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)

Trefoil peptides are a family of small proteins expressed by goblet cells that are secreted onto the apical gastrointestinal mucosal surface, where they are present in high concentrations. These peptides appear to both protect the epithelium and promote healing after injury. However, the factors regulating the expression and secretion of these proteins contributing to mucosal defense have not been characterized. To determine the mechanisms controlling production of trefoil peptides, the human colon cancer-derived model cell line HT-29 was exposed to a variety of potential secretagogues. Expression and secretion of human intestinal trefoil factor (hITF) as well as the intestinal apomucin MUC2 were assessed by Northern and Western blot analysis. Carbachol, an analog of acetylcholine, and the neuroendocrine peptides somatostatin and vasoactive intestinal polypeptide (VIP) stimulated increased expression of hITF mRNA within 5 min. These same factors stimulated parallel secretion of the hITF peptide, with maximal stimulation observed at concentrations ranging from 10(-6) M (carbachol and somatostatin) to 10(-7) M (VIP). Expression and secretion of hITF in response to carbachol, VIP, and somatostatin was independent of production of apomucin. hITF was not regulated by other neuroendocrine transmitters including histamine and substance P. Similarly, hITF expression and secretion was not modulated by peptide growth factors (epidermal growth factor, transforming growth factor-beta, and keratinocyte growth factor), cytokines [interleukin (IL)-1 beta, IL-2, IL-7, and IL-11], or arachidonic acid metabolites (prostaglandin E1/E2 and leukotriene B4). In conclusion, trefoil peptides appear to be integrated into mechanisms of mucosal defense and repair through the enteric neuroendocrine system and independent of the classical mucosal immune cytokine network.
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PMID:Trefoil peptide expression and secretion is regulated by neuropeptides and acetylcholine. 927 13

There is much evidence of the antiproliferative activity of somatostatin (SS) and melatonin (Mel) upon the normal and neoplastic tissues. It has also been found, that both substances are able to alter, under certain conditions, apoptotic processes. Recently, it has been postulated that apoptosis plays a pivotal role in the control of tumour growth. So far, there is no data about the effect of SS analogue--octreotide (Sandostatin, SMS) and Mel on the apoptosis of colon cancer cells. The aim of this study is to examine the effects of SMS and Mel administered separately or together on apoptosis, bromodeoxyuridine incorporation and weight of tumours in the murine transplantable Colon 38 cancer. The male mice were implanted subcutaneously (s.c.) with a suspension of Colon 38 cells. After 6 days, the animals were subcutaneously injected with SMS, Mel, SMS and Mel together (once daily at 6-8 p.m., for 6 days). The incorporation of bromodeoxyuridine (BrDU) into cell nuclei was used as an index of cell proliferation (labelling index-LI). The in situ labelling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). Given separately, both SMS and Mel significantly decreased the LI and increased the AI. However, we have not observed any additive effect of SMS and Mel on either BrDU incorporation or apoptosis. The mean AI in the group treated jointly with SMS and Mel was significantly lower than in groups treated separately with SMS or Mel. It was also found, that the proliferation/apoptosis ratio were significantly lower in the group treated with SMS or MEL, which means that the imbalance between these two processes changed in favour of cell death. Possibly, the observed antitumour effects of these two substances could be due to this alteration.
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PMID:Somatostatin analogue octreotide and melatonin inhibit bromodeoxyuridine incorporation into cell nuclei and enhance apoptosis in the transplantable murine colon 38 cancer. 985 48

The colon cancer cell line HT29 is a useful model to study intestinal chloride secretion. These cells have both cAMP-activated and calcium-activated chloride channels. Changes in elemental content of the cells after stimulation with agonists were determined by X-ray microanalysis in the scanning or scanning transmission electron microscope. Exposure of HT29 cells to pituitary adenylate cyclase activating polypeptide-27 (PACAP) caused a transient decrease in the cellular Cl and K concentrations, indicating (net) efflux of chloride. The effect of PACAP is inhibited by somatostatin, which is known to inhibit cAMP-activated as well as calcium-activated chloride secretion and by U-73122, an inhibitor of phospholipase C. Alloxan, an inhibitor of adenylate cyclase, did not significantly affect the PACAP-induced loss of chloride. The calcium-chelating agent EGTA inhibited the PACAP-induced loss of chloride, indicating the need for extracellular calcium ions. Also vasointestinal polypeptide (VIP) caused a decrease of the cellular chloride concentration in HT29 cells. VIP-induced loss of chloride could be inhibited by pre-treating the cells with somatostatin or UK14,304, an alpha-2 adrenergic agonist that has been shown previously to inhibit purinergically activated chloride efflux. Our results indicate that there is cross-talk between the cAMP- and the calcium-activated pathways for chloride secretion in HT29 cells.
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PMID:Effects of pituitary adenylate cyclase activating polypeptide-27 (PACAP) and vasoactive intestinal polypeptide (VIP) on chloride in HT29 cells studied by X-ray microanalysis. 1007 2

The effect on growth of the long-acting somatostatin analogue lanreotide (LAN), alone or in combination with 5-fluorouracil (5-FU) and mitomycin C (MIT), was investigated in three human colon cancer lines. Cell survival inhibition induced by LAN alone, as evaluated by sulforhodamine B assay, ranged from 20% to 40% as a function of cell line and concentration. The IC50, the concentration inhibiting cell survival by 50%, was never reached. The antiproliferative effect produced by a 48 h exposure to 5-FU or MIT was synergistically enhanced in all cell lines by a subsequent 48 h exposure to LAN. The synergistic interaction was not related to specific cell cycle perturbations or to the somatostatin receptor 2 (sst2) mRNA abundance. In conclusion, our study seems to indicate that LAN is a potentially useful modulating agent for enhancing 5-FU and MIT activity in colorectal cancer patients.
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PMID:Lanreotide-induced modulation of 5-fluorouracil or mitomycin C cytotoxicity in human colon cancer cell lines: a preclinical study. 1112 63

The resistance of advanced colorectal cancers to therapy is often related to mutations in the p53 tumor suppressor gene. Because somatostatin (SRIF) receptors (ssts) are present in colorectal carcinomas, the treatment with targeted cytotoxic SRIF analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to octapeptide SRIF carrier RC-121, may overcome this resistance by producing a higher concentration of the cytotoxic agent in the tumors. Four colon cancer cell lines, HCT-116 and LoVo expressing wild-type p53, and HCT-15 and HT-29 with mutated p53, were investigated. HCT-116, HCT-15, and HT-29, but not LoVo possess functional ssts. We analyzed changes in p53, p21, and proliferating cell nuclear antigen (PCNA) concentrations in these cells in vitro by immunoblotting after exposure to AN-238, its radical AN-201, or doxorubicin (DOX). Equitoxic doses of AN-238, AN-201, or DOX affected p53, p21, and PCNA differently. Analysis of the p21:p53 ratios revealed that DOX increased p53 levels, but most of p53 was mutated and inactive, whereas AN-238 produced smaller changes in p53 concentrations but enhanced its activity. In HCT-15 cells, PCNA:p21 ratios, which are indicators of proliferation and repair processes, remained unchanged after exposure to AN-238 but were increased by DOX. In vivo studies in nude mice demonstrated that AN-238, AN-201, and DOX were equally effective on HCT-116 tumors that express wild-type p53. However, AN-238 also inhibited the growth of HCT-15 and HT-29 cancers that express mutant p53, whereas AN-201 and DOX showed no effect. None of the compounds could suppress the proliferation of LoVo tumors that lack functional ssts. In conclusion, cytotoxic SRIF analogue AN-238 inhibits the growth of experimental colon cancers that express ssts, regardless of their p53 status.
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PMID:Targeted cytotoxic somatostatin analogue AN-238 inhibits somatostatin receptor-positive experimental colon cancers independently of their p53 status. 1183 May 33

The presence of cellular somatostatin receptors, particularly of subtype 2, has been reported in a large number of human primary non-neuroendocrine tumours, such as breast and colon cancer. Our aim was to evaluate whether subtype 2 expression may represent a prognostic factor in these tumours, and if the exact determination of its expression might help to identify patients eligible for a new treatment modality based on somatostatin analogues. Large groups of neuroblastomas as well as breast and colon cancers were studied for subtype 2 expression. In the two latter groups the expression of subtype 2 was evaluated both in tumour and in the corresponding normal tissue from the same patient, to correctly evaluate any modification of subtype 2 mRNA expression in cancer. Subtype 2 mRNA expression was measured with accurate quantitative retro transcription-polymerase chain reaction procedures (first, by competitive polymerase chain reaction and then, by real-time assays). When possible, results of mRNA measurement were compared with in vitro (in situ hybridisation and immunohistochemistry) and in vivo (octreoscan) demonstration of subtype 2 expression in the same patients. Our results seem to suggest the hypothesis that subtype 2 may represent a marker of cell differentiation in certain tumours, such as neuroblastoma, and another instance may be represented by breast and colon cancer. Beside this, the question whether subtype 2 may have an active role in inhibiting cancer cell proliferation, stays open.
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PMID:Somatostatin receptors in non-endocrine tumours. 1507 15

The action of the somatostatin analog SMS-201.995 (SMS) was tested in monotherapy and in combined therapy with the cytotoxic agent 5-fluorouracil (5-FU) on cell cycle kinetics of the human colon cancer cell line WiDr, expressing a mutant p53 (mp53). The data, obtained by flow cytometric DNA analysis, showed that SMS at 0.2 microg/ml increased apoptosis, augmenting the proportion of cells with subdiploid DNA content by 65 and 48% after 3 and 6 h, respectively. In cultures lasting 24 and 36 h, it also decreased the percentages of cells in G0/G1 phase by 22.9 and 14.3%; whereas at a dose of 0.1 microg/ml, SMS decreased the percentage of cells in G2/M by 14.3%. In contrast to SMS, 5-FU (0.1 microg/ml) augmented the apoptosis at 12 h, and markedly increased the fraction of cells in S phase, increasing its value from 24 and 72 h by 108 and 234%, respectively, in comparison to the control. The most evident finding after the combination of SMS (0.2 microg/ml) and 5-FU (0.1 microg/ml) was a potentiation of 5-FU-induced S-phase block by a further 7.9, 12.9 and 42.1% at 24, 36 and 72 h, respectively. Treatment with 5-FU also upregulated HLA class I expression of the cancer cells. In this sense, SMS was less effective and when given in combination with 5-FU did not change the effects induced by 5-FU. The data emphasize that SMS exhibits pro-apoptotic and anti-proliferative effects, which in proper dose combinations might enhance the effects of 5-FU on human colorectal cancer cells expressing mp53.
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PMID:SMS 201-995 enhances S-phase block induced by 5-fluorouracil in a human colorectal cancer cell line. 1616 75

Colorectal carcinoma is one of the more prevalent, highly malignant human tumors, occurring in about 7% of the population. However, if diagnosed and treated in its early stages, colon cancer is curable. In our study, we used a mouse xenograft model to investigate the capability of a fluorescent conjugate of a novel synthetic somatostatin (SST) analog to improve detection of human colorectal tumors that are characterized by over-expressed SST receptors. Human HT-29 colon carcinomas were induced in nude mice. After administration of the fluorescent SST conjugate, in vivo low- and high-magnification fluorescence microscopy, as well as high-resolution spectrally resolved imaging were performed, and the time-dependent biodistribution was determined quantitatively (using fiber-optic spectroscopy). Administration of the conjugate (at concentrations of 6 mg/kg body weight) enabled targeting small (1-5 mm diameter) tumors with high sensitivity and selectivity. Toxicity studies at dosages up to 1,000 mg/kg body weight did not reveal any drug related abnormalities. In conclusion, the SST conjugate significantly enhanced the detection of HT-29 colon tumors by fluorescence imaging because of a 5- to 8-fold increase in the contrast between malignant and normal tissues.
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PMID:Diagnostic targeting of colon cancer using a novel fluorescent somatostatin conjugate in a mouse xenograft model. 1818 91

Activation of pro-survival pathways and apoptotic cell death escape are considered hallmarks of oncogenic cell transformation. Tissue microenvironment strongly influences tumorigenesis, redirecting some pathways versus a persisting pro-survival state. Here, we report evidence on the role of interleukin 6 (IL-6) in affecting pro-survival pathways in colon cancer progression, modulating the expression and the molecular interactions among the pro-apoptotic factor Bax, the DNA repair proteins Ku70/86 and Clusterin isoforms. In human colorectal carcinomas (n = 50) at different stages of disease, we found an increased IL-6 production, the loss of Ku86 and Clusterin 50-55 kDa pro-apoptotic isoform. Conversely, we observed the overexpression of Bax and the 40 kDa prosurvival sClusterin (sCLU) isoform. Bax co-localized with Ku70 that was found atypically expressed in the cytoplasm of advanced stage colon cancers (Dukes'C-D; n = 22). IL-6 treatment of a colon cancer cell line, Caco-2, modulated the expression of genes involved in tumor invasion and apoptosis, as observed by microarrays. In particular, IL-6 downmodulated Bax expression at mRNA level. Concomitantly, IL-6 exposure influenced Bax also at protein level acting on the Bax-Ku70-sCLU physical interactions in the cytoplasm, by affecting the Ku70 acetylation and phosphorylation state, thus leading to the inhibition of Bax pro-apoptotic activity. In addition, we found that IL-6 treatment induced a significant downregulation of Ku86 and a strong increase of sCLU, confirming tumor biopsies data. In contrast Somatostatin treatment of Caco-2 cells was able to restore apoptosis, demonstrating that Ku70-Bax-CLU interactions could be dynamically modulated. Hence, IL-6 could favor tumor expansion, promoting cell survival and apoptosis escape throughout the different stages of tumor evolution. Uncovering the molecular mechanisms of action of these factors may offer strategies for selectively manipulate the cancer cells sensitivity to therapy.
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PMID:Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression. 1917 10

A 44-year-old man was attending routine follow-up 5 years after colon cancer resection, when ultrasonography detected a pancreatic tumor with a low echoic area. He had no symptoms. Computed tomography (CT) showed a protruding-type tumor, 4 cm in diameter, in the pancreatic head with central necrosis. Angiography revealed that the tumor was hypervascular. The serum somatostatin level was elevated, at 27 pg/ml (normal range, 1.0-12 pg/ml). As somatostatinoma of the pancreas was suspected, we performed pylorus-preserving pancreaticoduodenectomy. Histological and immunohistochemical staining confirmed somatostatinoma of the pancreas without nodal metastasis. Thus, if an endocrine tumor of the pancreas is suspected in a patient with a hypervascular tumor, the possibility of somatostatinoma should be included in the differential diagnosis.
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PMID:Asymptomatic somatostatinoma of the pancreatic head: Report of a case. 2049 41


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