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In Vivo (Athens, Greece) 2006In this serial sacrifice experiment, celecoxib (C) was administered at a 0.1% dose level, in the diet of female Swiss Webster CFW outbred mice. The animals also received... (Comparative Study)
Comparative Study
In this serial sacrifice experiment, celecoxib (C) was administered at a 0.1% dose level, in the diet of female Swiss Webster CFW outbred mice. The animals also received either 1,2-dimethylhydrazine dihydrochloride (1,2-DMH) as ten weekly subcutaneous (s.c.) injections at 20 microg/g body weight or physiological saline (PS) as ten weekly s.c. injections at 0.01 ml/g body weight. Subsequently, the mice were sacrificed at 26 weeks or 35 weeks after the first injection of 1,2-DMH or PS. The number of mice with large intestinal tumors and the total number of these tumors were: Group 1 (1,2-DMH), 29 and 438; Group 2 (C + 1,2-DMH), 18 and 64; and Group 3 (PS), 1 and 1, in the mice sacrificed at 26 weeks. The corresponding tumor incidences in the mice sacrificed at 35 weeks were: Group 1 (1,2-DMH), 30 and 323; Group 2 (C + 1,2-DMH), 23 and 134; and Group 3 (PS), 0 and 0. Histopathologically, the tumors were diagnosed as polypoid adenomas and adenocarcinomas of the cecum, colon and rectum. Celecoxib treatment inhibited the development of large intestinal cancers in mice sacrificed at 26 or 35 weeks after the first injection of the carcinogen.
Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Adenoma; Administration, Oral; Animals; Animals, Outbred Strains; Anti-Inflammatory Agents, Non-Steroidal; Carcinogens; Celecoxib; Cyclooxygenase Inhibitors; Female; Incidence; Injections, Subcutaneous; Intestinal Neoplasms; Mice; Neoplasms, Experimental; Pyrazoles; Sulfonamides; Survival Rate; Time Factors
PubMed: 16900774
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Sep 2023Dichloromethane extract of Cleistocalyx nervosum var. paniala seeds exhibited an anticarcinogenicity against chemically-induced the early stages of carcinogenesis in...
2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone from Cleistocalyx nervosum var. paniala seeds attenuated the early stage of diethylnitrosamine and 1,2-dimethylhydrazine-induced colorectal carcinogenesis.
BACKGROUND
Dichloromethane extract of Cleistocalyx nervosum var. paniala seeds exhibited an anticarcinogenicity against chemically-induced the early stages of carcinogenesis in rats. This study aimed to identify anticarcinogenic compounds from C. nervosum seed extract (CSE).
METHODS
Salmonella mutation assay was performed to determine mutagenicity and antimutagenicity of partially purified and purified compounds of CSE. The anticarcinogenic enzyme-inducing activity was measured in Hepa1c1c7. Moreover, the anticancer potency was examined on various human cancer cell lines. The anticarcinogenicity of DMC was investigated using dual-organ carcinogenicity model. The number of preneoplastic lesions was evaluated in the liver and colon. The inhibitory mechanisms of DMC on liver- and colorectal carcinogenesis were investigated.
RESULTS
Six partially purified fractions (MK1 - MK6) and purified compounds, including 2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) and hariganetin, were obtained from CSE. Among these fractions, MK4 and DMC presented the greatest antimutagenicity against indirect mutagens in bacterial model. Moreover, MK5 possessed an effective anticarcinogenic enzyme inducer in Hepa1c1c7. The MK4, DMC and CSE showed greater anticancer activity on all cell lines and exhibited the most effective toxicity on colon cancer cells. Furthermore, DMC inhibited the formation of colonic preneoplastic lesions in carcinogens-treated rats. It reduced PCNA-positive cells and frequency of BCAC in rat colon. DMC also enhanced the detoxifying enzyme, GST, in rat livers.
CONCLUSIONS
DMC obtained from CSE may be a promising cancer chemopreventive compound of colorectal cancer process in rats. It could increase detoxifying enzymes and suppress the cell proliferation process resulting in prevention of post-initiation stage of colorectal carcinogenesis.
Topics: Humans; Rats; Animals; Syzygium; Diethylnitrosamine; 1,2-Dimethylhydrazine; Seeds; Carcinogenesis; Colorectal Neoplasms
PubMed: 37517291
DOI: 10.1016/j.biopha.2023.115221 -
Experimental & Molecular Medicine Oct 2009Triptolide, a diterpenoid triepoxide from the traditional Chinese medicinal herb Tripterygium wilfordii Hook. f., is a potential treatment for autoimmune diseases as...
Triptolide, a diterpenoid triepoxide from the traditional Chinese medicinal herb Tripterygium wilfordii Hook. f., is a potential treatment for autoimmune diseases as well a possible anti-tumor agent. It inhibits proliferation of colorectal cancer cells in vitro and in vivo. In this study, its ability to block progress of colitis to colon cancer, and its molecular mechanism of action are investigated. A mouse model for colitis-induced colorectal cancer was used to test the effect of triptolide on cancer progression. Treatment of mice with triptolide decreased the incidence of colon cancer formation, and increased survival rate. Moreover, triptolide decreased the incidence of tumors in nude mice inoculated with cultured colon cancer cells dose-dependently. In vitro, triptolide inhibited the proliferation, migration and colony formation of colon cancer cells. Secretion of IL6 and levels of JAK1, IL6R and phosphorylated STAT3 were all reduced by triptolide treatment. Triptolide prohibited Rac1 activity and blocked cyclin D1 and CDK4 expression, leading to G1 arrest. Triptolide interrupted the IL6R-JAK/STAT pathway that is crucial for cell proliferation, survival, and inflammation. This suggests that triptolide might be a candidate for prevention of colitis induced colon cancer because it reduces inflammation and prevents tumor formation and development.
Topics: Animals; Cell Transformation, Neoplastic; Colitis; Colonic Neoplasms; Dextran Sulfate; Dimethylhydrazines; Diterpenes; Epoxy Compounds; Humans; Interleukin-6; Janus Kinases; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Neoplasm Transplantation; Phenanthrenes; STAT3 Transcription Factor; Signal Transduction; Tumor Burden; rac1 GTP-Binding Protein
PubMed: 19561401
DOI: 10.3858/emm.2009.41.10.078 -
Cancer Biology & Therapy May 2017Pyrazinoic acid (PA) is structurally similar to nicotinic acid which acts on G-protein-coupled receptor (GPR109A). GPR109A expresses in colonic and intestinal epithelial...
Pyrazinoic acid (PA) is structurally similar to nicotinic acid which acts on G-protein-coupled receptor (GPR109A). GPR109A expresses in colonic and intestinal epithelial sites, and involves in DNA methylation and cellular apoptosis. Therefore, it may be assumed that PA has similar action like nicotinic acid and may be effective against colorectal carcinoma (CRC). CRC was produced via subcutaneous injection of dimethylhydrazine (DMH) at 40 mg/kg body weight once in a week for 4 weeks. After that, PA was administered orally at 2 doses of 10 and 25 mg/kg daily for 15 d to observe the antiproliferative effect. Various physiologic, oxidative stress, molecular parameters, histopathology, RT-PCR and NMR based metabolomics were performed to evaluate the antiproliferative potential of PA. Our results collectively suggested that PA reduced body weight, tumor volume and incidence no. to normal. It restored various oxidative stress parameters and normalized IL-2, IL-6, and COX-2 as compared with carcinogen control. In molecular level, overexpressed IL-6 and COX-2 genes became normal after PA administration. Again, normal tissue architecture was prominent after PA administration. Score plots of PLS-DA models exhibited that PA treated groups were significantly different from CRC group. We found that CRC rat sera have increased levels of acetate, glutamine, o-acetyl-glycoprotein, succinate, citrulline, choline, o-acetyl choline, tryptophan, glycerol, creatinine, lactate, citrate and decreased levels of 3-hydroxy butyrate, dimethyl amine, glucose, maltose, myoinositol. Further the PA therapy has ameliorated the CRC-induced metabolic alterations, signifying its antiproliferative properties. In conclusion, our study provided the evidence that PA demonstrated good antiproliferative effect on DMH induced CRC and thus demonstrated the potential of PA as a useful drug for future anticancer therapy.
Topics: Animals; Apoptosis; Carcinoma; Cell Proliferation; Colonic Neoplasms; Dimethylhydrazines; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Oxidative Stress; Pyrazinamide; Rats; Stress, Physiological
PubMed: 28358223
DOI: 10.1080/15384047.2017.1310341 -
The American Journal of Clinical... Nov 2013Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and increases specific biomarkers in the colon of rats.
OBJECTIVES
We investigated whether cured meat modulates biomarkers of cancer risk in human volunteers and whether specific agents can suppress cured meat-induced preneoplastic lesions in rats and associated biomarkers in rats and humans.
DESIGN
Six additives (calcium carbonate, inulin, rutin, carnosol, α-tocopherol, and trisodium pyrophosphate) were added to cured meat given to groups of rats for 14 d, and fecal biomarkers were measured. On the basis of these results, calcium and tocopherol were kept for the following additional experiments: cured meat, with or without calcium or tocopherol, was given to dimethylhydrazine-initiated rats (47% meat diet for 100 d) and to human volunteers in a crossover study (180 g/d for 4 d). Rat colons were scored for mucin-depleted foci, putative precancer lesions. Biomarkers of nitrosation, lipoperoxidation, and cytotoxicity were measured in the urine and feces of rats and volunteers.
RESULTS
Cured meat increased nitroso compounds and lipoperoxidation in human stools (both P < 0.05). Calcium normalized both biomarkers in rats and human feces, whereas tocopherol only decreased nitro compounds in rats and lipoperoxidation in feces of volunteers (all P < 0.05). Last, calcium and tocopherol reduced the number of mucin-depleted foci per colon in rats compared with nonsupplemented cured meat (P = 0.01).
CONCLUSION
Data suggest that the addition of calcium carbonate to the diet or α-tocopherol to cured meat may reduce colorectal cancer risk associated with cured-meat intake. This trial was registered at clinicaltrials.gov as NCT00994526.
Topics: Abietanes; Acetylcysteine; Adult; Aged; Animals; Biomarkers; Blood Glucose; C-Reactive Protein; Calcium, Dietary; Carcinogenesis; Carcinogens; Cholesterol; Colon; Colorectal Neoplasms; Creatinine; Cross-Over Studies; Dimethylhydrazines; Diphosphates; Feces; Female; Healthy Volunteers; Humans; Inulin; Meat Products; Middle Aged; Rats; Rats, Inbred F344; Rutin; Single-Blind Method; Thiobarbituric Acid Reactive Substances; alpha-Tocopherol
PubMed: 24025632
DOI: 10.3945/ajcn.113.061069 -
BioMed Research International 2015Bread is rich in dietary fibre and many phytochemical compounds, which may influence chemoprevention of colon cancer. In the present study, we evaluated the effect of...
Bread is rich in dietary fibre and many phytochemical compounds, which may influence chemoprevention of colon cancer. In the present study, we evaluated the effect of three kinds of bread on DMH-induced colorectal tumours in F344 rats. F344 rats were divided into four groups (Steinmetz Three-Grain bread, Steinmetz Country bread, White bread, and MF). All groups were injected with 1,2-dimethylhydrazine (DMH, 20 mg/kg body weight) once a week for 8 consecutive weeks from 5 weeks of age. To investigate the antioxidant effect of bread, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging rate of bread and the serum levels of 8-hydroxy-deoxyguanosine (8-OHdG) in rats were examined. The number of colorectal aberrant crypt foci (ACF) and the incidence of colorectal tumours were studied after 34 weeks of DMH treatment. The Steinmetz Three-Grain and Steinmetz Country bread groups had higher scavenging rates of the DPPH free radical and lower serum levels of 8-OHdG and incidence of ACF, adenomas, and adenocarcinomas of colon than the White bread and MF group. Steinmetz Three-Grain bread and Steinmetz Country bread have various ingredient combinations that may inhibit colorectal cancer progression.
Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Animals; Antioxidants; Bread; Colorectal Neoplasms; Male; Rats; Rats, Inbred F344
PubMed: 26075268
DOI: 10.1155/2015/829096 -
Biological & Pharmaceutical Bulletin Nov 2007The effects of esculetin (6,7-dihydroxycoumarin) and its 6-glycoside, esculin, on 8-oxo-2'-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical...
Inhibitory effect of natural coumarin compounds, esculetin and esculin, on oxidative DNA damage and formation of aberrant crypt foci and tumors induced by 1,2-dimethylhydrazine in rat colons.
The effects of esculetin (6,7-dihydroxycoumarin) and its 6-glycoside, esculin, on 8-oxo-2'-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical carcinogen, 1,2-dimethylhydrazine (DMH), were examined in the colons of male Fischer 344 rats. Animals were given water containing esculetin or esculin for 7 d before subcutaneous injection of DMH (20 mg/kg body wt), killed 24 h after DMH treatment, and the levels of thiobarbituric acid reactive substances (TBARS) and 8-oxodG in the colons were determined. Both esculetin and esculin suppressed significantly the DMH-induced increases in 8-oxodG and TBARS in rat colon mucosa. We further investigated the modifying effect of esculin intake on the development of DMH-induced colonic aberrant crypt foci (ACF). Animals were given DMH once a week for 4 weeks to induce ACF. They then received water containing esculin ad libitum for 5 weeks (initiation phase) or 11 weeks after DMH treatment (post-initiation phase). Animals in the positive control group received tap water throughout the experiment. At the end of the experiment (16 weeks), the ingestion of esculin during the initiation phase significantly reduced the incidence of gross tumors, the number of ACF per rat and the mean number of AC per focus, while the esculin treatment during the post-initiation phase significantly decreased only the number of ACF per rat. These results suggest that esculin intake has an inhibitory effect on DMH-induced oxidative DNA damage and carcinogenesis in rat colons.
Topics: 1,2-Dimethylhydrazine; 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Carcinogens; Colonic Neoplasms; DNA Damage; Deoxyguanosine; Esculin; Intestinal Mucosa; Male; Oxidation-Reduction; Random Allocation; Rats; Rats, Inbred F344; Thiobarbituric Acid Reactive Substances; Umbelliferones
PubMed: 17978474
DOI: 10.1248/bpb.30.2052 -
PloS One 2013T lymphoma invasion and metastasis 1 (Tiam1) is a potential modifier of tumor development and progression. Our previous study in vitro and in nude mice suggested a...
BACKGROUND
T lymphoma invasion and metastasis 1 (Tiam1) is a potential modifier of tumor development and progression. Our previous study in vitro and in nude mice suggested a promotion role of Tiam1 on invasion and metastasis of colorectal cancer (CRC). In the present study, we generated Tiam1/C1199-CopGFP transgenic mice to investigate the tumorigenetic, invasive and metastatic alterations in the colon and rectum of wild-type and Tiam1 transgenic mice under 1,2-dimethylhydrazine (DMH) treatment.
METHODS
Transgenic mice were produced by the method of pronuclear microinlectlon. Whole-body fluorescence imaging (Lighttools, Edmonton, Alberta, Canada), PCR, and immunohistochemical techniques (IHC) were applied sequentially to identify the transgenic mice. The carcinogen DMH (20 mg/kg) was used to induce colorectal tumors though intraperitoneal (i.p.) injections once a week for 24 weeks from the age of 4 weeks on Tiam1 transgenic or non-transgenic mice.
RESULTS
We successfully generated Tiam1/C1199-CopGFP transgenic mice and induced primary tumors in the intestine of both wild type and Tiam1 transgenic mice by DMH treatment. In addition, Tiam1 transgenic mice developed larger and more aggressive neoplasm than wild-type mice. Moreover, immunohistochemical staining revealed that upregulation of Tiam1 was correlated with increased expression of β-Catenin and Vimentin, and downregulation of E-Cadherin in these mice.
CONCLUSIONS
Our study has provided in vivo evidence supporting that Tiam1 promotes invasion and metastasis of CRC, most probably through activation of Wnt/β-catenin signaling pathway, in a Tiam1 transgenic mouse model.
Topics: 1,2-Dimethylhydrazine; Animals; Colorectal Neoplasms; Guanine Nucleotide Exchange Factors; Mice; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphoma Invasion and Metastasis-inducing Protein 1; Wnt Signaling Pathway
PubMed: 24069171
DOI: 10.1371/journal.pone.0073077 -
Genetics and Molecular Research : GMR Mar 2015Resistant starch is formed from starch and its degradation products and is not digested or absorbed in the intestine; thus, it is characterized as a fiber. Because fiber...
Resistant starch is formed from starch and its degradation products and is not digested or absorbed in the intestine; thus, it is characterized as a fiber. Because fiber intake is associated with the prevention of DNA damage and cancer, the potential antigenotoxic, antimutagenic, and anticarcinogenic capabilities of resistant starch from green banana flour were evaluated. Animals were treated with 1,2-dimethylhydrazine and their diet was supplemented with 10% green banana flour according to the following resistant starch protocols: pretreatment, simultaneous treatment, post-treatment, and pre + continuous treatment. The results demonstrated that resistant starch is not genotoxic, mutagenic, or carcinogenic. The results suggest that resistant starch acts through desmutagenesis and bio-antimutagenesis, as well as by reducing aberrant crypt foci, thereby improving disease prognosis. These findings imply that green banana flour has therapeutic properties that should be explored for human dietary applications.
Topics: Aberrant Crypt Foci; Animals; Carcinogenesis; Colorectal Neoplasms; Comet Assay; DNA Damage; Dietary Fiber; Dimethylhydrazines; Disease Models, Animal; Flour; Food Handling; Functional Food; Male; Mice; Micronucleus Tests; Musa; Starch
PubMed: 25867310
DOI: 10.4238/2015.March.6.14 -
International Journal of Cancer Sep 2012Atorvastatin and suberoylanilide hydroxamic acid (SAHA) were evaluated for chemoprevention of mouse lung tumors. In Experiment 1, lung tumors were induced by vinyl...
Atorvastatin and suberoylanilide hydroxamic acid (SAHA) were evaluated for chemoprevention of mouse lung tumors. In Experiment 1, lung tumors were induced by vinyl carbamate in strain A/J mice followed by 500 mg/kg SAHA, 60 or 180 mg/kg atorvastatin, and combinations containing SAHA and atorvastatin administered in their diet. SAHA and both combinations, but not atorvastatin, decreased the multiplicity of lung tumors, including large adenomas and adenocarcinomas with the combinations demonstrating the greatest efficacy. In Experiment 2, lung tumors were induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol in strain A/J mice followed by 180 mg/kg atorvastatin, 500 mg/kg SAHA, or both drugs administered in the diet. SAHA and the combination of both drugs, but not atorvastatin alone, decreased the multiplicity of lung tumors and large tumors, with the combination demonstrating greater efficacy. In Experiment 3, lung tumors were induced by 1,2-dimethylhydrazine in Swiss-Webster mice followed by 160 mg/kg atorvastatin, 400 mg/kg SAHA, or a combination of both drugs administered in the diet. SAHA and the combination, but not atorvastatin, decreased the multiplicity of lung tumors with the combination demonstrating greater efficacy. The multiplicity of colon tumors was decreased by SAHA, atorvastatin, and the combination, without any significant difference in their efficacy. mRNA expression analysis of lung tumor bearing mice suggested that the enhanced chemopreventive activity of the combination is related to atorvastatin modulation of DNA repair, SAHA modulation of angiogenesis, and both drugs modulating invasion and metastasis pathways. Atorvastatin demonstrated chemoprevention activity as indicated by the enhancement of the efficacy of SAHA to prevent mouse lung tumors.
Topics: Animals; Atorvastatin; Colonic Neoplasms; Dimethylhydrazines; Female; Heptanoic Acids; Histone Deacetylase Inhibitors; Hydroxamic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung Neoplasms; Mice; Nitrosamines; Pyrroles; RNA, Messenger; Urethane; Vorinostat
PubMed: 22161747
DOI: 10.1002/ijc.27395