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)

Retinoids are proposed chemopreventive agents that inhibit cell proliferation and induce differentiation. Their ability to prevent azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors and to modulate cell proliferation was investigated in the colon of male F344 rats. Thirteen retinoids were evaluated for prevention of ACF and two of them, 9-cis-retinoic acid (RA) and 4-(hydroxyphenyl)retinamide (4-HPR), were also evaluated for prevention of colon cancer. The retinoids were administered continuously in the diet starting 1 week prior to the first of two weekly 15 mg/kg i.p. injections of AOM and for a total of either 5 or 36 weeks in order to evaluate their effect on colonic ACF and tumors. At a concentration of 1 mmol/kg diet, 2-(carboxyphenyl)retinamide caused the greatest reduction (57.7%) in the yield of ACF. 9-cis-RA was toxic at 1 mmol/kg so that it was evaluated at 0.1 mmol/kg, resulting in a 41.6% reduction in ACF. The ability of the retinoids to reduce the proliferating cell nuclear antigen (PCNA) labeling index in ACF and in non-involved crypts correlated with their ability to prevent ACF. Both 9-cis-RA (0.1 and 0.2 mmol/kg diet) and 4-HPR (1 and 2 mmol/kg diet) were highly effective in decreasing the yield of AOM-induced colon tumors. In summary, retinoids were demonstrated to reduce cell proliferation and to prevent ACF and tumors in the colon, suggesting promise as preventive agents for colon cancer.
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PMID:Prevention by retinoids of azoxymethane-induced tumors and aberrant crypt foci and their modulation of cell proliferation in the colon of rats. 939 11

Colorectal epithelial cell proliferative kinetics are altered in patients at increased risk for colon cancer: proliferation rates [labeling index (LI)] are higher and there is a shift of the proliferative zone from one confined to the lower 60% of the colonic crypt to one that includes the entire crypt (higher phi(h)). To assess factors associated with LI and phi(h), we performed a cross-sectional analysis using baseline rectal mucosal biopsies from sporadic adenoma patients participating in a chemoprevention trial. Biopsies (taken without preparatory cleansing) were taken 10 cm above the level of the anus, and proliferation was assessed by detection of endogenous S-phase-associated proliferating cell nuclear antigen by immunohistochemical methods. High-quality, scorable biopsies were obtained for 115 patients, and using analysis of covariance and multiple linear regression, the LI and phi(h) were evaluated in relation to diet and other lifestyle factors, demographics, anthropometrics, family history of colon cancer, and polyp history. Statistically significant findings included the following: (a) The LI for those in the upper versus the lowest tertile of vegetable and fruit consumption was, proportionately, 35% lower (3.4% versus 5.3%; P < 0.001); for vitamin supplement users versus nonusers, it was 36% lower (3.3 versus 5.2%; P < 0.001); for recurrent versus incident polyp patients, it was 36% higher (6.2 versus 4.0%; P < 0.001); and for those with rectal polyps only versus those with colon polyps only, it was 28% higher (6.0 versus 4.3%; P = 0.05); and (b) the phi(h) for those in the upper versus the lowest tertile of sucrose consumption was, proportionately, 48% higher (7.1% versus 3.7%; P = 0.01). These results indicate that (a) colorectal epithelial cell proliferation rates are higher in recurrent adenoma patients than in incident adenoma patients and in patients with rectal adenomas only versus those with colon adenomas only, but they are lower in patients with higher intakes of vegetables and fruit and in those who take vitamin/mineral supplements, and (b) the distribution of proliferating cells is shifted toward more inclusion of the upper 40% of the crypt in patients with higher intakes of sucrose. The pattern of positive, negative, and null associations of potential risk factors with cell proliferation is similar to that commonly found with colonic neoplasms.
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PMID:Colorectal epithelial cell proliferative kinetics and risk factors for colon cancer in sporadic adenoma patients. 941 96

In persons at higher risk for colon cancer (e.g., those with sporadic adenoma or ulcerative colitis), compared to those at lower risk, colonic epithelial cell proliferation kinetics are altered. We have shown previously that calcium supplementation appears to normalize the distribution of proliferating cells without affecting the proliferation rate in the colorectal mucosa of sporadic adenoma patients. In a pilot randomized, double-blind, placebo-controlled, clinical trial conducted concurrently with our previously published sporadic adenoma trial, we tested whether calcium supplementation can also modulate cell proliferation kinetics in patients with ulcerative colitis. Ulcerative colitis patients (n = 31) were randomized to placebo or 2.0 g of supplemental calcium daily. Colorectal epithelial cell proliferation was determined by immunohistochemical detection of proliferating cell nuclear antigen labeling of cells in "nonprep" rectal biopsies taken at randomization and after 2 months treatment. All biopsies were scored by one reviewer. Differences in mean follow-up minus baseline labeling index (LI; the proportion of colon crypt epithelial cells that were labeled) and in the phi(h) (proportion of labeled cells that were in the upper 40% of the crypts) were compared with analysis of covariance. Pill-taking adherence was 97%. Biopsy-scoring reliability was high (r = 0.89). The pooled baseline LI and phi(h) were 6.3% and 5.6%, respectively. The LI in the calcium group decreased by 0.5% (proportionately, 3%) more than in the placebo group (P = 0.91). Similarly, the phi(h) in the calcium group decreased by 0.3% (proportionately, 10%) more than in the placebo group (P = 0.85). This pilot study does not suggest that 2.0 g of calcium as calcium carbonate daily can substantially normalize either the rate or distribution of proliferating cells over a 2-month period in the colon crypts of patients with ulcerative colitis; a more definitive answer to the question of whether calcium may be effective would require a study with a larger sample size and/or other study design modifications.
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PMID:Calcium and colorectal epithelial cell proliferation in ulcerative colitis. 941 97

We assessed the effect of sulindac sulfide (SS), a colon cancer chemopreventive agent, on the proliferation and apoptosis in the colon cancer cell lines HCT-15 and HT-29. We applied a triparameter flow cytometric analysis that simultaneously determined DNA content, expression of Ki-67 or proliferating cell nuclear antigen (PCNA), and extent of DNA strand breaks by TUNEL (TdT-mediated dUTP nick end labeling). HCT-15 and HT-29 cells were exposed to SS 200 microM and 175 microM, respectively, for up to 72 h. As expected, SS inhibited proliferation and induced apoptosis. SS also induced several subpopulations of cells defined by their expression of proliferation markers and DNA strand breaks. By 72 h the rapidly proliferating cells [PCNA/Ki-67(+)/TUNEL(-)] were reduced from > 90% to about one third. Of the remaining cells, about one third were apoptotic [PCNA/Ki-67(-)/TUNEL(+)] and one third were quiescent [PCNA/Ki-67(-)/TUNEL(-)]. Another subpopulation was detected that was PCNA/Ki-67(+)/TUNEL(+), some had a dominant subdiploid peak and over half were in S or G2/M phases by DNA content. Thus, a subpopulation of apoptotic cells strongly expressed PCNA and Ki-67, suggesting that their specificity as proliferation markers may need reassessment. Similar results were obtained with the HL-60 promyelocytic cell line.
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PMID:Sulindac sulfide induces several subpopulations of colon cancer cells, defined by PCNA/Ki-67 and DNA strand breaks. 943 28

A unique feature of p21 that distinguishes it from the other cyclin-dependent kinase (CDK) inhibitors is its ability to associate with the proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA polymerases delta and epsilon. While it is now well established that inhibition of cyclin/CDK complexes by p21 can result in G1 cell cycle arrest, the consequences of p21/PCNA interaction on cell cycle progression have not yet been determined. Here, we show, using a tetracycline-regulated system, that expression of wild-type p21 in p53-deficient DLD1 human colon cancer cells inhibits DNA synthesis and causes G1 and G2 cell cycle arrest. Similar effects are observed in cells expressing p21CDK-, a mutant impaired in the interaction with CDKs, but not in cells expressing p21PCNA-, a mutant deficient for the interaction with PCNA. Analysis of cells treated with a p21-derived PCNA-binding peptide provides additional evidence that the growth inhibitory effects of p21 and p21CDK result from their ability to bind to PCNA. Our results suggest that p21 might inhibit cell cycle progression by two independent mechanisms, inhibition of cyclin/CDK complexes, and inhibition of PCNA function resulting in both G1 and G2 arrest.
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PMID:p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. 946 56

The aim of this study was to compare the immunophenotype of the human colon cancer cell line HT29 tumour deposits in the lung which occurred spontaneously after subcutaneous implantation with those which arose after intravenous injection into severe combined immunodeficient (scid) mice. Irrespective of the route of implantation the colon cancer cells were readily observed in the lungs of the scid mice. Similar patterns of immunoreactivity for the proliferative markers (MiB-1, PCNA), and for the tumour suppressor gene (p53) were detected in both groups, and for carcinoembryonic antigen, with only minor quantitative differences in levels of marker expression. Whereas the marker CD44 variant 6 gave very little reaction after either route, cytokeratin expression varied amongst the different cytokeratins (CK 7, 18 or 20), and with the route of implantation. CA125 and E-cadherin were weakly expressed after intravenous injection, but generally not after subcutaneous implantation. Vimentin was not demonstrated in any of the specimens examined. In general, the expression of proliferative markers, and of oncogenes, appears to be independent of the implantation route, whilst expression of cell adhesion molecules can be dependent on the route of implantation.
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PMID:Immunophenotype of human HT29 colon cancer cell metastases in the lungs of scid mice: spontaneous versus artificial metastases. 956 Oct 26

To clarify the biological changes in the development and progression of colorectal cancer, immunohistochemical examination was performed with a particular focus on the activity of apoptosis, the expression of apoptosis-related gene products and cell proliferation activity, assessed by the labeling index of proliferating cell nuclear antigen (PCNA). Seventy-six resected specimens of colorectal cancer were used to investigate the expression of apoptosis-related gene products, Bcl-2 protein and PCNA labeling index, as well as the apoptotic index using the TUNEL method. Seventy-five percent of 60 advanced cancer specimens was negative for Bcl-2 protein, and the proportion was higher than that in early cancer specimens. The apoptotic index (AI) in the advanced cancers was significantly higher than in the early stage of cancers. Meanwhile, the percentage of PCNA-positive cells for the advanced cancers was significantly higher than for early cancer. This study demonstrated a decrease in Bcl-2 protein expression, an increase in tumor cell apoptosis, and opposite an increase of cellular proliferation activity in the progression of colon cancer from early to the advanced stage of the disease.
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PMID:[Immunohistochemical study on the progression of colorectal cancer--with respect to apoptotic index, expression of apoptosis-related gene products, and labeling index of proliferating cell nuclear antigen (PCNA)]. 958 44

The expressions of p53 and proliferating cell nuclear antigen (PCNA) were studied immunohistochemically from paraffin sections of 7 cases (9 lesions) of radiation-induced colon cancer and 42 cases of spontaneous colon cancer. Age distribution of radiation-induced and spontaneous colon cancer were 68.1 years (range, 56 to 77 years) and 67.4 years (range, 31 to 85 years), respectively. Among the radiation-induced colon cancers, there were 3 lesions of mucinous carcinoma (33%), a much higher than found for spontaneous mucinous cancer. Immunohistochemically, p53 protein expression was detected in 7/9 (78%) of radiation-induced cancers and in 23/42 (55%) of spontaneous colon cancers. chi 2 analysis found no significant differences between radiation-induced and spontaneous colon cancers in age distribution or p53-positive staining for frequency, histopathology, or Dukes' classification. In radiation colitis around the cancers including aberrant crypts, spotted p53 staining and abnormal and scattered PCNA-positive staining were observed. In histologically normal cells, p53 staining was almost absent and PCNA-positive staining was regularly observed in the lower half of the crypt. In radiation colitis including aberrant glands, cellular proliferation increased and spotted p53 expression was observed. This study suggests that radiation colitis and aberrant glands might possess malignant potential and deeply associate with carcinogenesis of radiation-induced colon cancer.
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PMID:Immunohistochemical study of p53 overexpression in radiation-induced colon cancers. 961 28

p53 tumor suppression is deficient in the majority of human cancers. Efforts to understand this pathway have identified cyclin-dependent kinase (CDK) inhibitors and suggested a potential for their replacement in human cancer. In the present studies, expression of a C-terminal deletion mutant of the human p21(WAF1/CIP1) CDK inhibitor completely suppressed the growth of colon cancer cells, whereas full-length p21 only partially suppressed growth. We prepared a replication-deficient adenoviral recombinant which expresses the p21 C-terminal mutant (Ad-WAF1-341) and compared its tumor suppressive abilities with Ad-p53 and Ad-LacZ. Ad-WAF1-341- and Ad-p53-infected cancer cells, but not Ad-LacZ-infected cancer cells, expressed a nuclear protein recognized by anti-p21 antibody and were deficient in cell cycle progression. The exogenous p21 mutant interacted with CDK2 but not proliferating cell nuclear antigen following infection of p21-/- cancer cells. Ad-WAF1-341 was more potent than Ad-p53 in inhibiting DNA synthesis in human papillomavirus 16 E6-expressing cancer cells. Most importantly, the Ad-WAF1-341-infected E6-expressing cells died, whereas most of the Ad-p53-infected cells continued to proliferate. Endonucleolytic cleavage of DNA was observed in Ad-WAF1-341-infected cancer cells. These observations suggest that Ad-WAF1-341 should be evaluated in the treatment of human papillomavirus-associated neoplasia and other neoplasias resistant to p53.
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PMID:Suppression of cancer cell growth by adenovirus expressing p21(WAF1/CIP1) deficient in PCNA interaction. 981 91

The cyclin-dependent kinase (CDK) inhibitor p21(Cip1/Waf1) plays an essential role in the control of cell proliferation by modulating the activity of cyclin/CDK complexes in response to various intracellular or extracellular signals. Small variations in p21 expression levels may determine whether it acts as an inhibitor or an assembly factor for cyclin/CDK complexes. It is therefore critical to better characterize the mechanisms regulating p21 abundance. Here, we show, using a tetracycline-regulated system in p53-deficient DLD-1 human colon cancer cells, that p21 protein levels and stability are regulated by the proteasome-dependent degradation pathway and by association with its partners, CDKs and PCNA. A p21 mutant deficient for interaction with CDKs, p21CDK-, displayed an enhanced stability and greatly reduced sensitivity to proteasome-mediated proteolysis, indicating that association with cyclin/CDK complexes may trigger p21 degradation. In contrast, a p21 mutant impaired in the interaction with PCNA, p21PCNA-, exhibited a decreased stability, suggesting that association with PCNA protects p21 from proteasome-dependent degradation. Furthermore, the abundance of p21 itself, in addition to protein-protein interactions, may also modulate p21 stability since we found that high levels of p21 expression overcome proteasome-dependent regulation of p21 accumulation.
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PMID:Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. 982 54


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