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)

Herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) gene therapy can induce apoptosis in tumor cells that are normally resistant to this type of cell death, although the cellular mechanisms by which this occurs remain to be elucidated. Human colon tumor cell lines expressing HSV-TK were treated with GCV or four other inducers of apoptosis: butyrate, camptothecin (CPT), Taxol (paclitaxel), or 7-hydroxystaurosporine (UCN-01). Over a 2-4 day treatment period with GCV or the other four drugs, protein levels of the apoptosis agonist Bak increased 1.5- to 3-fold, whereas a corresponding decrease in the levels of the apoptosis antagonist, Bcl-X(L), was observed in butyrate-, CPT-, and 7-hydroxystaurosporine (UCN-01)-treated cells. GCV and paclitaxel treatments resulted in increased levels of Bcl-X(L). In two-drug combinations with GCV plus one of the four other drugs, increased tumor cell killing was found with GCV plus UCN-01 or with some GCV/butyrate combinations; the other two tested combinations were largely antagonistic. The GCV/UCN-01 and GCV/butyrate combinations resulted in increased Bak and decreased Bcl-X(L) protein levels, while the GCV/CPT and GCV/paclitaxel combinations resulted in increased levels of both proteins. The results highlight the potential for new combination therapies of HSV-TK/GCV and chemotherapeutic drugs that result in increased tumor cell apoptosis for future treatments of colon cancer.
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PMID:Two-drug combinations that increase apoptosis and modulate bak and bcl-X(L) expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase. 1081 74

Theaflavin (TF-1), theaflavin-3-monogallate and theaflavin-3'-monogallate mixture (TF-2), and theaflavin-3,3'-digallate (TF-3) are the major black tea polyphenols. Here we compared the effects of these polyphenols on cell growth, apoptosis, and gene expression in normal and cancerous cells. We showed that TF-2 (10-50 microM) inhibited the growth of SV40 transformed WI38 human cells (WI38VA) and Caco-2 colon cancer cells but had little effect on the growth of their normal counterparts. The IC50s of TF-2 for the growth inhibition of WI38 and WI38VA cells were, respectively, 300 and 3 microM. The other two black tea polyphenols, TF-1 and TF-3, did not exhibit such differential growth-inhibitory effect. TF-2, but not TF-1 or TF-3, induced apoptosis in transformed WI38VA cells but not in normal WI38 cells, suggesting that apoptosis was responsible, at least in part, for the differential growth-inhibitory effect of TF-2. Cox-2 has been implicated in intestinal carcinogenesis. Among the tea polyphenols tested, TF-2 and, to a lesser degree, (-)-epigallocatechin gallate inhibited cyclooxygenase (Cox)-2 gene expression. TF-2 at 50 microM completely blocked the serum-induced Cox-2 gene expression at both mRNA and protein level. Other genes, including c-fos, c-myc, thymidine kinase, proliferating cell nuclear antigen, BRCA1, BRCA2, and Cox-1, were not significantly affected by TF-2. These findings suggest that TF-2 may be responsible, at least in part, for the chemopreventive activity in black tea extracts.
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PMID:Differential effects of theaflavin monogallates on cell growth, apoptosis, and Cox-2 gene expression in cancerous versus normal cells. 1110 14

We have isolated 462 bp of sequence termed ovarian-specific promoter 1 (OSP-1) that is part of a retrovirus-like element specifically expressed in the rat ovary. We have evaluated the ability of OSP-1 to activate gene expression in normal and neoplastic cell lines derived from the ovaries of rats and women. We have found that there was marked specificity in the ability of OSP-1 to drive reporter gene expression in an ovarian epithelial cell lineage manner. The expression of herpes simplex virus thymidine kinase (HSV-TK) under OSP-1 control was sufficiently ovarian cancer cell line specific to render ganciclovir approximately 50-fold more toxic in the A2780 human ovarian cancer cell line compared with clones of the HCT-116 and HT-29 colon cancer cell lines. Furthermore, ganciclovir had marked antitumor efficacy in vivo in severe combined immunodeficient mice bearing A2780OSP-1-HSV-TK as a s.c. xenograft. We suggest that these data support the use of OSP-1 as a tool to provide specificity to the gene therapy of ovarian cancer and to drive ovarian-specific oncogene expression for the creation of transgenic mouse models of ovarian cancer.
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PMID:Ovarian epithelial cell lineage-specific gene expression using the promoter of a retrovirus-like element. 1124 22

A method is described for the preparation of ganciclovir triphosphate (GCV-TP) using murine colon cancer cells (MC38) transduced with the herpes simplex virus-thymidine kinase (MC38/HSV-tk). Murine cells transduced with viral-tk contain required viral and host enzymes needed for complete cellular synthesis of this potent antiviral metabolite. Dose response studies showed optimal intracellular levels of GCV-TP occurred after exposure of MC38/HSV-tk cells to 300 microM ganciclovir for 24 h producing 7.5 nmol GCV-TP/10(6) cells. This reflects cellular accumulation of GCV-TP to levels 25-fold greater than the medium concentration of parent drug. A simple isolation scheme included methanolic extraction and anion-exchange chromatography to recover the target triphosphate. Mass spectral analysis and selective enzyme degradation provided structural confirmation of the purified product. Biological activity of the purified GCV-TP was demonstrated by competitive inhibition experiments using human DNA polymerase alpha and HSV DNA polymerase that showed substantially greater sensitivity for the viral polymerase in agreement with previous reports. The GCV-TP obtained was further used to enzymatically prepare GCV mono- and diphosphate in high yield. This method provides an easily scalable means of preparing milligram amounts of the triphosphates of pharmacologically active acyclic nucleosides like ganciclovir.
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PMID:Biosynthetic ganciclovir triphosphate: its isolation and characterization from ganciclovir-treated herpes simplex thymidine kinase-transduced murine cells. 1171 5

Human cells exposed to antifolates show a rapid increase in the levels of the enzyme dihydrofolate reductase (DHFR). We hypothesized that this adaptive response mechanism can be used to elevate cellular levels of proteins fused to DHFR. In this study, mouse cells transfected to express a green fluorescent protein-DHFR fusion protein and subsequently exposed to the antifolate trimetrexate (TMTX) showed a specific and time-dependent increase in cellular levels of the fusion protein. Next, human HCT-8 and HCT-116 colon cancer cells retrovirally transduced to express a DHFR-herpes simplex virus 1 thymidine kinase (HSV1 TK) fusion protein and treated with the DHFR inhibitor TMTX exhibited increased levels of the DHFR-HSV1 TK fusion protein and an increase in ganciclovir sensitivity by 250-fold. The level of fusion protein in antifolate-treated human tumor cells was increased in response to a 24-h exposure of methotrexate, trimetrexate, as well as dihydrofolate. This effect depended on the antifolate concentration and was independent of the fusion-protein mRNA levels, consistent with this increase occurring at a translational level. In a xenograft model, nude rats bearing DHFR-HSV1 TK-transduced HCT-8 tumors and treated with TMTX showed, after 24 h, a 2- to 4-fold increase of fusion-protein levels in tumor tissue from treated animals compared with controls, as determined by Western blotting. The fusion-protein increase was imaged with positron-emission tomography, where a substantially enhanced signal of the transduced tumor was detected in animals after antifolate administration. Drug-mediated elevation of cellular DHFR-fused proteins is a very useful method to modulate gene expression in vivo for imaging as well as therapeutic purposes.
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PMID:Cells exposed to antifolates show increased cellular levels of proteins fused to dihydrofolate reductase: a method to modulate gene expression. 1189 21

Using a cultured human colon cancer cell line (Col 2), a structurally diverse group of chemopreventive agents was evaluated for their potential to induce apoptosis. As a result, 1,4-phenylenebis(methylene)selenocyanate (p-xylylselenocyanate; p-XSC) was found to be active in this process. p-XSC, a synthetic organoselenium compound, has been shown to inhibit tobacco-specific 4-(methylnitrosoamino)-(3-pyridyl)-1-butanone-induced tumorigenesis in A/J mouse lung, rat tongue carcinogenesis and colon cancer. Known chemopreventive mechanisms include inhibition of DNA methylation, inhibition of thymidine kinase and reduction of oxidative DNA damage. In order to assess apoptosis induction, the cells were exposed to various concentrations of test substances for 48 hours. Enrichment of mono- and oligonucleosomes in the cytoplasm was monitored as an indication of apoptosis using an ELISA kit. As a result, p-XSC caused dose-dependent enrichment of fragmented nucleosomes. In further studies, p-XSC was found to induce DNA laddering in a dose-dependent manner, while apoptotic cells accumulated in a time-dependent manner up to 96 hours. The apoptotic peaks after treatment of p-XSC were also found as confirmed by the flow cytometric analysis of cell cycle distribution. In an additional study, however, p-XSC-mediated apoptosis was not shown to be dependent on p53 expression. Taken together, these results suggest that induction of apoptosis is one possible mechanism for the cancer chemopreventive activity mediated by p-XSC.
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PMID:Induction of apoptosis by 1,4-phenylenebis(methylene)selenocyanate in cultured human colon cancer cells. 1201 40

The adenomatous polyposis coli (APC) or beta-catenin genes are frequently mutated in colorectal cancers, leading to activation of downstream genes with beta-catenin/T-cell factor (Tcf)-responsive promoters. We have developed a gene therapy approach selectively targeting colorectal cancer cells in which beta-catenin/Tcf4 pathway is activated by using a recombinant adenovirus AdTOP-CMV-TK, which carries a herpes simplex virus thymidine kinase gene (HSV TK) under the control of a beta-catenin/Tcf-response promoter linking to a minimum CMV promoter. AdTOP-CMV-TK and ganciclovir (GCV) treatment significantly suppressed the growth of human DLD-1 colon cancer cells in nude mice. Furthermore, no significant tumor suppression effect was observed in human hepatoma cell line SK-HEP-1, in which the beta-catenin/Tcf pathway is not activated, as a control experiment. In summary, we demonstrated the selective targeting of colorectal cancers with activated beta-catenin by AdTOP-CMV-TK and GCV treatment in animal models, as well as its therapeutic potential for colon cancer metastasized to liver.
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PMID:The suppression of colon cancer cell growth in nude mice by targeting beta-catenin/TCF pathway. 1244 97

N-Methanocarbathymidine [(N)-MCT], a thymidine analogue incorporating a pseudosugar with a fixed Northern conformation, exhibits antiherpetic activity against both herpes simplex virus (HSV) HSV-1 and HSV-2, with a potency greater than that of the reference standard, ganciclovir (GCV). In the present study, we have assessed the cytotoxic activity in vitro of (N)-MCT in wild-type murine colon cancer cells (MC38) and in cells expressing the herpes simplex thymidine kinase gene (MC38/HSV-tk), and the antitumor activity of (N)-MCT in vivo against HSV-tk transduced and nontransduced MC38 murine tumors. In vitro, when assessed over a 48-h period, the growth-inhibitory activity (IC50) of (N)-MCT toward MC38/HSV-tk cells was 2.9 microM. In parallel studies, the cytostatic activity of the reference compound GCV in these tumor lines was 3.0 microM. In studies in vivo, both (N)-MCT and GCV (100 mg/kg) given twice daily for 7 days completely inhibited the growth of HSV-tk-transduced MC38 tumors while exhibiting no effect on nontransduced MC38 tumors in mice. In nontransduced cells both in vitro and in vivo, only low levels of (N)-MCT and its monophosphate could be detected after administration of the parent drug, whereas in HSV-tk-transduced cells (N)-MCT was phosphorylated to its respective mono-, di-, and triphosphates. Furthermore, data showed that (N)-MCT incorporated in high levels into cellular DNA whereas trace levels were measured into RNA. These observations indicate that (N)-MCT may be a useful candidate prodrug for HSV-tk suicide gene therapy of cancer.
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PMID:Antitumor activity and metabolic activation of N-methanocarbathymidine, a novel thymidine analogue with a pseudosugar rigidly fixed in the northern conformation, in murine colon cancer cells expressing herpes simplex thymidine kinase. 1247 18

Anticancer suicide gene therapy using herpes simplex virus-thymidine kinase (HSV-tk) and ganciclovir (GCV) features the unique advantage of being able to elicit brisk host immune response against tumors and the host response reportedly can be potentiated with the co-expression of other appropriate immune- or apoptosis-related genes. We introduced a novel antiapoptotic gene, bfl-1, to test its applicability in the HSV-tk/GCV system. CT-26 murine colon cancer cells transfected with HSV-tk, alone or in combination with bcl-xL or bfl-1, were either grown in vitro or injected into syngeneic mice, followed by GCV administration. The co-expression of bfl-1 was associated with the upregulation of CD95 and CD40 ligand (CD40L) in vitro and with pronounced intratumoral T-lymphocyte infiltration in vivo. These results add to the previous findings that antiapoptotic genes can be used as an adjunctive component in the HSV-tk/GCV system to enhance host immune response against tumors.
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PMID:Co-expression of bfl-1 enhances host response in the herpes simplex virus-thymidine kinase/ganciclovir gene therapy system. 1267 Apr 75

5-Fluorouracil (5-FU) is the most routinely administered drug in the treatment of colon cancer. The main mechanism of the drug is not completely understood and its method of administration has been strongly disputed. A 24-hour infusion of 5-FU has clinically yielded better response rates and lower toxicities in comparison to bolus administration, but an exploration into possible mechanisms needs to be performed. Experiments were conducted with two 5-FU resistant cell lines where cytotoxicity, thymidylate synthase (T.S.) activity, thymidine kinase (T.K.) activity, DNA and RNA incorporation, and T.S. expression were contrasted between a 10 microM/24 hour administration of 5-FU (simulating continuous exposure) and a 100 microM/1 hour schedule (simulating bolus administration). After 6 days from the initial exposure, the 10 microM/24 hour schedule (schedule A) inhibited more cell growth than the 100 microM/1 hour regimen (schedule B) by more than 38% and 17% in the two cell lines. After the 6-day observation, schedule A inhibited twice as much T.S. activity as schedule B. Incorporation of [14C]-5-FU into DNA and total RNA was higher in cells exposed to schedule A in comparison to schedule B over the 6 days. T.S. expression and T.K. activity patterns were variable over time. Thus, the exposure of 10 microM/24 hour 5-FU results in superior cytotoxicity when compared to a 100 microM/1 hour regimen and its effectiveness may be explained mechanistically by T.S. activity and DNA and RNA incorporation.
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PMID:Cytotoxic effects and mechanisms of an alteration in the dose and duration of 5-fluorouracil. 1268 Feb 47


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