Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Several new aspects have evolved during the past years concerning factors that influence survival in surgically and medically treated colon cancer patients that are relevant to the treating team for the treatment strategy and patient's choice. The 5-year-survival rates dependent on UICC stages/substages (I: 68%-100%, II: 58%-90%, III: 33%-76%, IV: <5%-9%) show remarkable variations between published reports, surgical hospital units, individual surgeons, and continents (USA vs Europe). Those variations may be due to surgical techniques, training status, hospital and individual case volume, and, also, referral patterns and statistical evaluation methods. Survival times and cure rates are significantly improved by adjuvant chemotherapy in UICC III and in substages of UICC II (e.g. UICC II B) by 5%-12%, when compared with surgical controls. In three recently published trials standard adjuvant chemotherapy was further improved by increased survival rates, e.g. from 59% to 71% in stage III and IIB patients. Molecular and genetic factors, such as thymidylate synthase (TS), microsatellite instability (MSI) or loss of chromosome 18q/"DCC" might have an independent impact on prognosis in the spontaneous course, and TS could help to better select patients for adjuvant chemotherapy.
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PMID:Colon cancer: survival after curative surgery. 1545 34

In a panel of 18 colon cancer cell lines we found that the thymidylate synthase (TS) genotype was related to TS enzyme activity, but not to TS protein and mRNA levels. In addition, no relation with drug sensitivity was observed. TS genotyping of different tissues from 78 colorectal cancer patients revealed a high level of homology in polymorphic status between normal and malignant tissues and the heterozygous genotype to be the most frequent.
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PMID:Polymorphism of the thymidylate synthase gene and thymidylate synthase levels in colon cancer cell lines and different tissues of colorectal cancer patients. 1557 Dec 63

The action of 5-Fluorouracil (5-FU) is mediated by inhibition of thymidylate synthase (TS), which is regulated by cell cycle proteins controlled by protein phosphorylation. We studied the effects of staurosporine and its analogue UCN-01, inhibitors of protein kinase C (PKC) on 5-FU cytotoxicity in Lovo colon cancer cells. Each drug contributes equally to the cell cycle effects of the 5-FU combinations. In sequential drug administration, the cell cycle distribution was determined by the first drug. Simultaneous 5-FU combinations induced additive effects in induction of apoptosis. When staurosporine was used as the second drug, induction of apoptosis was 2-fold higher than the sum of both drugs alone. Based on induction of apoptosis 5-FU addition prior to the PKC inhibitors seemed preferable.
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PMID:Combinations of 5-fluorouracil with UCN-01 or staurosporine. 1557 Dec 86

Previous studies from our laboratory indicated that expression of the MLH1 DNA mismatch repair (MMR) gene was necessary to restore cytotoxicity and an efficient G(2) arrest in HCT116 human colon cancer cells, as well as Mlh1(-/-) murine embryonic fibroblasts, after treatment with 5-fluoro-2'-deoxyuridine (FdUrd). Here, we show that an identical phenomenon occurred when expression of MSH2, the other major MMR gene, was restored in HEC59 human endometrial carcinoma cells or was present in adenovirus E1A-immortalized Msh2(+/+) (compared with isogenic Msh2(-/-)) murine embryonic stem cells. Because MMR status had little effect on cellular responses (i.e. G(2) arrest and lethality) to the thymidylate synthase inhibitor, Tomudex, and a greater level of [(3)H]FdUrd incorporation into DNA was found in MMR-deficient cells, we concluded that the differential FdUrd cytotoxicity between MMR-competent and MMR-deficient cells was mediated at the level of DNA incorporation. Analyses of ATPase activation suggested that the hMSH2-hMSH6 heterodimer only recognized FdUrd moieties (as the base 5-fluorouracil (FU) in DNA) when mispaired with guanine, but not paired with adenine. Furthermore, analyses of incorporated FdUrd using methyl-CpG-binding domain 4 glycosylase indicated that there was more misincorporated FU:Gua in the DNA of MMR-deficient HCT116 cells. Our data provide the first demonstration that MMR specifically detects FU:Gua (in the first round of DNA replication), signaling a sustained G(2) arrest and lethality.
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PMID:DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. 1561 Oct 52

Trifluorothymidine (TFT) is a fluorinated thymidine analog that after conversion to its monophosphate derivative can inhibit thymidylate synthase (TS) and be incorporated into DNA. TFT is a good substrate for thymidine phosphorylase (TP), and the combination of TFT and a TP inhibitor (TPI), called TAS-102, has been developed to enhance the bioavailability of TFT in vivo, and is currently being studied in a phase I study. We aimed to determine the limiting factor(s) in the cytotoxicity of TFT with or without TPI to cancer cells. Colon cancer and lung cancer cell lines with either an overexpression or deficiency of one of the enzymes involved in TFT metabolism were used to study the effect of TPI on TFT sensitivity and the role of TS inhibition. The synthesis of radioactive TFT metabolites was studied using thin-layer chromatography together with the incorporation of TFT into DNA. We found that despite a high rate of TFT phosphorolysis, cells with high TP expression are not more resistant to TFT, while TPI did not increase TFT sensitivity. High TS-expressing cells were shown to be cross-resistant to a 72-h exposure to TFT compared to 5-fluorouracil (5-FU), although this was more pronounced at a 4-h exposure (3.4-fold or more for TFT and 1.4-fold or more for 5-FU). Despite a moderate inhibition of TS activity in cells expressing high TS, these cells were more sensitive to TFT than 5-FU (3.8-fold or more). Only in Colo320TP1 cells expressing high TP, inhibition of TFT phosphorolysis by TPI increased formation of active TFT metabolites 1.8-fold, although this was not related to an increase in TFT incorporation into DNA. These studies show that uptake of TFT and subsequent phosphorylation of TFT by cancer cells is very rapid. Despite a high rate of degradation, the activation pathways are still saturated and sufficient to inhibit TS and enable incorporation into DNA, although the contribution of each effect is exposure time dependent.
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PMID:Determinants of trifluorothymidine sensitivity and metabolism in colon and lung cancer cells. 1571 Nov 80

The human thymidylate synthase (TS) gene promoter is polymorphic, having either double or triple tandem repeats of a 28-base-pair (bp) sequence. Here, we determined the significance of this polymorphism in predicting the clinical outcomes for patients with colon cancer. We reviewed 121 consecutive patients with stage II or III colon cancer who underwent a curative resection. After DNA extraction from paraffin-embedded tissues, the promoter region of the TS gene was amplified by polymerase chain reaction. In addition to the conventional prognostic factors, patient survivals were compared with regard to the pattern of TS polymorphism. Sixty-eight subjects were homozygotes for the triple-repeat variant (250 bp, group A), and 53 subjects (group B) were either homozygotes for the double-repeat variant (220 bp) or heterozygotes (220 and 250 bp). We found a significant difference between groups A and B in survival (53% versus 80%, P=0.0481). The difference was particularly significant in the patients with stage III disease (41% versus 77%, P=0.0414). Tumor stage and the TS polymorphism were identified as significant prognostic factors by multivariate analysis. We found the TS polymorphism to be a significant and independent prognostic factor for colon cancer.
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PMID:Thymidylate synthase gene polymorphism as a prognostic factor for colon cancer. 1574 93

The rTS gene was discovered because it codes for a complementary (antisense) RNA to the messenger RNA for thymidylate synthase (TS). It was later shown that rTS also encodes 2 proteins, rTSa and rTSb. Recently, it has become apparent that rTSb overexpression can cause the downregulation of TS protein in a colon cancer cell line through the production of > or = 1 previously unknown signaling molecules. This observation signified the presence of a previously unidentified signaling pathway. The existence of a signaling pathway that can regulate TS protein levels and the widespread expression of the rTSb protein suggests that a new target for drug development may be on the horizon. This review describes the relationship between the rTS and TS genes and the known and potential effects of rTS RNAs and rTS proteins. We also present the structure of an identified TS downregulatory compound that may serve as a lead compound for development.
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PMID:The rTS signaling pathway as a target for drug development. 1592 1

Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01(+) PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.
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PMID:Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. 1600 79

Folate metabolism supports the synthesis of nucleotides as well as the transfer of methyl groups. Polymorphisms in folate-metabolizing enzymes have been shown to affect risk of colorectal neoplasia and other malignancies. Using data from a population-based incident case-control study (1,600 cases and 1,962 controls), we investigated associations between genetic variants in the reduced folate carrier (RFC), thymidylate synthase (TS), methionine synthase (MTR), and 5,10-methylenetetrahydrofolate reductase (MTHFR) and colon cancer risk. The TS enhancer region (TSER) variant was associated with a reduced risk among men [2rpt/2rpt versus 3rpt/3rpt wild-type; odds ratio (OR), 0.7; 95% confidence interval, 0.6-0.98] but not women. When combined genotypes for both TS polymorphisms (TSER and 3'-untranslated region 1494delTTAAAG) were evaluated, ORs for variant genotypes were generally below 1.0, with statistically significantly reduced risks among women. Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk. Because folate metabolism is characterized by interrelated reactions, we evaluated gene-gene interactions. Genotypes resulting in reduced MTHFR activity in conjunction with low TS expression were associated with a reduced risk of colon cancer. When dietary intakes were taken into account, individuals with at least one variant TSER allele (3rpt/2rpt or 2rpt/2rpt) were at reduced risk in the presence of a low folate intake. This study supports findings from adenoma studies indicating that purine synthesis may be a relevant biological mechanism linking folate metabolism to colon cancer risk. A pathway-based approach to data analysis is needed to help discern the independent and combined effects of dietary intakes and genetic variability in folate metabolism.
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PMID:Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. 1628 71

TNM staging in colon cancer has several limitations. Prognostic molecular markers are now being developed to address these limitations. The aim of this study was to identify a combination of genes and markers whose expression is predictive of nodal status and outcome in colon cancer. The expression of 12 genetic markers were examined in 66 node-positive and 65 node-negative T3 colon cancers. Gene expression was quantified using real-time polymerase chain reaction. Microsatellite instability status was available through the registry. Association with lymph node status was examined using univariate and multivariate logistic regression. Thymidylate synthase expression was statistically significantly associated with lymph node status (odds ratio 0.36; 95% confidence interval: 0.16-0.81). Microsatellite instability and the other genes were not associated with nodal status. Multiple logistic regression did not identify a significant multivariate predictive model. Decreased expression of thymidylate synthase is associated with a higher risk of lymph node metastasis in patients with T3 colon cancers. Microsatellite instability and the expression of other genes are not predictive of nodal status in this population. Thymidylate synthase gene expression may help identify patients at greater risk for progression of disease.
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PMID:Molecular predictors of lymph node metastasis in colon cancer: increased risk with decreased thymidylate synthase expression. 1633 76


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