Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate possible nephroblastoma induction in young Sprague-Dawley male rats by 1,2-dimethylhydrazine (DMH), agents including inhibitors and stimulators of the carcinogenesis were tested concurrently in 2 experiments. In series A, rats, 27 days of age, were fed the following as supplements in a basal diet at the final wt% given: hydralazine (0.035%), disulfiram (250 ppm), ferrous sulfate heptahydrate (0.55%; 0.11 g% Fe), isotretinoin (240 ppm), dehydroepiandrosterone (0.30%) in addition to selenium (2 ppm; drinker). At day 15, DMH was injected s.c. at 108 mg base/kg; duration on the diets: 51 weeks. Series B comprised 33 day-old males which were partially hepatectomized (control and indomethacin at 10 mg/l by drinker) or bilaterally gonadectomized for comparison vs sham-operated, and intact groups on s.c. injection of estradiol benzoate (15 micrograms/kg), progesterone (30 mg/kg) and diallyl sulfide (100 mg/kg), the respective controls receiving the peanut oil vehicle. Treatments were begun 8 days post-operative and 17 days later, the single dosage of DMH as in the above was injected. The oil solutions were administered at the specified weekly levels for a total of 52 injections, 2 doses being introduced per week for the 1st 3 weeks. Colon adenocarcinomas comprised the main tumors and occurred in about 15-50% of the rats with total frequencies in the respective control ranges except for decrements with the disulfiram- and iron-fed groups. Renal changes were more involved with series B and nephroblastomas of the left kidney occurred in one animal each of the estradiol benzoate- and diallyl sulfide-injected groups. Of interest, bilateral nephroblastomas were present in one of the saline-injected controls which was gonadectomized. Under the conditions explored, concurrent treatment with DMH inhibitors or synergists had a minimal effect on nephroblastoma induction.
 ...
PMID:Tumors produced in rats with a single dosage of 1,2-dimethylhydrazine. 839 10

Ras mutations are an important early event in a number of carcinogen-induced rodent tumors. Colon carcinogenesis induced in rats by azoxymethane is a useful model as it mimics the adenoma-carcinoma sequence observed in humans. In addition, aberrant crypt foci develop in the rat and these lesions appear to be potentially important precursors to adenomas in colorectal cancer. Recent studies have shown that specific K-ras codon 12 and 13 mutations are present in up to 66% of carcinogen-induced rat colon adenocarcinomas. We studied the frequency of these mutations during the aberrant crypt focus-adenoma-carcinoma sequence in azoxymethane-induced Fisher F344 rats. K-ras codon 12 GAT and codon 13 GAC mutations were detected with a sensitive assay based on the amplification of DNA using the polymerase chain reaction. No mutations were present in normal mucosa. Of 27 aberrant crypt foci, K-ras mutations were identified in 2 lesions containing 5 and 10 aberrant crypts, respectively. Mutations were present in 1 of 23 and 10 of 27 adenomas and adenocarcinomas, respectively. These data suggest that K-ras mutations play a role during the stages of carcinogenesis in azoxymethane-induced rat colon cancer. The demonstration of a genetic mutation in aberrant crypt foci provides further evidence for the significance of these lesions as precursor markers of malignant potential during colorectal tumorigenesis.
Carcinogenesis 1993 Sep
PMID:K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. 840 99

Colon carcinogenesis models exist at epidemiologic, physiologic and molecular biologic levels. Thinking about the coherence of such models is useful both to inform colon cancer research and because the reasoning process may be generalizable. The consistent epidemiologic risk factors are low vegetable/fiber and high fat/meat/protein intakes. Others include physical activity, alcohol and reproduction. These epidemiologic risk factors appear to map to physiologic variables that provide mechanistic explanations for the associations: higher bile acids, fiber fermentation and effects of specific anticarcinogens found in vegetables. The possibility that the meat/fat association is due to carcinogens or promoters produced in cooked foods adds complexity to the physiologic model. As a link across genetics, physiology and epidemiology, the role of acetylator status is considered. Finally, whether relationships might exist between the epidemiologic/physiologic risk factors and the recently described molecular genetic changes and other colon cancer molecular mechanisms is considered.
 ...
PMID:Colon cancer--do the nutritional epidemiology, the gut physiology and the molecular biology tell the same story? 842 97

Epidemiological studies suggest that consumption of diets containing fruits and vegetables, major sources of phytochemicals and micronutrients, may reduce the risk of developing cancer of the colon. Several phytochemicals and micronutrients present in fruits and vegetables are known to exert cancer-chemopreventive effects in several organs, including the colon. Monoterpenes such as d-limonene and perillyl alcohol derived from orange peels and lavender, respectively, have been shown to possess chemopreventive properties against mammary, liver, and/or lung carcinogenesis. The present study was designed to investigate the efficacy of dietary 40 and 80% maximum tolerated dose (MTD) levels of perillyl alcohol on azoxymethane (AOM)-induced colon carcinogenesis. The effect of this agent on the process of apoptosis in colon tumors was also investigated. Prior to the efficacy study, the MTD of perillyl alcohol was determined in male F344 rats in a 6-week subchronic toxicity study and found to be a 2.5-g/kg diet when added to the AIN-76A diet. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or diets containing 1 and 2 g perillyl alcohol/kg diet, representing 40 and 80% MTD levels, respectively. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of AOM (15 mg/kg body weight/week). All animals were continued on their respective dietary regimen for 52 weeks after AOM treatment and then sacrificed. Colon tumors were evaluated histopathologically using routine procedures. Perillyl alcohol at the 1-g/kg level significantly inhibited the incidence (percentage of animals with tumors) and multiplicity (tumors/ animals) of invasive adenocarcinomas of the colon, whereas perillyl alcohol at 2 g/kg diet inhibited the incidence of total adenocarcinomas of the colon and small intestine as compared to the control diet. Our studies also indicate that the colon tumors of animals fed perillyl alcohol exhibited increased apoptosis as compared to those fed the control diet. These results demonstrate the potential chemopreventive activity of perillyl alcohol against colon carcinogenesis. The chemopreventive activity of perillyl alcohol is mediated through the tumor cell loss by apoptosis.
 ...
PMID:Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. 901 68

The aim of this study was to characterize colon tumor development and invasiveness associated with dietary zinc deprivation. Colon carcinogenesis was initiated by eight weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH) at 12 mg DMH base/kg body wt in groups of mice maintained on diets containing 30 micrograms/kg dietary zinc (zinc adequate, ZA) or 3 micrograms/kg dietary zinc (zinc deprived, ZD). All mice were killed 24 weeks after the last injection of DMH. Mean zinc concentration in the liver was significantly lower in the ZD group than in the ZA group. The total number of grossly detectable colon tumors was the same in both dietary groups. However, histopathological study of each tumor revealed significantly more adenomatous polyps (AP) and invasive adenocarcinomas (CA) in the ZA group, whereas the ZD group had significantly more noninvasive carcinomas in situ (CIS). It appears that zinc deprivation stimulated progression of AP to noninvasive CIS but retarded the progression of noninvasive CIS to invasive CA. Immunohistochemistry of tumors from ZA and ZD mice indicated increased amounts of type IV collagenase in epithelial tumor cells and in stromal cells adjacent to tumor tissue regardless of the amount of dietary zinc consumed. It is suggested that zinc deprivation may limit function of zinc-requiring enzymes such as superoxide dismutase and type IV collagenase, resulting in enhanced progression of AP to noninvasive CIS and retardation of invasion of CIS to become CA, respectively.
 ...
PMID:Zinc deprivation promotes progression of 1,2-dimethylhydrazine-induced colon tumors but reduces malignant invasion in mice. 910 49

Clarification of the mutational fingerprints of HCAs offers a promising approach in the investigation of the role of heterocyclic amines (HCAs) in human carcinogenesis. We analyzed mutations in the tumor related genes of tumors induced by HCAs, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which mainly yield DNA-adducts of C8-guanine. The G-->T transversion at codon 13-2nd position in Ha-ras was predominantly observed in mouse forestomach and rat Zymbal gland tumors induced by MeIQ. In contrast, various types of mutation were detected in the ras family genes of rat Zymbal gland tumors induced by IQ; the presence of a methyl group at position 4 of imidazo[4,5-f]quinoline gave rise to a remarkable difference in the mutational fingerprint. Apc mutations were detected in PhIP- and IQ-induced rat colon tumors, with incidences of 50% (4/8) and 15% (2/13), respectively. All five mutations detected in the four PhIP-induced tumors consisted of a guanine deletion from the 5'-GGGA-3' sequence, in contrast with T to C and C to T mutations in IQ-induced tumors. Four of these five mutations shared seven common nucleotides, -GTGGGAT- surrounding the guanine; indicating that PhIP leaves a characteristic mutational fingerprint in Apc. Colon tumors induced by PhIP were also found to have mutations in their microsatellite sequences, and similar results were detected in mammary gland tumors induced by PhIP, contrasting with no mutations in IQ-induced colon tumors and a very low frequency of mutations in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Although the mechanisms involved in the induction of microsatellite mutations are not known yet, microsatellite mutations which can also be detected in sporadic human tumors, including colon and breast tumors, were indicated to be a characteristic of PhIP. Mammary tumors induced by PhIP showed loss of heterozygocity (LOH) at the distal part of chromosome 10, which shows synteny with the distal part of human chromosome 17, where LOH frequently occurs in human breast cancer. In conclusion, each heterocyclic amine leave a mutational fingerprint which is specific to each compound. Since the tumor-related genes involved in PhIP-induced tumors have characteristics in common with those in human cancers, further detailed analysis will provide us with useful information on mutational fingerprints, and on the possible contribution of PhIP to human colon cancer.
 ...
PMID:Genetic changes induced by heterocyclic amines. 920 52

Several phytochemicals and micronutrients that are present in fruits and vegetables are known to exert cancer chemopreventive effects in several organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogenic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogenesis and to study its modulatory role on the levels of activity of 8-isoprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F2alpha dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of male F344 rats. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or a diet containing 250 ppm genistein. Beginning 2 weeks later, all animals except those in the vehicle-treated groups were given weekly s.c. injections of AOM (15 mg/kg body weight) for 2 successive weeks. All rats were continued on their respective dietary regimen for 52 weeks after AOM treatment and were then sacrificed. Colon tumors were evaluated histopathologically. Colonic mucosae and tumors were analyzed for COX, 15-PGDH, and 8-isoprostane levels. Administration of genistein significantly increased noninvasive and total adenocarcinoma multiplicity (P < 0.01) in the colon, compared to the control diet, but it had no effect on the colon adenocarcinoma incidence nor on the multiplicity of invasive adenocarcinoma (P > 0.05). Also, genistein significantly inhibited the 15-PGDH activity (>35%) and levels of 8-iosoprostane (50%) in colonic mucosa and in tumors. In contrast, genistein had no significant effect on the COX synthetic activity, as measured by the rate of formation of prostaglandins and thromboxane B2 from [14C]arachidonic acid. The results of this investigation emphasize that the biological effects of genistein may be organ specific, inhibiting cancer development in some sites yet showing no effect or an enhancing effect on the tumorigenesis at other sites, such as the colon. The inhibition of 8-isoprostane levels by genistein indicates its possible antioxidant potential, which is independent of the observed colon tumor enhancement, yet this agent may also possess several biological effects that overshadow its antioxidant potential. The exact mechanism(s) of colon tumor enhancement by genistein remain to be elucidated; it is likely that its colon tumor-enhancing effects may, at least in part, be related to inhibition of prostaglandin catabolic enzyme activities.
 ...
PMID:Enhancement of experimental colon cancer by genistein. 928 78

The effect of supplementation of the diet with autohydrolyzed lignin on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied using 112 male Sprague-Dawley rats. Rats received eight weekly injections of DMH (9.5 mg/kg s.c.) or the saline vehicle solution and then were maintained on a basal AIN-76 fiber-free diet or the basal fiber-free diet plus 5% or 10% (wt/wt) lignin for 24 weeks. Rats were killed 32 weeks after the start of the experiment. Colon tumor incidence, location, and multiplicity were determined. Body weight, caloric intake, fecal dry weight, gut transit time, pH of cecal contents, and total fecal bile acid excretion were measured. Supplementation of the diet with 5% or 10% lignin resulted in increased fecal dry weight and total fecal bile acid excretion and in decreased gut transit time, colon pH, and fecal bile acid concentration. Dietary lignin did not significantly affect colon tumor incidence or multiplicity compared with the fiber-free diet. Thus dietary supplementation with autohydrolyzed lignin, a food fiber with good bulking characteristics, had a significant effect on several factors that have previously been linked to reduction of colon cancer risk, but the consumption of high levels of lignin did not decrease the risk for colon cancer.
 ...
PMID:The nonfermentable dietary fiber lignin alters putative colon cancer risk factors but does not protect against DMH-induced colon cancer in rats. 929 Jan 24

Glucocorticoids, such as dexamethasone, induce amiloride-sensitive Na+ conductances in rat distal colon epithelium. The activity of these conductances diminishes from the surface to the base of the crypt whereas cAMP-stimulated Cl- secretion decreases from the crypt base to the surface. These gradients are likely to be perturbed during carcinogenesis. We therefore determined the magnitude of Na+ and Cl- conductances in colonocytes isolated from normal and carcinogen-treated rats. Colon carcinogenesis was induced by injection of dimethylhydrazine (DMH) (18 mg/kg) for 5 weeks. Before sacrifice animals were treated for 3 days with dexamethasone. Colonocyte populations from the surface to the crypt base (C1-C5) were harvested from the distal colon by a Ca2+-chelating procedure. The activity of Na+ conductances was determined by uptake of 22Na+ by surface and crypt colonocyte populations and by membrane vesicles in the presence and absence of 10 microM amiloride. In control rats Na+ conductance was highest in surface colonocytes and absent in the crypt base. As early as 2 weeks after initiation of DMH treatment amiloride-inhibited Na+ uptake was virtually absent in the upper crypt. Transcriptional assessment of the alpha-, beta- and gamma-subunits that constitute the epithelial Na+ channel revealed that DMH treatment reduces the expression of beta-subunit mRNA. We then examined 36Cl- efflux from isolated colonocytes of normal and carcinogen-treated rats in response to forskolin (0.01 mM). Forskolin induced a marked rise in cAMP in lower crypt cells concomitant with a significant stimulation of 36Cl- efflux. Intracellular cAMP increased in upper crypt cells in response to forskolin without an increase in 36Cl- efflux. By contrast, upper crypt colonocytes from DMH-treated rats showed forskolin-stimulated efflux beginning 4 weeks after initiation of treatment. We conclude that induction of Na+ conductances by glucocorticoids is inhibited during the early stages of chemical carcinogenesis due to lack of induction of the beta-subunit of the channel. By contrast, Cl- transport is stimulated both in surface and lower crypt cell compartments during different stages of chemical carcinogenesis.
 ...
PMID:Characterization of sodium and chloride conductances in preneoplastic and neoplastic murine colonocytes. 930 15

CD44 glycoprotein is the main extracellular receptor for hyaluronic acid. The CD44 gene is composed of 20 exons and encodes a variety of isoforms generated by alternative splicing of 10 variant exons. Overexpression of discrete CD44 isoforms containing products of variant exons have been implicated in the progression of cancer, including human colon carcinoma. The pattern of CD44 transcripts changes during early colorectal carcinogenesis, and their relation to CD44 protein expression remains to be defined under experimental conditions. In the current study we investigated CD44 expression in a murine model of human colon adenoma/carcinoma. Colon tumors were induced in 19 ICR/Ha mice by 1,2-dimethylhydrazine injections and CD44 expression was studied by RT-PCR/ Southern blot analysis as well as immunohistochemistry. CD44 transcripts were strongly overexpressed in tumors compared to normal colon. Both neoplastic and normal colon samples exhibited the same species of CD44 transcript representing standard and variant isoforms. Seventy-five percent of neoplasms contained foci of CD44-positive tumor cells, whereas in normal colon the epithelial immunoreactivity was confined to the crypt base. Immunostaining of neoplastic cells was heterogeneous and there was a significant tendency toward the progressive loss of CD44 immunoreactivity in large invading tumors. It is concluded that early events in murine colorectal carcinogenesis are characterized by a marked global overexpression of standard and variant CD44 transcripts.
 ...
PMID:Changes in CD44 expression during carcinogenesis of the mouse colon. 931 89


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>