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)

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.
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PMID:Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci. 1006 62

A network composed of activation and inactivation pathways to regulate mitomycin C (MMC) action is suggested to exist in human cancer cells. COLO201 colon cancer cells were stably transfected with human NQO1 cDNA that encodes NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD), and a clonal cell line with about 57-fold elevated DTD activity was obtained. Northern analysis revealed that expression of the NADPH:cytochrome P450 reductase (P450 reductase) gene was decreased in the transfectant, COLO201/NQO1, associated with the increase of NQO1 expression. Biochemical characterization of the cells showed a significant increase of the glutathione (GSH) content concomitantly with the decrease of the P450 reductase activity. As a result of these coordinated modulations, sensitivity of COLO201/NQO1 to MMC was not increased as compared to the parent cells. Analyses of inhibition by specific inhibitors of DTD, P450 reductase and glutathione S-transferase (GST) in 5 human colon cancer cell lines including the transfectant showed that DTD and P450 reductase play significant roles in MMC activation in cells with sufficiently high DTD activity and with marginal DTD activity, respectively. In contrast, GST appeared to participate in MMC inactivation in cells with a high level of GST activity. These results indicated that DTD, P450 reductase, GSH and GST may act together compensatively or competitively, depending on their levels in cells, to determine the cellular sensitivity to MMC.
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PMID:Regulatory network of mitomycin C action in human colon cancer cells. 1039 Oct 98

The effect of the NSAIDs, retinoids and DFMO on AOM-induced colon tumors, and ACF, cell proliferation, and apoptosis is summarized in Table 1. The ability to prevent AOM-induced ACF has been used as an assay to screen agents for chemoprevention. As discussed above, all six potential chemopreventive agents, aspirin, 2-CPR, DFMO, 4-HPR, piroxicam, and 9-cis-retinoic acid, decreased the level of AOM-induced ACF. However, two of the agents, aspirin (at doses that greatly reduced the yield of ACF) and 2-CPR did not prevent AOM-induced colon tumors. Hence, aspirin and 2-CPR would appear to be false positive in the ACF assay. Besides being a false positive in the ACF assay, 2-CPR actually had the opposite effect of doubling the yield of colon tumor. The false positive result for aspirin could be due to the lower sensitivity of the AOM-induced colon cancer assay compared to the ACF assay. However, aspirin [table: see text] significantly reduced the yield of ACF at a dose (600 mg/kg diet) one-third the dose (1800 mg/kg diet) that did not reproducibly reduce the yield of colon tumors. Thus, although there were no false negative results, two of the six agents gave false positive results in the AOM-induced ACF assay with respect to their ability to prevent colon cancer. Two other potential biomarkers for chemopreventive activity are the ability to reduce the level of cell proliferation and to enhance the level of apoptosis. All six of the agents including aspirin and 2-CPR reduced the level of cell proliferation in adenomas. Thus, similar to their ability to prevent ACF, the ability of aspirin and 2-CPR to decrease cell proliferation were also false positive responses with respect to prevention of colon cancer, but not with respect to the prevention of ACF. Piroxicam, the most potent of the six agents in preventing AOM-induced colon cancer, did not significantly affect the level of cell proliferation in adenomas which is a false negative response. Hence, only three of the six agents (50%) were correctly identified as potential chemopreventive agents by their ability to reduce the level of cell proliferation. In contrast, retinoids, including the three discussed here, demonstrated good correlation between the ability to prevent AOM-induced ACF and the ability to decrease cell proliferation in colonic mucosa or ACF. Thus, within some classes of agents such as the retinoids, the ability to prevent ACF and to reduce cell proliferation appear to correlate, while in other classes including the NSAIDs, the correlation appeared not to exist. The four agents that prevented colon cancer all enhanced the level of apoptosis, while the two agents that did not prevent colon cancer did not effect apoptosis. Three other chemopreventive agents, including phenylethyl-3-methylcaffeate and the NSAIDs, curcumin and sulindac, have been shown by Samaha et al. to enhance apoptosis in AOM-induced colon tumors. Thus, although a very limited number of chemopreventive agents have been evaluated for the ability to enhance apoptosis in the colon, there appears to be an association between the ability to enhance apoptosis and the ability to prevent colon cancer. The use of the AOM-induced ACF assay to screen agents for the ability to prevent colon tumors would appear to result in false positive responses including agents (2-CPR and quercetin) that actually promote colon cancer. However, our results suggest that false positive responders could be distinguished by their inability to enhance apoptosis while potential chemopreventive agents would enhance it. It is therefore proposed that a Two Step Procedure be used to screen agents for the ability to prevent colon cancer. Step 1 would be the determination of the ability to prevent ACF. Because the ACF assay appears to suffer more from false positive than from false negative responders, apparently few potent chemopreventive agents would be missed. Also the ACF assay could be the source of foci for evaluation of the effect
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PMID:Prevention of colon cancer and modulation of aberrant crypt foci, cell proliferation, and apoptosis by retinoids and NSAIDs. 1070 74

Modulation of gene expression in tumors has the potential of being a surrogate end-point biomarker for chemoprevention. Thus, we determined the modulation by chemopreventive agents of the protein and mRNA expression of genes in rat colon tumors. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane. Forty-seven weeks later, they received aspirin (600), calcium chloride (50 000), 2-(carboxyphenyl) retinamide (2-CPR, 315), alpha-difluoromethylornithine (DFMO, 3000), piroxicam (200), quercetin (33 600), 9-cis retinoic acid (9-cis RA, 30), rutin (3000), or sulindac (280) in their diet at the indicated mg/kg concentration for 7 days and were then killed. In colon tumors relative to the mucosa, the protein and mRNA levels of c-myc were increased, while the levels of p16 and p27 were decreased. Calcium chloride, DFMO, piroxicam and sulindac administered for 7 days decreased the mitotic index and reduced the protein and mRNA levels of c-myc in colon tumors. Calcium chloride, DFMO and piroxicam increased the protein and mRNA levels of p16 and along with sulindac increased the protein level of p27, but not its mRNA. The other agents failed to modulate both the mitotic index and the expression of the genes. The ability of the chemopreventive agents to prevent colon tumors was determined. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane and 8 weeks later they were administered aspirin, 2-CPR, DFMO, piroxicam, 9-cis RA and rutin in their diet. The rats were killed 26 weeks after they started to receive the chemopreventive agents. The multiplicity of colon tumors was reduced by DFMO and piroxicam, increased by rutin and not affected by the other agents. Hence, agents that prevented colon cancer decreased the mitotic index and altered the expression of c-myc, p16 and p27 suggesting that modulation in the expression of these genes are potential biomarkers for chemopreventive activity.
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PMID:Altered expression of c-myc, p16 and p27 in rat colon tumors and its reversal by short-term treatment with chemopreventive agents. 1218 86

We describe REMIND, a data mining framework that accurately infers missing clinical information by reasoning over the entire patient record. Hospitals collect computerized patient records (CPR's) in structured (database tables) and unstructured (free text) formats. Structured clinical data in the CPR's is often poorly recorded, and information may be missing about key outcomes and processes. For instance, for a population of 344 colon cancer patients, important clinical outcomes, such as disease state and its evolution, are stored only as unstructured data (doctors' dictations) in the CPR. Raw evidence (extracted directly from the CPR) is not a good predictor of disease state. Yet by combining this evidence in a principled fashion (using methods from uncertain and temporal reasoning), REMIND accurately infers disease state sequences for recurrence, a complex time-varying outcome, for these patients. These outcomes can now be added back into the CPR in structured form.
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PMID:Mining time-dependent patient outcomes from hospital patient records. 1246

Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, alpha-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9-cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer.
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PMID:Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer. 1475 Feb 12

RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), which is currently in clinical trials, is a diaziridinyl benzoquinone bioreductive anticancer drug that was designed to be activated by the obligate two-electron reductive enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). In this electron paramagnetic resonance (EPR) study we showed that RH1 was reductively activated by the one-electron reductive enzyme NADPH cytochrome P450 reductase and by a suspension of HCT116 human colon cancer cells to yield a semiquinone free radical. As shown by EPR spin trapping experiments RH1 was reductively activated by cytochrome P450 reductase and underwent redox cycling to produce damaging hydroxyl radicals in reactions that were both H2O2- and iron-dependent. Thus, reductive activation by cytochrome P450 reductase or other reductases to produce a semiquinone that can redox cycle to produce damaging hydroxyl radicals and/or DNA-reactive alkylating species may contribute to the potent cell growth inhibitory effects of RH1. These results also suggest that selection of patients for treatment with RH1 based on their expression levels of NQO1 may be problematic.
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PMID:The reductive activation of the antitumor drug RH1 to its semiquinone free radical by NADPH cytochrome P450 reductase and by HCT116 human colon cancer cells. 1701 78

Aberrant crypt foci (ACF) are recognized as preneoplastic lesions for colon cancer, and ACF in rodents are widely used as an intermediate biomarker to predict tumorigenicity in the colon. However, a lack of correlations between the formation of ACF and the development of colonic tumors has been reported in several studies. For example, 2-(carboxyphenyl) retinamide (2-CPR) and genistein were reported to inhibit the carcinogen-induced formation of ACF, whereas both of them were later found to enhance colon tumorigenesis in rats treated with azoxymethane (AOM). Recently, we have identified b-catenin-accumulated crypts (BCAC) in the colon of rats shortly after administration of AOM, and provided evidence that these are independent early lesions of classical ACF, and BCAC might be direct precursors for colon cancers. In the present study, we performed a comparative analysis of the modifying effects of 2-CPR and genistein on 1,2-dimethylhydrazine (DMH)-induced BCAC and ACF in male F344 rats. Dietary administration of 2-CPR (315 ppm) significantly reduced the total number, multiplicity and size of ACF in DMH-exposed colonic mucosa, while genistein (250 ppm) had no significant effects on DMH-induced ACF formation. In contrast, both of 2-CPR and genistein significantly enhanced the multiplicity and size of DMH-induced BCAC when compared with DMH alone group. In addition, both 2-CPR and genistein significantly increased the proliferating cell nuclear antigen (PCNA) index preferentially in BCAC. Together with previous findings that 2-CPR and genistein are tumor promoters in the colon, our results support the concept that BCAC are precursors of colon tumors and suggest that these lesions are more reliable short-term biomarkers for colon carcinogenesis in rodents than ACF.
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PMID:Effect of 2-(carboxyphenyl) retinamide and genistein on the formation of early lesions in 1,2-dimethylhydrazine-induced colon carcinogenesis in rats. 1747 68

P450-mediated bioactivation of azoxymethane (AOM), a colon carcinogen, leads to the formation of DNA adducts, of which O(6)-methylguanine (O(6)-mG) is the most mutagenic and contributes to colon tumorigenesis. To determine whether P450 enzymes of the liver and intestine both contribute to AOM bioactivation in vivo, we compared tissue levels of AOM-induced DNA adducts, microsomal AOM metabolic activities, and incidences of colonic aberrant crypt foci (ACF) among wild-type (WT), liver-specific P450 reductase (Cpr)-null (LCN), and intestinal epithelium-specific Cpr-null (IECN) mice. At 6 h following AOM treatment (at 14 mg/kg, s.c.), O(6)-mG and N(7)-mG levels were highest in the liver, followed by the colon, and then small intestine in WT mice. As expected, hepatic adduct levels were significantly lower (by >60%) in LCN mice but unchanged in IECN mice, whereas small-intestinal adduct levels were unchanged or increased in LCN mice but lower (by >50%) in IECN mice compared to that in WT mice. However, colonic adduct levels were unchanged in IECN mice compared to that in WT mice and increased in LCN mice (by 1.5-2.9-fold). The tissue-specific impact of the CPR loss in IECN and LCN mice on microsomal AOM metabolic activity was confirmed by rates of formation of formaldehyde and N(7)-mG in vitro. Furthermore, the incidence of ACF, a lesion preceding colon cancer, was similar in the three mouse strains. Thus, AOM-induced colonic DNA damage and ACF formation is not solely dependent on either hepatic or intestinal microsomal P450 enzymes. P450 enzymes in both the liver and intestine likely contribute to AOM-induced colon carcinogenesis.
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PMID:Role of hepatic and intestinal p450 enzymes in the metabolic activation of the colon carcinogen azoxymethane in mice. 2455 95

Our case describes a 70 year-old male patient with no significant cardiac history who presented for a hemicolectomy for recurrence of colon cancer. Induction of general anesthesia was uneventful. A dexmedetomidine infusion was started prior to incision and a bolus of bupivacaine was administered via an indwelling epidural catheter. Twenty minutes after surgical incision, the patient acutely developed bradycardia that progressed to asystolic arrest. CPR was immediately initiated with return of circulation after three minutes. The case was aborted and the patient made a full recovery. The patient was evaluated by cardiology postoperatively. A detailed evaluation uncovered additional pertinent history of a syncopal event 1.5 years ago, and an episode of hypotension and bradycardia more recently that was not further investigated. In this case, dexmedetomidine and bupivacaine likely functioned synergistically to exacerbate an underlying propensity for bradycardia and increased vagal tone from surgical manipulation that culminated in asystole under anesthesia.
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PMID:Arrest Under Anesthesia - What was the Culprit? A Case Report. 3026 37


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