UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have established a syngeneic mouse tumor model to test the efficacy of the drug-sensitizing enzyme thymidine kinase from herpes simplex virus (HSVtk) in vivo. Activated mutant Ki-ras(G12V) is frequently found in human colon cancer and adenocarcinomas of the lung and pancreas. We have transformed BALB/c-3T3 cells by stable transfection of a plasmid directing the expression of the mutant Ki-ras cDNA. To transfer the HSVtk gene into tumor cells we used a Moloney murine leukemia virus (MoMLV)-based retroviral vector that carries the HSVtk gene. In this study we show that the activity of HSV-TK inhibits tumor growth in immune-compromised nude mice following GCV treatment for up to 50 days but is not sufficient to completely eliminate all tumor cells in these mice as evidenced by the occurrence of tumors between 40 and 50 days after tumor cell implantation. By contrast, immune-competent BALB/c mice develop a long-lasting antitumor immunity in response to HSVtk transduction and GCV treatment, indicating that the immune system is important for the long-term tumor suppression in vivo. In the presence of GCV co-culturing of tumor cells with HSVtk transfected cells leads to the efficient killing of HSVtk negative tumor cells. While this retroviral vector independent HSV-TK/GCV-mediated bystander effect is not sufficient to inhibit tumor formation in athymic animals it is very efficient in immune-competent syngeneic mice. Taken together the data indicate that the antitumor activity of HSV-TK is enhanced by an intact immune system.
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PMID:Anti-tumor immunity is involved in the thymidine kinase-mediated killing of tumors induced by activated Ki-ras(G12V). 881 52

Hepatic metastasis of colon cancer is an important prognostic factor for survival. In this study, we examined the effect of gene therapy using the herpes simplex virus-thymidine kinase (HS-tk) gene with short-course ganciclovir (GCV) treatment for multiple hepatic metastases of murine colon cancer. Colon26 cells transfected with the HS-tk gene were found to be sensitive to GCV in a concentration-dependent way. On the other hand, induction of the HS-tk gene in the cells had no influence on cell growth in vitro. However, multiple hepatic metastases of Colon26 cells transfected with HS-tk gene were significantly suppressed by the GCV treatment. These results thus suggest that HS-tk gene therapy is useful for the treatment of hepatic metastasis in colon cancer.
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PMID:Effect of gene therapy with the herpes simplex virus-thymidine kinase gene on hepatic metastasis in murine colon cancer. 903 98

Herpes simplex virus-thymidine kinase (HS-tk) gene therapy with ganciclovir (GCV) treatment has been reported to inhibit the tumor growth, which is applied to the gene therapy targeted to the malignant brain tumor. To suppress the tumor growth completely, the authors designed the HS-tk gene therapy in combination with granulocyte macrophage-colony stimulating factor (GMCSF) gene using the hepatic metastatic model of murine colon cancer. The transduction of the HS-tk gene in combination with the GMCSF gene, followed by GCV, showed a complete inhibition of hepatic metastases of murine colon cancer, which was significantly superior to that of HS-tk gene alone. The growth of cancer cells transduced with both HS-tk and GMCSF genes was inhibited in vitro, and long-lasting antitumor immunity after hepatic metastasis of cancer cells transduced with both HS-tk and GMCSF genes was acquired. It is suggested that HS-tk gene therapy in combination with the GMCSF gene is effective for the complete inhibition of hepatic metastasis of murine colon cancer.
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PMID:Inhibition of establishment of hepatic metastasis in mice by combination gene therapy using both herpes simplex virus-thymidine kinase and granulocyte macrophage-colony stimulating factor genes in murine colon cancer. 940 3

A bystander effect is described when nontransduced or genetically unmodified cells are killed during death of genetically modified tumor cells transduced with a suicide gene. The "bystander effect" greatly enhances the efficacy of the herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy approach for cancer. The mechanism of the bystander effect is controversial. In this study, we examined the role of intercellular gap junction communication (GJIC) for the bystander effect in human gastrointestinal tumor cells. Our results show that the extent of the bystander effect varied amongst the tumor cell lines; pancreatic cancer cells BXPC-3 exhibited excellent bystander effects in vitro and in vivo studies whereas other gastrointestinal tumor cell lines such as pancreatic cancer cells MIAPACA-2, and colon cancer cells HT-29 showed poor bystander effects. Bystander effects were only found in the presence of cell-to-cell contact. The extent of the bystander effect was independent of the level of HSV-TK activity in the transduced tumor cells and was correlated with GJIC as demonstrated by an in vitro dye-transfer assay. Expression of the mRNA levels of gap junction protein connexin 43 was 8- to 26-fold or greater and connexin 26 gene expression was 2- to 229-fold greater in BXPC-3 cells compared to HT-29, MIAPACA-2, and PANC3 cells. Our results suggest that intercellular communication is essential for the bystander effect. The correlation between GJIC and the extent of the bystander effect suggest a role for GJIC in mediating the bystander effect. Analysis of tumors for GJIC or expression of gap junction proteins may identify the subset of patients suitable for gene therapy with the HSV-TK/GCV approach.
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PMID:Intercellular communication mediates the bystander effect during herpes simplex thymidine kinase/ganciclovir-based gene therapy of human gastrointestinal tumor cells. 955 19

A 5-fluorouracil (5-FU)-resistant subline, DLD-1/5-FU, was established by repeated 5-d exposures of human colon cancer DLD-1 cells to 5-FU. DLD-1/5-FU cells were 41- and more than 75-fold resistant to 96-h and 1-h exposures to 5-FU, respectively. When exposed to 5-FU, DLD-1/5-FU cells exhibited marked resistance to in situ thymidylate synthase (TS) inhibition by 5-FU as compared to DLD-1 cells, and incorporation of 5-FU into cellular RNA in DLD-1/5-FU cells decreased to 25% of that in DLD-1 cells. As causes of resistance to DNA and RNA-directed actions of 5-FU, remarkable reduction of intracellular levels of both 5-fluorouridine 5'-triphosphate (FUTP) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) in DLD-1/5-FU cells was confirmed. It was found that activities of uridine kinase, orotate phosphoribosyltransferase and thymidine kinase of DLD-1/5-FU cells were significantly lower than those of the parent cells. Intracellular levels of TS were similar between the two cell lines. These results indicated that the mechanism of resistance to 5-FU in DLD-1/5-FU cells involves reduced enzymatic activation of 5-FU.
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PMID:Mechanisms for 5-fluorouracil resistance in human colon cancer DLD-1 cells. 965 39

We examined the effects of two biochemical modulators, 5'-aminothymidine (5'-AdThd) and leucovorin (LV), on the in vitro incorporation of iododeoxyuridine (IdUrd) into DNA and its subsequent radiosensitization in two human colon cancer cell lines, HT 29 and HCT 116. 5'-AdThd is a modulator of thymidine kinase activity while LV is an essential cofactor for thymidylate synthase activity. In HT 29 cells, the combination of 5'-AdThd (10 &mgr;m) and IdUrd (1-10 &mgr;m) resulted in a significant increase in IdUrd triphosphate pools and in IdUrd-DNA incorporation. Coadministration of LV (10 &mgr;m) with IdUrd (1-10 &mgr;m) resulted in a significant decrease in thymidine triphosphate pools and a comparable increase in IdUrd-DNA incorporation as the combination of 5'-AdThd + IdUrd. The increase in radiosensitization by clonogenic survival with either combination was a direct linear function with the percentage of IdUrd-DNA incorporation. For HCT 116 cells, however, the results were different. While 5'-AdThd + IdUrd resulted in an increase in IdUrd triphosphate and percentage of IdUrd-DNA incorporation, significant cytotoxicity was noted. The radiosensitivity of HCT 116 cells treated with 5'-AdThd + IdUrd was not a linear function above 25% IdUrd-DNA incorporation. Also, no increase in IdUrd-DNA incorporation or radiosensitization was observed with LV + IdUrd although LV enhanced the decrease in thymidine triphosphate pools by IdUrd treatment. These results indicate heterogeneity in the response of different colon cancer cells to these modulators which may be related to the regulation of deoxynucleotide metabolic enzymes.
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PMID:Effects of 5'-aminothymidine and leucovorin on radiosensitization by iododeoxyuridine in human colon cancer cells 981 98

This in vivo study examines the ability of 5'-amino-5'-deoxythymidine (5'-AdThd) to modulate 5-iododeoxyuridine (IdUrd) cellular metabolism in two human colon cancer xenografts (HT 29 and HCT-116), two actively proliferating normal mouse tissues (bone marrow and intestine), and a quiescent normal mouse tissue (liver). 5'-AdThd is a thymidine analogue that at low concentrations (<30 micrometer) can increase thymidine kinase activity, which is the rate-limiting enzyme for activation of IdUrd. We reported recently that the in vitro incubation of HT 29 and HCT-116 cells in 5'-AdThd + IdUrd resulted in an enhancement of 5-iodo-2'-dUTP pools, IdUrd DNA incorporation, and subsequent radiosensitization compared with incubation with IdUrd alone (Clin. Cancer Res., 1: 407-416, 1995). These in vitro effects were more significant in the radioresistant cell line HT 29. Using a 6-day continuous infusion of IdUrd (50 or 100 mg/kg/day) and/or 5'-AdThd (200 mg/kg/day), no increase in systemic toxicity (percentage of body weight loss) was observed in athymic nude mice with 5'-AdThd alone or when combined with IdUrd. There was significant dose-dependent, systemic toxicity with IdUrd, which was reversible within 3 days of completing the lower-dose IdUrd infusion. However, a comparison of plasma levels during the 6-day continuous infusion of IdUrd +/- 5'-AdThd showed a significant interaction of IdUrd and 5'-AdThd, resulting in higher plasma levels by day 6 of both compounds and the principal metabolites, iodouracil and deoxyuridine, which is consistent with nonlinear saturating effects on dihydrouracil dehydrogenase. Coadministration of IdUrd and 5'-AdThd resulted in an increase in the percentage of IdUrd DNA incorporation in the two proliferating normal tissues, which was significant only with the lower IdUrd dose. No effect on IdUrd DNA incorporation was found in normal liver at either IdUrd dose +/- 5'-AdThd. Similar to our in vitro data, the continuous infusion of IdUrd and 5'-AdThd showed a significant effect by increasing the percentage of IdUrd DNA incorporation in HT-29 xenografts at both IdUrd doses, whereas coadministration of 5'-AdThd had no such effect in HCT-116 xenografts.
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PMID:In vivo modulation of iododeoxyuridine metabolism and incorporation into cellular DNA by 5'-amino-5'-deoxythymidine in normal mouse tissues and two human colon cancer xenografts. 981 59

Sodium butyrate causes alteration of colon cancer cell morphology and biology towards that of a more differentiated phenotype. The retinoblastoma gene encodes a nuclear phosphoprotein (pRb) present in a wide range of human cancer cell lines including colon cancer cell lines. pRB is synthesized throughout the cell cycle and phosphorylated in a phase specific manner: the predominant proteins in G0/G1 are the unphosphorylated species (110 kD) whereas phosphorylated pRb (112-114 kD) are in S and G2. 110 kD pRb binds transcription factors and prevents transcription of responsive genes such as the gene for thymidine kinase, which are expressed in late G1. The precise mechanisms controlling cell arrest are unknown, but recent data suggest that cyclin-dependent kinase inhibitors such as p16 may play a role. The aim of the present study was to assess the effect of sodium butyrate on cell cycle staging, thymidine kinase activity, phosphorylation of the pRb protein and expression of p16. We show that sodium butyrate treatment induces differentiation of LS174T colon cancer cells, inhibits thymidine kinase activity concomitantly with induction of pRb dephosphorylation, p16 transcription and cell cycle arrest at G0/G1. Initial dephosphorylation was observed 24 h after treatment of LS174T cells with sodium butyrate, whereas complete shift to the dephosphorylated form was observed 3 days after treatment. Induction of pRb dephosphorylation by sodium butyrate preceded inhibition of growth and the specific cell cycle arrest. RNase protection assay with a p16 specific riboprobe showed undetectable levels in proliferating cells to several fold increase in differentiated colonocytes. In conclusion, the results provide evidence for a specific cellular mechanism of butyrate induced growth arrest and differentiation of a colon cancer cell line.
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PMID:Sodium butyrate induces retinoblastoma protein dephosphorylation, p16 expression and growth arrest of colon cancer cells. 982 7

Gene therapy with retroviral mediated gene transfer of the herpes simplex thymidine kinase (HS-tk) gene into a tumor mass confers sensitivity of the tumor cells to ganciclovir (GCV). Tumor-specific immunologic responses may develop following treatment of the primary tumor with retroviral HS-tk and GCV. In the present study we assessed whether GCV treatment of HS-tk transduced colon cancer (TK+) implanted in the peritoneal cavity induced a systemic antitumor response that would inhibit growth of a second wild-type (TK-) tumor implanted in the liver. DHDK12 rat colon cancer cells were transduced in vitro with the retroviral HS-tk vector and established as a permanent cell line (TK+ cells). TK+ or TK- DHDK12 cells (6x10(6) cells) were injected intraperitoneally on day 0 into BD-IX rats. On day 10, TK- cells (3x10(6) cells) were injected into the liver in all the groups. The animals were then treated with GCV (150 mg/kg) for 13 days. TK+ peritoneal tumors underwent significant regression during therapy with GCV (0.05+/-0.004 g; n=7) compared to wild-type (TK-) tumors (2.2+/-0.7g; n=6) (P<0.05). The volume of TK- tumors in the liver was significantly lower in GCV-treated rats with TK+ peritoneal tumors (12.5+/-8.3 mm3) compared to rats with TK- peritoneal tumors (96.7+/-18.1 mm3) (P<0.05). Histology of the liver tumors in the TK+ groups showed a dense monocytic infiltrate with fibrosis and only occasional viable tumor cells. Gene therapy with retroviral HS-tk vectors may provide a novel approach to treatment of gastrointestinal cancer by both direct cytotoxicity and an indirect mechanism that may include enhanced immuno logic responses against disseminated disease.
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PMID:Development of systemic immunologic responses against hepatic metastases during gene therapy for peritoneal carcinomatosis with retroviral HS-tk and ganciclovir. 983 88

A major obstacle to the successful application of suicide gene therapy strategies that rely on in situ transduction of tumor cells is the poor distribution of the vector throughout the tumor mass. To address this problem, we evaluated the use of Ad.TK(RC), an E1b Mr 55,000 deleted replicating adenoviral vector engineered to express the herpes simplex virus type 1 thymidine kinase gene (HSV-tk) in combination with ganciclovir (GCV) as a treatment for human colon cancer xenografts in nude mice. We compared the efficacy of this system with that of a standard replication-deficient adenovirus expressing HSV-tk (Ad.TK) in mice bearing LS180 tumors. In this system, Ad.TK(RC) alone was as effective as a traditional Ad.TK vector in combination with GCV. The addition of GCV significantly enhanced the antitumor effect of Ad.TK(RC). Furthermore, we demonstrated that the survival of HT-29 human colon cancer xenografted mice treated with Ad.TK(RC) and GCV was prolonged compared with Ad.TK(RC) alone or with administration of a single cycle of topotecan. These data demonstrate that the addition of direct viral oncolysis to the HSV-tk/GCV suicide gene system resulted in a striking improvement in treatment efficacy and that it may offer advantages over the use of chemotherapeutic agents for treatment of localized disease.
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PMID:Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of herpes simplex virus-thymidine kinase. 992 55

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