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)

Ornithine decarboxylase (ODC), a key enzyme in mammalian polyamine biosynthesis, has been proposed to be a marker of colonic epithelial cell proliferation and risk for colorectal cancer. We investigated the basal levels of ODC activity in sigmoid and rectal mucosae, and basal and tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced levels of skin ODC activity in individuals with a personal history of colon cancer (n = 9 colon; n = 58 skin), a family history of nonpolyposis hereditary colorectal cancer (n = 49; n = 42), adenomas (n = 16; n = 40), and healthy, family history-negative control subjects (n = 40; n = 79). Using a fresh tissue assay and samples obtained after a standard colon lavage preparation, colon mucosal ODC levels ranged from 0 to 192 pmol/mg/h (sigmoid, 0-163 pmol/mg/h; mean, 36 +/- 32 pmol/mg/h; rectum, 0-192 pmol/mg/h; mean, 35 +/- 32 pmol/mg/h). No differences among the four groups of subjects were found for either colon or skin ODC levels, and there were no sex differences overall or in any group. These results are not compatible with the suggestion that ODC levels are a useful marker of risk for colorectal cancer.
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PMID:Levels of colorectal ornithine decarboxylase activity in patients with colon cancer, a family history of nonpolyposis hereditary colorectal cancer, and adenomas. 130 5

Three colon cancer cell lines (Colo 205, HT29 and T84) were investigated by X-ray microanalysis with respect to elemental composition and the effect of cAMP on the cellular concentrations of Na, K, and Cl. The cultures were not homogeneous with respect to their elemental composition, but appeared to consist of two sub-groups, low-K cells and high-K cells. In all three cell lines, the low-K cells had, in addition, higher Ca, markedly lower Cl, and somewhat lower P and S concentrations. Differences in Na and Mg concentrations were absent or not consistent. Exposure of cells to cAMP caused a decrease of the cellular Cl and K content in high-K (high-Cl) cells. Changes in Na were not significant. No difference between the three cell lines could be noted. Incubation of the cells with phorbol myristate acetate (PMA), which has been shown to down-regulate the expression of the cystic fibrosis (CF) transmembrane conductance regulator gene and thus confer CF-like characteristics on the cells, significantly decreased the response in the cellular Cl concentration to cAMP stimulation. It is concluded that cAMP initially activates predominantly the apical Cl- channel and the basolateral K+ channel.
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PMID:Ion transport in colon cancer cell cultures studied by X-ray microanalysis. 132 9

Orotic acid, first discovered in ruminant milk, is an intermediate in the pyrimidine biosynthesis pathway of animal cells. Its synthesis is initiated by the formation of carbamoyl phosphate (CP) in the cytoplasm, with ammonia derived from glutamine. Ureotelic species also form CP in the first step of urea synthesis in liver mitochondria. For that, ammonia is derived from tissue fluid. When there is insufficient capacity for detoxifying the load of ammonia presented for urea synthesis, CP leaves the mitochondria and enters the pyrimidine pathway, where orotic acid biosynthesis is stimulated, orotic acid excretion in urine then increases. Orotic acid synthesis is abnormally high with hereditary deficiencies of urea-cycle enzymes or uridine monophosphate synthase. It is also elevated by ammonia intoxication and during feeding of diets high in protein, high in lysine with respect to arginine, or deficient in arginine, ornithine, and citrulline. Rats fed 1% orotic acid or diets deficient in urea-cycle amino acids develop fatty livers, which has not been demonstrated in other species. Humans consuming 6 g of orotic acid daily have not shown adverse effects. Rats fed 1% orotic acid or arginine-deficient diets also showed more and larger foci positive for gamma-glutamyl transpeptidase and more liver tumors after administration of carcinogens and partial hepatectomy. Orotic acid feeding was also associated with the tendency for development of larger mammary tumors induced by chemical carcinogens in rats and with development of urinary bladder calculi containing high concentrations of orotic acid in mice. Conditions that raise tissue orotic acid change purine-pyrimidine ratios. It is unknown whether tissue orotate concentrations play a role in the recently observed enhanced proliferation of cells in the colon of rats fed high-protein, high-fat diets or in the promotion of chemically induced colon cancer by intrarectal administration of ammonium acetate.
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PMID:Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance. 154 44

To examine whether protein kinase C (PKC) plays a role in mediating growth inhibitory effects of hexamethylene bisacetamide (HMBA) we compared a control H29 colon cancer cell line to a derivative, HT29-PKC7, that overexpresses high levels of PKC beta 1. We found that although HMBA markedly inhibited the growth of the control cells, no inhibition was seen with the HT29-PKC7 cells. On the other hand the tumor promoter 12-0-tetradecanoyl-phorbol-13 acetate inhibited the growth of HT29-PKC7 cells, but no inhibition was seen with the control cells. Maximum inhibition of the growth of both cell lines was obtained by combined treatment with HMBA and TPA. These results may be relevant to the use of HMBA in combination with other agents in the therapy of specific cancers.
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PMID:The modulation of growth by HMBA in PKC overproducing HT29 colon cancer cells. 175 60

Described herein are structure-activity studies of new antitumor agents based on the pyrrolo[1,2-a]benzimidazole (PBI) ring system. These compounds were designed as new DNA cross-linkers mimicking the mitomycin antitumor agents. Actually, the PBI derivatives were found to have anthracycline-like features: (i) shared cross resistance with doxorubicin in a human myeloma line, (ii) cardiotoxicity, and (iii) excellent DNA strand cleaving capability. The DNA strand cleavage is thought to result from reductive alkylation of DNA followed by the generation of reactive oxygen radicals. The best antitumor agent studied is 6-N-aziridinyl-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo- [1,2-a]benzimidazole-5,8-dione 3-acetate (PBI-A), which possesses nanomolar IC50 values against various human ovarian and colon cancer cell lines.
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PMID:Structure-activity studies of antitumor agents based on pyrrolo[1,2-a]benzimidazoles: new reductive alkylating DNA cleaving agents. 192 Mar 49

Treatment of rodent cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C, leading to increased expression of several genes, including a gene originally designated TPA-S1 or phorbin (M. D. Johnson, G. M. Housey, P. T. Kirschmeier, and I. B. Weinstein, Mol. Cell Biol., 7: 2821-2829, 1987). Sequence analysis of this cloned gene indicated homology with human erythroid-potentiating activity and tissue inhibitor of metalloproteinase (TIMP-1). Elevated levels of phorbin mRNA have been observed in human colon tumors (J. G. Guillem, M. F. Levey, L. L. Hsieh, M. D. Johnson, P. LoGerfo, K. A. Forde, and I. B. Weinstein, Mol. Carcinogen., 3: 68-74, 1990) and this increase correlated with the extent of invasion. To further investigate this phenomenon at the protein level, monoclonal antibodies were developed against the recombinant form of TIMP-1. A competitive enzyme-linked immunosorbent assay was developed for quantitation of the TIMP-1 protein in tissue extracts. Elevated levels of TIMP-1 protein were found in 31 human colon tumors, compared to paired samples of adjacent normal mucosa. In a subset of samples, previously analyzed for phorbin mRNA levels (n = 25), there was a good correlation between the abundance of TIMP-1 protein and phorbin mRNA. Immunoaffinity column purification of tumor extracts followed by Western blot analysis was used to confirm the enzyme-linked immunosorbent assay data. These results provide evidence that phorbin and TIMP-1 represent the same gene. In addition, the immunoassays we have developed may be useful in further studies on the role of TIMP-1 in human colon cancer.
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PMID:Immunological quantitation of levels of tissue inhibitor of metalloproteinase-1 in human colon cancer. 193 83

Human cancers have an apparent low growth fraction, the bulk of cells presumed to being out of cycle in a G0 quiescent state due to the inability in the past to distinguish G0 from G1 cells. The allosteric M1 subunit of ribonucleotide reductase (M1-RR) is constitutively expressed by cycling cells (i.e., G1, S, G2-M). It is acquired during transition from G0 to G1, lost during exit to G0 and thus distinguishes G0 from G1 cells. To estimate the proportion of G0 and G1 cells in primary human breast (n = 5) and colorectal (n = 12) adenocarcinomas, we used both analytical DNA flow cytometry (ADFC) and immunoperoxidase staining of sections with the monoclonal antibody to M1-RR (MAb M1-RR). ADFC of fresh tumors revealed a low percentage of cells in the S phase (4.0 +/- 3.4%) but immunoperoxidase staining for M1-RR revealed an unexpectedly high proportion of positive cells (52.4 +/- 12.7%) in the G1, S, G2-M phases indicating a high G1 content of primary human tumors. Thus, human cancers are blocked in transition in G1 and are not predominantly in a G0 or quiescent differentiated state. This block was interpreted to mean that human cancers are responding to putative regulatory events at a restriction point in the G1 phase, such as relative growth factor deficiency, density inhibition, antiproliferative cytokines, or gene products. Using flow cytometry for both DNA and M1-RR content we found that human colon cancer cell lines arrest in the G1 but not G0 phase upon serum deprivation or density inhibition. Similarly, human breast cancer cell lines are arrested in G1 but not G0 phase by medroxyprogesterone acetate (MPA) or tamoxifen exposure. These findings match our in situ observations, and support the concept of a restriction point block in primary human tumors.
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PMID:Quantitation of G0 and G1 phase cells in primary carcinomas. Antibody to M1 subunit of ribonucleotide reductase shows G1 phase restriction point block. 199 36

We investigated the effects that phorbol ester and diacylglycerol protein kinase C (PKC) activators had on the chemosensitivity of the human colon cancer cell line KM12L4a to Adriamycin (ADR), vincristine (VCR), and vinblastine (VLB) and on the intracellular accumulation of those drugs. Exposure of the cells to the PKC activator phorbol-12,13-dibutyrate (PDBu) (15 nM) during a 96-hr in vitro chemosensitivity assay significantly reduced the sensitivity of KM12L4a cells to ADR, VCR, and VLB, but not to 5-fluorouracil. Because a 96-hr treatment with 15 nM PDBu did not down-regulate PKC activity in KM12L4a cells, activation of PKC appeared to be responsible for the observed protection conferred by PDBu. PDBu-induced alterations in drug accumulation may account for its protective effects against these cytotoxic drugs, because both PDBu and the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate significantly reduced accumulation of [3H] VCR and [14C]ADR in the cultured human colon cancer cells. Unsaturated diacylglycerols are structural and functional analogues of phorbol ester PKC activators that are present in the lumen of the colon. We found that treatment of KM12L4a human colon cancer cells with the diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG) significantly reduced [14C]ADR and [3H]VCR accumulation in the cells. The effects of OAG were dose dependent at physiological diacylglycerol concentrations and were completely reversed by the protein kinase inhibitor H7. OAG, which is rapidly metabolized in cultured cells, did not protect KM12L4a cells against the cytotoxic drugs in our 96-hr in vitro chemosensitivity assay. However, rapid metabolism of diacylglycerols should not limit their capacity to activate PKC in the colonic epithelium in vivo, because that tissue is chronically exposed to replenished supplies of unsaturated diacylglycerols in the intestinal tract. Our results provide evidence that unsaturated diacylglycerols may be environmental factors that contribute to the intrinsic drug resistance of colon cancer in vivo by reducing drug accumulation in the cancer cells.
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PMID:In vitro model for intrinsic drug resistance: effects of protein kinase C activators on the chemosensitivity of cultured human colon cancer cells. 201 56

Protein kinase C (PKC) is a Ca2(+)- and phospholipid-dependent serine and threonine protein kinase which binds and is activated by tumor promoters such as the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA). PKC can be activated in vitro by phosphatidylserine (PS) plus Ca2+. We report here that the compound fecapentaene-12 can replace the requirement for PS in the activation of PKC by Ca2+. In addition, at low concentrations fecapentaene-12 can enhance the activation of PKC by Ca2+ and PS. It can also either enhance or inhibit activation of PKC by the tumor promoter teleocidin, depending on the assay conditions. These results are of interest since fecapentaene is known to be a potent mutagen that is produced by Bacteroides species present in the lumen of the human colon. The present studies raise the possibility that this compound might also play a role in colon cancer by altering the activity of PKC.
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PMID:Effects of a fecapentaene on protein kinase C. 201 37

The prevention of cancer by agents in our diet has led to the concept that oxygen radicals are a necessary component of a variety of human cancers including breast, colon and prostatic cancer. These cancers are putatively promoted by estradiol, bile acids and androgens. Epidemiological studies have shown that these cancers are suppressed in vegetarian populations. Vegetable components that may be responsible for this cancer prevention are Vitamin A, retinoids and protease inhibitors (PIs). These agents have been shown to suppress the formation of hydrogen peroxide in promoter-induced neutrophils. They also have been shown to block two-stage carcinogenesis and breast cancer when fed to animals. PIs also suppress experimentally-induced colon cancer and spontaneous liver cancer. Moreover, a new series of cancer-preventive agents, Sarcophytols (isolated by Fujiki and co-workers), are capable of suppressing two-stage carcinogenesis, breast and colon cancers in rodents when given in low concentrations. Sarcophytols were also active suppressors of H2O2 formation of 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced neutrophils. These observations point to an essential role of oxygen radicals in carcinogenesis. Suppression of the oxygen radical response of neutrophils in relation to cancer preventive agents is a facile assay of these important substances. The mechanism of action of oxygen radicals in promoting carcinogenesis is a multiple one, including: (1) activation of oncogenes, (2) modification of DNA bases, and (3) formation of single-strand breaks leading to poly(ADP)ribose polymerase activation.
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PMID:Prevention of cancer by agents that suppress oxygen radical formation. 206 Aug 47


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