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: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence has suggested that tumor cells having a wild-type p53 status are more sensitive to chemotherapeutic agents and radiation than cells that lack functional p53. The heightened sensitivity of wild-type p53 cells is thought to be attributable to their propensity to undergo p53-mediated apoptosis after insult. Given that suicide gene therapy is essentially tumor-targeted chemotherapy, we examined the hypothesis that coexpression of wild-type p53 could enhance the efficacy of adenovirus-mediated suicide gene therapy. Human Hep3B and SK-OV-3 cells, which are null for p53, were infected with a pair of replication-deficient adenoviruses that expressed a cytosine deaminase/herpes simplex virus thymidine kinase (CD/HSV-1 TK) fusion gene without (fusion gene nonreplicative adenovirus, FGNR) or with (FGNRp53) the wild-type human p53 gene. The sensitivity of cells to the CD/5-fluorocytosine (CD/5-FC) and HSV-1 TK/ ganciclovir (GCV) enzyme/prodrug systems was determined in vitro and in vivo. Coexpression of p53 did not enhance the cytotoxicity of either the CD/5-FC or HSV-1 TK/GCV system in vitro. The failure to observe an effect of p53 could not be explained on the basis of insufficient or transient p53 expression, because FGNRp53-infected cells growth arrested in G1, induced Bax, and underwent apoptosis at an increased rate after prodrug treatment, particularly when the adenovirus E1A protein was present. Intratumoral injection of FGNRp53 concomitant with single or double pro-drug therapy resulted in a tumor growth delay that was equal to or less than that observed with the FGNR virus. Our results indicate that coexpression of p53 may not necessarily improve the efficacy of adenovirus-mediated CD/ 5-FC and HSV-1 TK/GCV suicide gene therapies in vivo.
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PMID:Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy. 1063 64

Thymidylate synthase and thymidine kinase are key enzymes involved in the de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. Thymidylate synthase is inhibited by 5-fluorodeoxyuridine monophosphate, forming an inactive ternary complex with intracellular folate. We investigated the effects of 1-(2-tetrahydrofuryl)-5-FU plus uracil (UFT) with or without leucovorin on 1,2-dimethylhydrazine-induced rat colorectal carcinomas. Thirty-week administration of UFT with or without leucovorin markedly suppressed both colorectal carcinogenesis and tumor growth, resulted in the increase of thymidylate synthase inhibition and the decrease of thymidine kinase activity in the tumor cells. These results indicate that the combination of UFT with leucovorin could be useful in the development of pre- and post-operative adjuvant chemotherapy programs.
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PMID:Effects of long-term administration of UFT plus leucovorin on colorectal tumors induced with 1,2-dimethylhydrazine in rats. 1069 23

We report here the use of viral fusogenic membrane glycoproteins (FMGs) as a new class of therapeutic genes for the control of tumor growth. FMGs kill cells by fusing them into large multinucleated syncytia, which die by sequestration of cell nuclei and subsequent nuclear fusion by a mechanism that is nonapoptotic, as assessed by multiple criteria. Direct and bystander killing of three different FMGs were at least one log more potent than that of herpes simplex virus thymidine kinase or cytosine deaminase suicide genes. Transduction of human tumor xenografts with plasmid DNA prevented tumor outgrowth in vivo, and cytotoxicity could be regulated through transcriptional targeting. Syncytial formation is accompanied by the induction of immunostimulatory heat shock proteins, and tumor-associated FMG expression in immunocompetent animals generated specific antitumor immunity.
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PMID:Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth. 1074 10

Herpes simplex virus thymidine kinase (HSV-tk) gene transfer and ganciclovir (GCV) administration have been suggested for the treatment of malignant gliomas. To understand tissue responses and possible ways to improve the treatment effect, we studied tumor growth, tissue reactions, and survival time after HSV-tk/GCV treatment in a syngeneic BT4C rat glioma model by mixing various ratios of stably transfected HSV-tk-expressing BT4C-tk glioma cells with wild-type BT4C glioma cells (percentage of BT4C-tk cells: 0%, 1%, 10%, 30%, 50%, and 100%), followed by injection into BDIX rat brains (n = 79). With the exception of some animals with end-stage tumors, very little astroglia or microglia reactivity was detected in the wild-type tumors as analyzed by immunocytochemistry using glial fibrillary acid protein (GFAP)-, vimentin-, human histocompatibility leukocyte antigen-DR-, OX-42-, and CD68-specific monoclonal antibodies. After 14 days of GCV treatment, tumors induced with > or = 10% BT4C-tk cells showed a significant reduction in tumor size (P < .05) and prolonged survival time (P < .01). Astrogliosis, as indicated by a strong GFAP and vimentin immunoreactivity, was seen in the tumor scar area. GFAP and vimentin reactivity was already present after the GCV treatment in tumors induced with 1% BT4C-tk cells. Much less human histocompatibility leukocyte antigen-DR-positive microglia was seen in the treated animals, indicating low microglia reactivity and immunoactivation against the tumor. However, GCV-treated tumors were positive for apoptosis, indicating that apoptosis is an important mechanism for cell death in the BT4C-tk glioma model. Our results suggest that > or = 10% transfection efficiency is required for a successful reduction in BT4C glioma tumor size with HSV-tk/GCV treatment in vivo. Tissue reactions after 14 days of GCV treatment are characterized by astrogliosis and apoptosis, whereas microglia response and immunoactivation of the brain cells appear to play a minor role. Stimulation of the microglia response by gene transfer or other means might improve the efficacy of the HSV-tk/GCV treatment in vivo.
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PMID:Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model: effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissue reactions. 1076 47

The inhibitory effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and its arabinosyl derivative (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU) on the growth of both MDA-MB-435 human breast carcinoma and 9L rat gliosarcoma cells expressing the thymidine kinase (tk)-encoding gene of the Varicella zoster virus (VZV) or the Herpes simplex virus (HSV) were evaluated. In vitro, BVDU and BVaraU effectively killed both cell types expressing VZVtk, with 50% inhibitory concentration values ranging from 0.06 to 0.4 microM, whereas ganciclovir (GCV) lacked activity. On HSVtk+ cells, BVDU had high cytotoxic activity, with 50% inhibitory concentration values that were similar to those of GCV, whereas BVaraU was inactive. In vivo, BVDU applied intraperitoneally caused a 50% tumor growth inhibition in nude mice inoculated subcutaneously with VZVtk+ as well as HSVtk+ mammary tumor cells. In mice and at variance with the in vitro results, BVaraU had very little activity against the VZVtk+ mammary cells; GCV had the highest activity on the HSVtk+ cells, resulting in a 50% eradication of the tumors. With the 9L rat gliosarcoma model, the VZVtk/BVDU system completely failed to inhibit the development of VZVtk+ glioma tumors induced subcutaneously in syngeneic rats, although BVDU had a similar 45-minute half-life in both rats and mice. Factors other than degradation of the prodrug and related to the mode of action of these analogs are possibly involved in the observed discrepancies between the in vitro and in vivo results.
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PMID:Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase. 1077 Jun 29

Bystander effect (BSE) refers to killing of cells adjacent to a cell engineered to express a killing gene segment. BSE is considered an important aspect of suicide gene therapy with thymidine kinase. We evaluated the BSE of adenovirus expressing herpes simplex thymidine kinase (AdCMVtk) in rat medullary thyroid carcinomas (rMTC) and three rat thyroid epithelial cancer cell lines using an in vitro BSE assay. In the assay, different proportions of infected and uninfected cells are mixed. Only the proportion of directly infected cells was inhibited in the proliferation assay using rMTC cells. This indicates that there is little BSE in this cell line. One rat thyroid epithelial cancer cell line (RTC-R2) has a high BSE, with BSE index (BSEi) of 7. In the proliferation assay a greater proportion of cells was inhibited than those directly infected. BSE was also evaluated during in vivo tumor growth by subcutaneous injection of mixtures of AdCMVtk infected and uninfected cells. Ganciclovir (GCV) treatment of tumors developing from a 1:1 mixture of infected to uninfected rMTC cells failed to inhibit their growth. In contrast, GCV treatment of a 2:8 mixture of infected to uninfected RTC-R2 cells completely inhibit tumor development, indicating a high BSE. BSE is related to in vivo antitumor efficacy when replication-defective adenovirus AdCMVtk is directly injected into rMTC tumors. After treatment with 100 mg/kg per day of GCV, a growth-retardation effect was observed in small tumors (<100 mm3), but there was little antitumor activity in large tumors (>100 mm3). Our results indicate that there is a good correlation between this in vitro BSE assay and in vivo treatment efficacy. Not all kinds of tumors are suitable for thymidine kinase (TK)/GCV gene therapy because some lack BSE. Methods to improve BSE and/or transduction efficiency are needed in order to obtain an effective therapeutic result. It will be appropriate to test the BSE in human tumor cells before performing clinical trials with current adenoviral vectors expressing TK.
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PMID:Gene therapy of established medullary thyroid carcinoma with herpes simplex viral thymidine kinase in a rat tumor model: relationship of bystander effect and antitumor efficacy. 1080 59

G207 is a multimutated, conditionally replicating herpes simplex virus type 1 (HSV-1) that retains an intact viral thymidine kinase (HSV-tk) gene. The virus exhibits oncolytic activity in various tumors and is being evaluated in patients with recurrent malignant glioma. In view of the potential for ganciclovir (GCV) to either enhance or inhibit the antitumoral activity of HSV-tk-retaining HSV-1 vectors, we evaluated the effect of GCV administration on the antitumoral activity of G207. In culture, addition of GCV either had no effect or inhibited the cytocidal action of G207 at replication-permissive temperatures, while it significantly increased the cell killing in three of the four cell lines studied when virus replication was inhibited at nonpermissive temperatures. Using a G207-permissive immunocompetent mouse tumor model, subcutaneous N18 neuroblastoma in syngeneic A/J mice, we found that GCV treatment did not affect G207-mediated tumor growth inhibition at a variety of viral doses (10(5), 10(7), and 10(7) x 2 plaque-forming units). In A/J mice harboring intracerebral N18 tumors, GCV administration had no significant effect on the prolongation of survival by G207 inoculation. These findings suggest that GCV administration may not be beneficial to the efficacy of G207 tumor therapy under conditions that favor active viral replication, because the potential HSV-tk/GCV-mediated enhancement of G207 oncolytic activity may be balanced out by the inhibitory action of GCV on viral replication.
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PMID:Evaluation of ganciclovir-mediated enhancement of the antitumoral effect in oncolytic, multimutated herpes simplex virus type 1 (G207) therapy of brain tumors. 1088 26

Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene, followed by administration of ganciclovir (GCV), generates the "bystander effect," in which HSVtk-negative wild-type cells are killed by GCV, as are HSVtk-expressing cells. Our previous study demonstrated that intracranial 9L gliomas could be efficiently treated due to this bystander effect by injecting the 9L glioma cells transduced with the HSVtk gene in the vicinity of the preimplanted wild-type 9L glioma and then administering GCV. For a possible clinical application of the bystander effect-mediated cell killing, we tested HSVtkgene-transduced allogeneic C6 glioma cells (C6tk) instead of syngeneic 9L glioma cells transduced with the HSVtk gene. Fisher rats were implanted intracranially with wild-type 9L glioma cells, subsequently injected with C6tk cells at the same brain coordinate, and thereafter treated with GCV or saline. When the rats were treated with GCV, a significant retardation of tumor growth was observed by serial magnetic resonance imaging, although this growth retardation was less prominent than that observed with 9L glioma cells transduced with the HSVtk gene; consequently, survival was prolonged (P < .01). Tumors that received C6tk cells contained almost no HSVtk-positive cells after treatment with GCV. Rejection of allogeneic tumor cells, although possibly incomplete in the brain, can also contribute to the safety of this therapeutic strategy.
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PMID:Treatment of rat experimental brain tumors by herpes simplex virus thymidine kinase gene-transduced allogeneic tumor cells and ganciclovir. 1088 27

Immunotherapy in combination with suicide gene therapy for breast cancer was tested using a metastatic animal model. Subcutaneous injection of the nonimmunogenic breast cancer cell line 4T1 in BALB/C mice gave rise to tumors in 100% of mice with both micrometastases and macrometastases in the lung. We used the herpes simplex virus thymidine kinase (HSV-TK) gene along with the cytokine genes granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) to determine their effect on tumor regression and inhibition of lung metastasis. Adenoviral (AV) vectors carrying these transgenes, in separate constructs, were used in this study. Intratumoral administration of AV-TK followed by 10 days of ganciclovir treatment resulted in a delay in tumor growth and, in some cases, in a low to moderate reduction in tumor volume. Inclusion of either GM-CSF or IL-2 gene with HSV-TK resulted in a slightly greater reduction in tumor volume, although these data were not significantly different from those obtained for TK treatment alone. However, when both cytokine genes were combined with TK, a substantial reduction in tumor growth was observed compared with HSV-TK alone (P < .02). Tumor weight data also exhibited superior efficacy of TK/GM-CSF/IL-2 treatment when compared with animals treated with TK gene only (P < .01). More importantly, TK/GM-CSF/IL-2 combination gene therapy induced a significant reduction in lung metastasis compared with any other treatment groups in the 4T1 model (P < .001 between TK GM-CSF/IL-2 versus TK only). Surgical excision of primary tumors after TK/GM-CSF/IL-2 plus ganciclovir treatment resulted in anti-metastatic activity that was similar to that observed for animals in which no surgery was performed. Survival analysis showed a significant difference between animals treated with AV-TK/GM-CSF/IL-2 and animals treated with TK only at 35 days after virus injection (P < .01). Immunophenotypic data suggest infiltration of lymphocytes within the tumor microenvironment in TK- and cytokine gene-treated animals. Thus, the overall data presented here demonstrate that TK gene therapy in combination with GM-CSF and IL-2 gene-mediated immunotherapy strategies have important implications in the treatment of breast cancer.
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PMID:Efficacy of herpes simplex virus thymidine kinase in combination with cytokine gene therapy in an experimental metastatic breast cancer model. 1091 12

Interleukin 2 (IL-2) enhancement of herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV)-induced tumor killing was studied by cloning the human interleukin 2 gene into an HSV-TK-bearing adeno-associated viral (AAV) vector (TK/IL-2). The mouse hepatocellular carcinoma cell line Hepa 1-6 was used as a model in this study. We found that TK/IL-2-transduced Hepa 1-6 cells were more susceptible to ganciclovir treatment than tumor cells transduced with only TK in both nude mice and immunocompetent C57L/J mice. TK/IL-2-transduced tumors also showed shrinkage without GCV treatment. The tumor-killing effect of AAV-mediated TK/IL-2 gene transfer was further studied by inoculating animals with TK/IL-2- or TK-transduced tumor cells mixed with unmodified cells with or without GCV treatment. Although tumor growth in each group was inhibited, the best result was obtained from the TK/IL-2-transduced group without GCV treatment. In this group, 10% of the transduced tumor cells could eradicate the whole tumor in 50% of the animals tested as well as provide long-term protection against tumor cell rechallenge. When this group was treated with GCV, the antitumor effect of TK/IL-2 was reduced. We attribute this to the early ablation of transgene-bearing tumor cells by GCV treatment, which thus reduces the duration of IL-2 expression. We conclude that (i) TK/IL-2 plus GCV treatment generates a stronger tumor-killing effect than HSV-TK plus GCV and (ii) tumor killing of TK/IL-2 is more effective in non-GCV-treated animals than in GCV-treated animals.
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PMID:Adeno-associated viral-mediated gene transfer to hepatoma: thymidine kinase/interleukin 2 is more effective in tumor killing in non-ganciclovir (GCV)-treated than in GCV-treated animals. 1093 75


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