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)

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

To investigate whether resistant starch (RS) affects putative risk factors for colon cancer, 24 healthy men consumed a daily RS supplement for 4 wk in addition to their habitual diet in a single-blind, randomized, balanced multiple crossover trial. During the first week, all subjects consumed the control supplement containing glucose. Subsequently, each subject consumed, in random order, a supplement with RS2 (uncooked high-amylose cornstarch), RS3 (extruded and retrograded high-amylose cornstarch), and glucose, each for 1 wk. The RS2 and RS3 supplements provided 32 g RS/d. Lithium was added to the supplements to measure compliance. Feces, 24-h urine, and breath samples, as well as a 24-h food-consumption recall were obtained weekly from each subject. Compliance as measured by urinary lithium recovery was satisfactory. The mean composition of the background diet did not differ between the various supplementation periods. Breath-hydrogen excretion, stool weight, and fecal starch excretion were significantly higher during RS than during glucose supplementation, but did not differ during RS2 and RS3 supplementation. There were no significant differences in fecal dry weight, pH, or short-chain fatty acid concentrations, nor in the pH, bile acid concentrations, cytotoxicity, or osmolality of fecal water. It is concluded that in healthy men, supplementing the habitual diet for 1 wk with 32 g RS2 or RS3/d compared with glucose had no effect on putative risk factors for colon cancer, except for increasing stool weight and colonic fermentative activity. There were no significant differences between the effects of RS2 and RS3 on the indexes studied.
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PMID:Limited effect of consumption of uncooked (RS2) or retrograded (RS3) resistant starch on putative risk factors for colon cancer in healthy men. 945 82

Metastatic rat colon cancer cells but not normal rat hepatocytes showed activity of cathepsin B on their plasma membranes. Activity was visualized in living cells with a new fluorogenic substrate, [Z-Arg]2-cresyl violet, and confocal microscopy. When these cancer cells were injected into the portal vein of rats, the animals developed tumors in the liver in a heterogeneous fashion. Three- to four-fold more tumors were found in the small caudate lobe than in the other three large lobes of the liver. Oral treatment with a selective water-soluble inhibitor of extracellular cathepsin B, Mu-Phe-homoPhe-fluoromethylketone, resulted in 60% reduction of the number of tumors and 80% reduction of the volume of tumors in the three large lobes whereas tumor development was not affected in the small caudate lobe. This study supports the conclusions that (a) extracellular cathepsin B plays a crucial but complex role in liver colonisation by rat colon carcinoma cells in vivo, (b) its selective inhibition suppresses tumor growth heterogeneously in the liver and (c) the caudate lobe of the liver is a relatively large risk factor for tumor development.
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PMID:Heterogeneous suppression of experimentally induced colon cancer metastasis in rat liver lobes by inhibition of extracellular cathepsin B. 951 97

The history of the recognition of the importance of dietary fiber, their current classification into water-soluble and water-insoluble fiber, and lignin, a single non-carbohydrate fiber, and the physiologic role of dietary fiber, with particular reference to retrograde starch resistance to small intestine digestion, are briefly presented. Dietary fiber are highly hygroscopic, thus they greatly contribute to stool voluminosity by binding water, decrease the glycemic index, and exert a protective action, via an as yet unknown mechanism, against the occurrence of colon cancer. It should be added that some dietary fiber decrease the concentration of cholesterol in the blood, i.e. in the human body. The importance of the methodology used for NSP determination is underlined, since some methods determine only some of the polysaccharides, other also measure some other substances, whereas Englyst's method determines NSP only.
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PMID:Dietary fiber and retrograde starch. 959 16

The possible association between the risk of colon cancer and hardness levels in drinking water from municipal supplies was investigated in a matched case-control study in Taiwan. All eligible colon cancer deaths (1,714 cases) of Taiwan residents from 1989 through 1993 were compared with deaths from other causes (1,714 controls) and the hardness levels of the drinking water used by these residents were determined. Data on water hardness throughout Taiwan have been collected from Taiwan Water Supply Corporation (TWSC). The control group consisted of people who died from other causes and the controls were pair matched to the cases by sex, year of birth, and year of death. The results show a significant negative relationship between drinking water hardness and colon cancer mortality. Odds ratio and 95% confidence intervals were 1.22 (1.04-1. 43) and 1.46 (1.22-1.75), respectively, for exposure to moderately hard water and soft water compared with the use of hard water. Trend analyses showed an increasing odds ratio for colon cancer with decreasing levels of hardness in drinking water. This is an important finding for the Taiwan water industry and human health.
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PMID:Colon cancer mortality and total hardness levels in Taiwan's drinking water. 960 33

Synthesis and preliminary biological evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)-guanine ([18F]FHBG) is reported. 9-(4-Hydroxy-3-hydroxymethylbutyl)-guanine (penciclovir) 4 was converted to 9-[N2, O-bis-(methoxytrityl)-3-(tosylmethybutyl)]guanine 7 by treatment with methoxytrityl chloride followed by tosylation. The tosylate 7 was reacted with either tetrabutylammonium fluoride or KF in the presence of kryptofix 2.2.2. to produce the 4-fluoro-N2-O-bis-(methoxytrityl) derivative 8. Removal of the methoxytrityl groups by acidic hydrolysis produced FHBG 5. Radiolabeled product [18F]FHBG was prepared by fluorination of the tosylate 7 with [18F]KF and kryptofix 2.2.2. The labeled product was isolated by HPLC purification on a reverse-phase C18 column, and eluted at 12 min with 15% acetonitrile in water at a flow rate of 2.25 mL/min. Radiochemical yield was 8.0-22.3% with an average of 12% in 7 runs (corrected for decay). Synthesis time was 90 to 100 min including HPLC purification with radiochemical purity >99%, and average specific activity of 320 mCi/micromol. In vitro studies of the compound in HT-29 colon cancer cells revealed 18.2-fold higher uptake into transduced cells compared to control in 3 h. The agent may be useful for imaging viral infection or transfected cells in gene therapy.
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PMID:Synthesis and preliminary evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG): a new potential imaging agent for viral infection and gene therapy using PET. 962 Jun 20

Short chain fatty acids (SCFAs) have been the subject of much research over the past few decades. They play a vital role in maintenance of colonic integrity and metabolism. They are produced when dietary fibre is fermented by colonic bacteria. SCFAs are avidly absorbed in the colon, at the same time as sodium and water absorption and bicarbonate secretion. Once absorbed, SCFAs are used preferentially as fuel for colonic epithelial cells and have trophic effects on the epithelium. Clinically, SCFAs have been studied as possible therapeutic agents in diversion colitis, ulcerative colitis, radiation proctitis, pouchitis and antibiotic-associated diarrhoea. Although some promising effects have been observed in uncontrolled studies, a specific therapeutic role for SCFAs remains to be defined. SCFAs may be the effector of the beneficial role of fibre in prevention of colon cancer.
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PMID:Review article: short chain fatty acids in health and disease. 967 8

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine++ +] is a water-soluble analogue of camptothecine used in the second-line treatment of advanced colon cancer. Recently, we identified, in the plasma of patients and in human liver microsomal incubations, the presence of a new metabolite of irinotecan, 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine (NPC), which is produced by cleavage of the distal piperidine ring of irinotecan. The kinetics of biotransformation of the lactone and carboxylate forms of irinotecan into NPC were studied using human liver microsomes. The formation of NPC was characterized by the following parameters: KM = 48.2 +/- 6.8 and 273 +/- 122 microM and Vmax = 74.1 +/- 4.9 and 78.6 +/- 27.7 pmol/min/mg of protein for the lactone and carboxylate forms of irinotecan, respectively. Interestingly, there was no formation of NPC from 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine, a major metabolite of irinotecan that has an open distal piperidine ring and could be considered a possible metabolic precursor of NPC. The transformation of irinotecan into NPC was found to be catalyzed principally by cytochrome P450 (CYP) 3A, based on three key results, as follows: 1) the CYP3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited NPC formation by 99 and 100%, respectively; 2) of a series of microsomal preparations from transfected lymphoblastoid cells expressing specific CYPs, only those from CYP3A4 cDNA-transfected cells transformed irinotecan into NPC; and 3) incubations with 15 individual preparations of human liver microsomes yielded highly significant correlations between the formation of NPC and both immunoreactivity with anti-CYP3A antibodies and testosterone 6beta-hydroxylation (an activity specifically mediated by CYP3A). The effects of 11 drugs (used at 100 microM) on this metabolism were studied with irinotecan lactone (25 microM). Although ondansetron, loperamide, and racecadotril inhibited this pathway by 75, 95, and 95%, respectively, the concentrations used may not be clinically achievable. However, significant inhibition by ketoconazole and troleandomycin indicates that NPC formation in patients may be influenced by coadministration of drugs with known anti-CYP3A activities.
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PMID:Biosynthesis of an aminopiperidino metabolite of irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by human hepatic microsomes. 969 91

Epidemiological studies have suggested a protective effect of lycopene and lycopene-rich tomatoes against various cancers. Here, the inhibition of colon carcinogenesis by lycopene and tomato juice was investigated. Seven-week-old female F344/NSlc rats received an intrarectal dose of 2 mg (experiment I) or 4 mg (experiment II) of N-methylnitrosourea 3 times a week for 3 weeks, and had free access to one of 4 drinking fluids: plain water (control group), 17 ppm lycopene water solution (Ly group), and diluted tomato juice containing 17 ppm (Tj group) or 3.4 ppm (tj group) lycopene, throughout the experiments. The colon cancer incidence at week 35 was significantly lower in the Tj group, but not in the Ly group, than in the control group: 21% and 33% vs. 54%, in experiment I (24 rats in each group). It was significantly lower in the Tj group than in the tj and control groups, 40% vs. 72% and 84%, in experiment II (25 rats in each group). An appreciable amount of lycopene (0.02 microgram/g) was detected in the colon mucosa of rats in the Tj group, but not in the tj group. The results suggest that tomato juice rich in lycopene may have a protective effect against colon carcinogenesis.
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PMID:Prevention of N-methylnitrosourea-induced colon carcinogenesis in F344 rats by lycopene and tomato juice rich in lycopene. 984 77

The material comprises a group of 33 patients in whom CT check-ups revealed the presence of recurrence after colon cancer surgery. CT examinations were performed using 3% gastrographine contrast enema, air insufflation and filling the intestine with water with the patient lying on the back and abdomen. The anastomotic recurrence was found in 11 patients (33.3%), peri-anastomotic in 14 cases (42.4%) and distant in 8 patients (24.3%). The authors emphasise the value of air insufflation in visualising the anastomotic segment and thickness of intestinal walls. They are consistent with literature data in pointing to the purposefulness of target biopsy, guided CT and determination of the level of blood serum carcinoembryonal antigen in revealing recurrences.
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PMID:[The value of CT examination for diagnosis of postoperative colonic cancer recurrences using bi-contrast and mono-contrast enema and air]. 1002 68


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