Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carrageenans are seaweed extracts comprising high molecular weight sulphated polygalactosides. They are used in foods at concentrations of up to 2.5% as thickening and gelling agents. When degraded to lower molecular weight forms, they have been shown to induce ulcerative colitis and colon cancer in laboratory animals. Furthermore, undegraded carrageenan (CG) has been shown to promote azoxymethane and methylnitrosourea initiated carcinogenesis, but the promotion mechanism is unclear. To determine if this mechanism involves alterations of tissue drug-metabolizing enzyme system (DMES) activities, six groups of five guinea-pigs each were administered 0.2% kappa undegraded, 0.2% i undegraded, 1% kappa degraded or 1% i degraded CG, or control solutions in the drinking-water for 8 wk. Microsomal and cytosolic DMES activities of the liver, small intestine and colon were determined. The kappa undegraded CG group exhibited significant (P less than 0.05) increases in small intestine cytochrome P-450 levels and benzo[a]pyrene hydroxylase activities. These data suggest that undegraded CG may selectively induce DMES activities in the small intestine mucosa.
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PMID:The effects of carrageenan on drug-metabolizing enzyme system activities in the guinea-pig. 212 69

Human colonic tissue is exposed to a variety of toxic chemicals and potential carcinogens in the diet and the intestinal microenvironment. Colonic adenocarcinoma is commonly resistant to the cytotoxic effects of most chemotherapeutic drugs. We have examined drug metabolic and detoxification pathways in clinical specimens of colon carcinoma and normal adjacent mucosa from 17 patients. All elements of xenobiotic metabolism examined are present in these tissues, including cytochrome P-450-dependent enzymes, glutathione, and glutathione-utilizing enzymes. In comparison of tumor tissue to its respective normal mucosa specific alterations in the pathways affecting a number of chemotherapeutic agents were detected, including significantly higher glutathione, glutathione peroxidase, and anionic glutathione-S-transferase activity. These and other alterations found here could be the target of therapeutic maneuvers to enhance the efficacy of antineoplastic treatment of human colon cancer.
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PMID:Implications for therapy of drug-metabolizing enzymes in human colon cancer. 275 17

The identification of low-penetrance genes, the polymorphisms of which increase an individual's risk of developing cancer, are likely to be extremely important in the general population. In this report we analyzed two genes involved in detoxification. In a number of loci, we identified polymorphic variation correlating with the expression of the gene product. We analyzed two such loci, the cytochrome P-450 gene CYP2D6 and the N-acetyltransferase 2 (NAT2) genes, in patients with bladder and colon cancer, respectively. We observed no statistically significant associations between the control and cancer populations; however, there was a small increase in heterozygote number in bladder cancer.
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PMID:Polymorphisms in drug-metabolizing enzymes as modifiers of cancer risk. 749 46

Irinotecan (CPT-11) is a water-soluble analogue of camptothecin showing activity in colon cancer. Recently, we identified a major metabolite of CPT-11 in patients' plasma, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), which is produced by the oxidation of the distal piperidine ring (P. Rivory et al, Cancer Res., 56: 3689-3694, 1996). As with all active camptothecin derivatives, CPT-11 is subject to spontaneous interconversion between a lactone and a carboxylate form in aqueous media. The kinetics of biotransformation of the two forms of CPT-11 into APC was studied using pooled human liver microsomes. The formation of APC was characterized by the following parameters: Km = 18.4 +/- 1.4 and 39.7 +/- 11.6 microM; and Vmax = 26.0 +/- 0.6 and 13.4 +/- 1.7 pmol/min/mg protein for the lactone and carboxylate forms of CPT-11, respectively. This reaction was found to be catalyzed principally by cytochrome P-450 (CYP) 3A because of three key results: (a) the CYP 3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited APC formation by 98 and 100%, respectively, mostly in a competitive way; (b) using microsomes from transfected lymphoblastoid cells expressing specific CYPs, we found that only those from CYP 3A4 cDNA-transfected cells transformed CPT-11 into APC; and (c) using 15 individual preparations of human liver microsomes, we observed highly significant correlations between the activity of CPT-11 metabolism into APC and both immunoreactivity with anti-CYP 3A antibodies and testosterone 6beta hydroxylation, an activity specifically mediated by CYP 3A. The effect on this metabolism of 11 drugs used at 100 microM was studied with CPT-11 lactone at 25 microM. Amikacin, Bactrim, ciprofloxacin, rocephine, 5-fluorouracil, metoclopramide, morphine, and paracetamol had no effect, but ondansetron, loperamide, and racecadotril inhibited this pathway by 25, 50, and 50%, respectively. These concentrations exceed those expected in vivo. APC formation in patients may thus be influenced by coadministered ketoconazole therapy and may decline after administration of CPT-11 because of the lactonolysis of the latter.
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PMID:Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. 945 91

Cancers of the colon and breast are two of the most prevalent cancers in developed countries. The present experiments were conducted to determine the influence of several dietary doses of grape seed proanthocyanidins on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis and azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a dual-organ tumor model. In addition, the effects of the grape seed proanthocyanidins on liver cytochrome P-450 1A and 2E1 and glutathione S-transferase activities and on colonic ornithine decarboxylase activity were examined to determine possible mechanisms of action. Feeding female rats diets containing 0.1-1.0% grape seed proanthocyanidins was associated with a significant 72-88% inhibition of AOM-induced aberrant crypt foci formation and a 20-56% inhibition of ornithine decarboxylase activity in the distal third of the colon. Feeding the grape proanthocyanidins resulted in no significant effect on the activity of liver cytochrome P-450 2E1. There was no effect of feeding these doses of proanthocyanidins on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumorigenesis. This lack of action on mammary tumorigenesis in part may be due to lack of effect of dietary proanthocyanidins on the liver carcinogen-metabolizing enzymes cytochrome P-450 1A and glutathione S-transferase. These results indicate that grape polyphenolics warrant further evaluation as potential colon cancer chemopreventive agents.
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PMID:Effect of grape seed proanthocyanidins on colon aberrant crypts and breast tumors in a rat dual-organ tumor model. 1175 89

Colorectal cancer is one of the leading causes of cancer deaths in the Western world. More than 56,000 newly diagnosed colorectal cancer patients die each year in the United States. Available therapies are either not effective or have unwanted side effects. Epidemiological data suggest that dietary manipulations play an important role in the prevention of many human cancers. Curcumin the yellow pigment in turmeric has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries. Curcumin is a naturally occurring powerful anti-inflammatory medicine. The anticancer properties of curcumin have been shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin inhibits the promotion/progression stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2/M cell cycle phase and induction of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair deficient and microsatellite instable phenotype. Curcumin should be considered as a safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers arise in the setting of chromosomal instability as well as microsatellite instability.
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PMID:Chemotherapeutic potential of curcumin for colorectal cancer. 1217 41

Several polymorphic cytochrome P-450 and glutathione S-transferase (GST) enzymes are involved in the activation and detoxification of many potential carcinogens and may therefore be important in susceptibility to cancer induction. CYP1A1 MspI, GSTM1, and GSTT1 are polymorphic enzymes and some alleles have been correlated with an increased risk of developing some cancers. In the present study, we examined possible associations between genetic polymorphisms of CYP1A1 MspI, GSTM1, and GSTT1 and colon cancer in a United Kingdom population. An excess of CYP1A1 MspI, and GSTM1 null genotypes was observed amongst colon cancer patients, although this did not reach the level of statistical significance. We found no significant increase in the risk of colon cancer for either CYP1A1 MspI (OR = 1.39; 95%CI: 0.46-4.21) or GSTM1 null (OR = 1.41; 95%CI: 0.76-3.01) genotypes. Individuals with GSTT1 null genotype had no association with colon cancer (OR = 0.42; 95%CI: 0.09-2.02). No significant association was observed in the site of colon cancer (proximal vs. distal). This study suggests that the polymorphisms of CYP1A1 MspI, GSTM1, and GSTT1 are not associated with a significant risk of developing colon cancer in a United Kingdom population.
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PMID:Genetic polymorphisms in the cytochrome P450 1A1, glutathione S-transferase M1 and T1, and susceptibility to colon cancer. 1221 May 2

Estrogen replacement therapy is associated with a reduced risk of colon cancer. Therefore, we evaluated the following ten estrogen metabolism-associated single-nucleotide polymorphisms (SNPs) by sequencing-on-chip technology using solid-phase polymerase chain reaction (PCR) on oligonucleotide microarrays: catechol-O-methyltransferase (COMT) Val158Met G-->A, 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17) vlV A-->C, cytochrome P-450 (CYP) 17 A2 allele T-->C, CYP1A1 MspI RFLP T-->C, CYP1A1 Ile462Val A-->G, CYP19 Arg264Cys C-->T, CYP19 C1558T C-->T, CYP 1B1 Leu432Val, CYP1B1 Asn453Ser, and estrogen receptor (ER) alpha IVS1 -401-->C in 76 patients with a family history of colon cancer and 722 healthy controls. Using stepwise logistic regression models, we found that none of the investigated SNPs is associated with a family history of colon cancer in a univariate and multivariate logistic regression model. In addition, when all two-way interactions of the investigated SNPs were ascertained, no significant interactions between SNPs were observed. In conclusion, we found no association between the carriage of one or multiple SNPs of the estrogen metabolism and a family history of colon cancer.
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PMID:Ten polymorphisms of estrogen-metabolizing genes and a family history of colon cancer--an association study of multiple gene-gene interactions. 1620 20