes.

Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes. In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-glutamyltraspeptidase-positive foci were detected only in 3 of 10 rats. There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks. In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 microM. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic drug.

Androgen Antagonists↗
PubMed2004

Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis.

Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemically induced mouse models, colon polyp formation was significantly greater in mice nullizygous for PPAR-delta. In contrast to previous reports suggesting that activation of PPAR-delta potentiates colon polyp formation, here we show that PPAR-delta attenuates colon carcinogenesis.

Animals↗
PubMed2004

Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo.

Protein kinase C iota (PKCiota) has been implicated in Ras signaling, however, a role for PKCiota in oncogenic Ras-mediated transformation has not been established. Here, we show that PKCiota is a critical downstream effector of oncogenic Ras in the colonic epithelium. Transgenic mice expressing constitutively active PKCiota in the colon are highly susceptible to carcinogen-induced colon carcinogenesis, whereas mice expressing kinase-deficient PKCiota (kdPKCiota) are resistant to both carcinogen- and oncogenic Ras-mediated carcinogenesis. Expression of kdPKCiota in Ras-transformed rat intestinal epithelial cells blocks oncogenic Ras-mediated activation of Rac1, cellular invasion, and anchorage-independent growth. Constitutively active Rac1 (RacV12) restores invasiveness and anchorage-independent growth in Ras-transformed rat intestinal epithelial cells expressing kdPKCiota. Our data demonstrate that PKCiota is required for oncogenic Ras- and carcinogen-mediated colon carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of Ras, PKCiota, and Rac1.

Animals↗