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)

High iron consumption has been proposed to relate to an increase in the risk of colon cancer, whereas high levels of supplemental sodium phytate effectively reduce iron-induced oxidative injury and reverse iron-dependent augmentation of colorectal tumorigenesis. However, the protective role of intrinsic dietary phytate has not been determined. In this study, we examined the impact of removing phytate present in a corn-soy diet by supplemental microbial phytase on susceptibility of pigs to the oxidative stress caused by a moderately high dietary iron intake. Thirty-two weanling pigs were fed the corn-soy diets containing two levels of iron (as ferrous sulfate, 80 or 750 mg/kg diet) and microbial phytase (as Natuphos, BASF, Mt. Olive, NJ, 0 or 1200 units/kg). Pigs fed the phytase-supplemented diets did not receive any inorganic phosphorus to ensure adequate degradation of phytate. After 4 months of feeding, liver, colon, and colon mucosal scrapings were collected from four pigs in each of the four dietary groups. Colonic lipid peroxidation, measured as thiobarbituric acid reacting substances (TBARS), was increased by both the high iron (P< 0.0008) and phytase (P< 0.04) supplementation. Both TBARS and F2-isoprostanes, an in vivo marker of lipid peroxidation, in colonic mucosa were affected by dietary levels of iron (P< 0.03). Mean hepatic TBARS in pigs fed the phytase-supplemented, high iron diet was 43%-65% higher than that of other groups although the differences were nonsignificant. Moderately high dietary iron induced hepatic glutathione peroxidase activity (P= 0.06) and protein expression, but decreased catalase (P< 0.05) in the colonic mucosa. In conclusion, intrinsic phytate in corn and soy was protective against lipid peroxidation in the colon associated with a moderately high level of dietary iron.
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PMID:Dietary intrinsic phytate protects colon from lipid peroxidation in pigs with a moderately high dietary iron intake. 1032 Jun 35

This purpose of this study was to evaluate whether serum dehydroepiandrosterone (DHEA) and its sulfate conjugate, dehydroepiandrosterone sulfate (DHEAS), are associated with the likelihood of developing colon cancer. A nested case-control study was conducted using the serum bank and cancer registry in Washington County, Maryland. From a population of 20,305 county residents who donated blood in 1974, incident cases of colon cancer that occurred from 1975 to 1991 (n = 117) were matched to one cancer-free control by age, race, and sex. Serum specimens that were stored at -70 degrees C since 1974 were assayed for DHEA and DHEAS. Compared with the controls, the mean serum concentrations of cases were 3% lower for DHEA (P = 0.90) and 13% lower for DHEAS (P = 0.60). When DHEA levels were analyzed according to fourths, no noteworthy associations were observed. Compared with the lowest fourth, the highest fourth of serum DHEAS was nonsignificantly associated with a halving in the risk of colon cancer (odds ratio, 0.50; 95% confidence limits, 0.18, 1.37; Ptrend = 0.22), and further analyses showed the potential protective association was confined largely to males (highest-versus-lowest fourth odds ratio, 0.26; 95% confidence limits, 0.06, 1.16; Ptrend = 0.06). This prospective study does not provide strong evidence that circulating DHEA and DHEAS concentrations are associated with the risk of colon cancer. Among men, DHEAS was associated with a decreased risk of colon cancer, but the association was within the bounds of chance. Further studies are needed to either support or refute the potentially promising lead hinted at by the results for DHEAS.
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PMID:Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and the subsequent risk of developing colon cancer. 1081 98

To assess the effects of a macromolecular prodrug in reducing the nephrotoxicity of cisplatin (CDDP), chondroitin sulfate A (CSA) with a mean molecular weight of 23,000 Da was used to form a complex with CDDP, and the pharmacokinetics and toxicology of the resulting complex were examined in rats in comparison with those of CDDP. The total plasma platinum levels and urinary accumulation were determined up to 3 h following a bolus injection of 2 mg/kg. The results of the pharmacokinetic analysis showed that the complex suppressed the rapid distribution of CDDP, decreased the renal clearance and resulted in over fivefold higher AUC values within 3 h in comparison with CDDP treatment. In addition, the plasma levels of the drug following administration of the complex decreased greatly with time throughout the experimental period (3-24 h), whereas a slow elimination was observed following CDDP administration, which was due to the irreversible protein binding of CDDP. The tissue-to-plasma partition ratio at 10 min also indicated that the CDDP-CSA complex controlled the perfusion of CDDP to tissues, especially to the kidney. The accumulation in various tissues was evaluated at 3 h and 24 h following the injection of 5 mg/kg. Marked differences in renal accumulation were found within 3 h. Significant reductions in accumulation in the kidney, lung, muscle and whole blood were found within 24 h of administration of the complex. The renal toxicity of the CDDP-CSA complex was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (Cr) and the ratio of terminal kidney weight to body weight at doses of 2 mg/kg and 5 mg/kg. The complex displayed a much lower nephrotoxicity at 5 mg/kg in comparison to CDDP, and similar results were obtained at 2 mg/kg. This suggests that the complex changed the toxicodynamics of CDDP. Moreover, the anticancer activity of the CDDP-CSA complex, tested against SW 4800 human colon cancer cells and HeLa human cervix cancer cells in vitro, showed no decrease as compared with that of free CDDP. We conclude that the CDDP-CSA complex had the same activity as the parent drug but showed reduced nephrotoxicity at high doses of CDDP through an improvement in the pharmacokinetics of CDDP, which resulted from both the minimization of entry into normal tissues and renal clearance. In addition, it is also possible that different intracellular interactions in renal cells play a role in protection against the nephrotoxicity of high doses of CDDP.
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PMID:Effects of a cisplatin-chondroitin sulfate A complex in reducing the nephrotoxicity of cisplatin. 1100 75

The human heparanase gene, an endo-beta-glucuronidase that cleaves heparan sulfate at specific intrachain sites, has recently been cloned and shown to function in tumor progression and metastatic spread. Antisense digoxigenin-labeled heparanase RNA probe and monoclonal anti-human heparanase antibodies were used to examine the expression of the heparanase gene and protein in normal, dysplastic, and neoplastic human colonic mucosa. To our knowledge, this is the first systematic study of heparanase expression in human colon cancer. Both the heparanase gene and protein were expressed at early stages of neoplasia, already at the stage of adenoma, but were practically not detected in the adjacent normal-looking colon epithelium. Gradually increasing expression of heparanase was evident as the cells progressed from severe dysplasia through well-differentiated to poorly differentiated colon carcinoma. Deeply invading colon carcinoma cells showed the highest levels of the heparanase mRNA and protein associated with expression of both the gene and enzyme by adjacent desmoplastic stromal fibroblasts. A high expression was also found in colon carcinoma metastases to lung, liver, and lymph nodes, as well as in the accompanying stromal fibroblasts. Moreover, extracts derived from tumor tissue expressed much higher levels of the heparanase protein and activity as compared to the normal colon tissue. In all specimens, the heparanase gene and protein exhibited the same pattern of expression. These results suggest a role of heparanase in colon cancer progression and may have both prognostic and therapeutic applications.
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PMID:Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma. Evidence for its role in colonic tumorigenesis. 1102 21

The ATP-binding cassette transmembrane proteins play an important role in transport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions. MRP1 operates as an ATP-dependent primary active transporter for substrates conjugated with glucuronide, sulfate or glutathione. Leukotriene C4 is an important endogenous substrate for MRP1. Glutathione serves as a cofactor in MRP1-mediated drug transport as well. Genes encoding both MRP1 and the catalytic subunit of gamma-glutamylcysteine synthetase (gamma-GCS) are coordinately regulated in cultured cancer cell lines as well as colorectal cancer tissues from colon cancer patients. The induction of MRP1 and gamma-GCS expression by oxidative stress varies among different cell lines, and p53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione derivatives as photoreactive biochemical probes targeting the transporter protein. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-resistant cancer cells to anticancer prostaglandins in vitro, which was characterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.
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PMID:The human multidrug resistance-associated protein (MRP) gene family: from biological function to drug molecular design. 1109 46

Trypsinogen is a serine proteinase produced mainly by the pancreas, but it has recently been found to be expressed also in several cancers such as ovarian and colon cancer and in vascular endothelial cells. In this study, we found that trypsinogen-1 and -2 are present at high concentrations (median levels, 0.4 and 0.5 mg/L, respectively) in human seminal fluid and purified them to homogeneity by immunoaffinity and anion exchange chromatography. Purified trypsinogen isoenzymes displayed a M(r) of 25 to 28 kd in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Most of the trypsinogen-1 purified from seminal fluid was enzymatically active whereas trypsinogen-2 occurred as the proform, which could be activated by enteropeptidase in vitro. Immunohistochemically, trypsinogen protein was detected in the human prostate, urethra, utriculus, ejaculatory duct, seminal vesicles, deferent duct, epididymal glands, and testis. Expression of trypsinogen mRNA in the same organs was demonstrated by in situ hybridization. Trypsinogen mRNA was also detected in the prostate and seminal vesicles by reverse transcriptase-polymerase chain reaction and Northern blotting. Isolated trypsin was shown to activate the proenzyme form of prostate-specific antigen. These results suggest that trypsinogen isoenzymes found in seminal fluid are produced locally in the male genital tract and that they may play a physiological role in the semen.
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PMID:Expression and characterization of trypsinogen produced in the human male genital tract. 1110 74

We previously reported that intracolonic administration of enprostil, a prostaglandin-E(2) (PGE(2)) analogue, had therapeutic effects on acute colitis induced in rodents by dextran sulfate sodium (DSS). In addition, production of growth-regulated gene product/cytokine-induced neutrophil chemoattractant-1 [GRO/CINC-1; an interleukin(IL)-8 like cytokine] was suppressed in the inflamed tissues. In the present study we used a human colon cancer cell line (HT-29) to investigate enprostil effects on the IL-8 production of intestinal epithelial cells stimulated by various stimulants. In a MTT assay, concentrations of enprostil >10(-5)M had cytotoxitic effects on HT-29 cells. Furthermore, 10(-6) M enprostil suppressed IL-8 production in HT-29 cells, SW620 and CaCo2 stimulated with interleukin-1 beta (IL-1 beta) or lipopolysaccharide (LPS), but did not suppress this response when cells were stimulated with tumour necrosis factor (TNF)-alpha. These results suggest that enprostil affects a point in the pathway between the IL-1 receptor or LPS receptor and nuclear factor-kappa B(NF-kappa B), without affecting the pathway between the TNF receptor and NF-kappa B, with the latter factor being required for the IL-8 gene transcription. The therapeutic effect of exogenous enprostil on DSS colitis may involve the inhibition of IL-8 production in colonic epithelial cells stimulated by IL-1 beta or LPS.
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PMID:Enprostil, a prostaglandin-E(2) analogue, inhibits interleukin-8 production of human colonic epithelial cell lines. 1111 62

There is evidence suggesting that local intracrine formation of sex steroids from inactive precursors, dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and 4-androstenedione (4-DIONE) plays an important role in the regulation of growth and function of peripheral target tissues. Moreover, human solid tumors are often infiltrated by stromal/immune cells secreting a wide spectra of cytokines. These cytokines might in turn regulate the activity of both immune and neoplastic cells. Our data demonstrate that the potent regulatory effects of interleukin-4 (IL-4) and IL-6 on both estrogenic and androgenic 17beta-HSD/KSR activities in breast cancer cells depend on the cell-specific gene expression of various types of 17beta-HSD/KSR enzymes. However, in both estrogen-receptor (ER)-positive (ZR-75-1, T-47D) and ER-negative (MDA-MB-231, BT-20) human breast cancer cells, exposure to IL-4 and IL-13 caused a rapid and potent induction of 3beta-HSD type 1 gene expression. Such an induction was also observed in normal human mammary and prostate epithelial cells in primary culture as well as in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, and HT-29 colon cancer cells. The DNA-binding activity of Stat6, a member of the Signal Transducers and Activators of Transcription gene family, was activated after a 30 min exposure to IL-4 in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid DHEA, not only in breast cells but also in various cell types derived from peripheral target tissues.
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PMID:Crucial role of cytokines in sex steroid formation in normal and tumoral tissues. 1116 8

We investigated the effect of hepatocyte-derived extracellular matrix (ECM) on the expression of erb-B2 and erb-B3 in colon cancer cell lines, as well as the role of erb-B2 and erb-B3 in colon cancer cell proliferation. Colon cancer cell lines plated on hepatocyte-derived ECM had increased protein levels of both erb-B2 and erb-B3. The addition of soluble recombinant proteoglycan syndecan-4 also resulted in higher expression of erb-B2 and erb-B3. We prepared hepatocyte-derived ECM from 1 to 7 days' cultures of hepatocytes, which contained different amounts of sulfated glycosaminoglycans. There was a direct correlation between the amounts of sulfated glycosaminoglycans in the ECM and the levels of erb-B2 and erb-B3 in the colon cell line KM12. The stimulatory effect of hepatocyte-derived ECM was abolished when the colon cancer cells were cultured in the presence of antibodies to erb-B2. These studies show that hepatocyte-derived ECM and the heparan sulfate proteoglycans present in it are responsible for inducing erb-B2 and erb-B3 in colon cancer cells. The growth stimulatory effect of extracellular matrix is mediated, at least in part, by increased expression of erb-B2 and erb-B3.
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PMID:Soluble and matrix-associated heparan sulfate proteoglycans increase expression of erb-B2 and erb-B3 in colon cancer cell lines. 1116 53

Co-administration of synthetic chemically modified oligonucleotides with irinotecan, a selective topoisomerase I inhibitor, provided a significant enhancement in the antitumor activity of irinotecan. The enhancement of antitumor activity of irinotecan with co-administration of chemically modified oligonucleotides was observed in several tumor models--pancreatic cancer (Panc-1), colon cancer (HCT-116) and melanoma (A375). Inhibition of tumor growth in all three models required the co-administration of irinotecan and chemically modified oligonucleotides, but was independent of the nucleotide sequence of the oligonucleotides. The potentiation of antitumor activity was dependent on the dose of irinotecan and chemically modified oligonucleotides administered. The enhancement of antitumor activity of irinotecan was also observed by co-administration of a phosphorothioate oligonucleotide, however, to a lesser extent than did chemically modified oligonucleotides, suggesting that metabolic stability of the oligonucleotide contributes to the enhancement of antitumor activity seen with irinotecan. The co-administration of dextran sulfate sodium with irinotecan showed insignificant potentiation of antitumor activity of irinotecan, suggesting that the enhancement of antitumor activity of irinotecan observed was not a result of polyanionic characteristic of oligonucleotides. Co-administration of irinotecan and chemically modified oligonucleotides did not result in increased toxicity in the tumor models studied. Potentiation of antitumor activity of irinotecan observed with co-administration of oligonucleotides suggests that the oligonucleotides affect the pharmacokinetics and/or metabolism of irinotecan. The use of chemically modified oligonucleotides together with irinotecan may increase the therapeutic index of irinotecan in cancer patients and continued development of such agents should be considered.
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PMID:Potentiation of antitumor activity of irinotecan by chemically modified oligonucleotides. 1129 57


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