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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite multimodality treatment for thyroid cancer, including surgical resection, radioiodine therapy, thyrotropin (TSH)-suppressive thyroxine treatment, and chemotherapy/radiotherapy, survival rates have not improved over the last decades. Therefore, development and evaluation of novel treatment strategies, including gene therapy, are urgently needed. A variety of gene therapy approaches have been evaluated for the treatment of follicular cell-derived and medullary thyroid cancer, including corrective gene therapy (p53 restoration, expression of a dominant negative RET mutant), cytoreductive gene therapy (suicide gene/prodrug strategy herpes simplex virus-thymidine kinase [HSV-tk]/ganciclovir, antiangiogenic therapy with endostatin) and immunomodulatory gene therapy (expression of interleukin (IL)-2 and IL-12). Furthermore, cloning of the sodium iodide symporter (NIS) gene has paved the way for the development of a novel cytoreductive gene therapy strategy based on NIS gene transfer followed by the application of radioiodine therapy ((131)I). NIS gene delivery into medullary and follicular cell-derived thyroid cancer cells has been shown to be capable of establishing or restoring radioiodine accumulation and might therefore represent an effective therapy for medullary and dedifferentiated thyroid tumors that lack iodide accumulating activity. The data summarized in this review article clearly demonstrate that the currently available strategies represent potentially curative novel therapeutic approaches for future gene therapy of thyroid cancer. The combination of different therapeutic genes has been demonstrated to be very useful to enhance therapeutic efficacy and seems to have a promising role at least as part of a multimodality approach for advanced thyroid cancer.
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PMID:Gene therapy for thyroid cancer: current status and future prospects. 1524 69

Targeted gene expression can be achieved through the use of cell-selective promoters. However, when the expression cassette is delivered by an adenovirus, "promoter interference," resulting in the loss of specificity, has been reported. To overcome this problem, insulator elements (the bovine growth hormone transcription stop signal or HS4 chromatin insulators of the chicken beta-globin locus) have been used. The present study examines the efficacy of these insulators elements, when two independent expression cassettes (one in which a strong, ubiquitous promoter drives the expression of the green fluorescent protein and another in which the "cancer-selective" ERBB2 promoter drives the expression of the herpes simplex virus thymidine kinase [HSVtk] gene) are incorporated into the same recombinant adenovirus. As expected, the presence of either insulator does not alter the expression of HSVtk in ERBB2-positive cells, measured through sensitization of the cells to ganciclovir. When ERBB2-negative cells were infected at a multiplicity of infection (MOI) of 10, the uninsulated virus sensitized ERBB2-negative cells to the same extent as it did for ERBB2-positive cells; partial sensitization was observed when transcriptional terminators were used, indicating a partial insulating effect; and complete insulation (no sensitization to ganciclovir) was observed when HS4 chromatin insulators were used. However, this complete insulation was lost when the MOI of virus was increased to 100. Our study demonstrates the possibility of insulating a conditionally expressed transgene in the vicinity of another expression cassette, but this insulating effect is lost when the multiplicity of infection is increased.
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PMID:Direct comparison of the insulating properties of two genetic elements in an adenoviral vector containing two different expression cassettes. 1558 15

Activity of thymidine kinase 1 in serum (STK) is a useful marker for leukaemia and lymphoma, but not for solid tumors. We investigate thymidine kinase 1 concentration in serum (S-TK1) as a potential tumor marker. S-TK1 concentration and STK activity levels were determined in 9 human malignant diseases (breast, gastric, rectal, colorectal, lung, brain cancer, hepatoma, lymphoma, leukaemia) and in benign and non-cancerous diseases, representing 850 preoperative cases. Healthy volunteers (n=43) were used as positive controls. S-TK1 concentration was determined by ECL dot blot assay and STK activity levels by an RIA assay. S-TK1 concentrations and STK activity levels in preoperative malignant patients were significantly higher than in healthy individuals, in patients with benign tumors and in those with non-cancerous diseases. Significant correlations between concentration and activity level were only found in healthy individuals, in patients with benign tumors, and in some patients with malignancies, i.e. leukaemia, and breast and gastric cancers. About 90-95 percent of the malignant patients showed S-TK1 concentrations above those of the healthy controls. The corresponding value for STK activity was about 75 percent. When sera from malignant patients were diluted with sera from healthy individuals, S-TK1 concentrations and STK activity levels decreased more than expected. This indicates the presence of a compound (or compounds) in the serum of healthy individuals that destabilises S-TK1. We conclude that S-TK1 concentration is a more sensitive tumor marker in solid malignancies than is STK activity.
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PMID:Concentration of thymidine kinase 1 in serum (S-TK1) is a more sensitive proliferation marker in human solid tumors than its activity. 1614 66

We explored the possibility of entrapping retroviral vector producing cells (VPC) within porous 3D matrix to induce a local and sustained release of viral particles to the malignant milieu. PA317/STK, which constantly shed retroviral vectors, was used to transduce cancer cells with the herpes simplex virus thymidine kinase (HSV-tk) gene. Once HSV-tk is expressed, it preferentially phosphorylates nucleoside analog prodrugs, such as ganciclovir (GCV) and N-methanocarbathymidine (N-MCT), to their active triphosphate metabolites, which when incorporated into cellular DNA cause cell death. PA317/STK cells were seeded within 3D alginate scaffold at two different cell densities via static seeding procedure. In vitro assays determined that PA317/STK seeded at high-cell density in scaffolds maintained constant cell number, low cell leakage, and spheroid morphology with viral vector transfection activity. Postcell-seeding viral vector activity was confirmed by transfection of murine colon cancer cells (MC38) with conditioned media originated from VPC-containing scaffolds and the subsequent ability to generate N-MCT triphosphate. Preliminary in vivo transplantation of VPC-containing scaffolds into the peritoneal cavity of mice bearing intraperitoneal MC38 tumors with 2 weeks subsequent GCV administration resulted in a significantly higher survival rate relative to control groups. Our results demonstrate the feasibility of employing alginate scaffolds to efficiently entrap and support PA317/STK cells for cancer gene therapy.
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PMID:Entrapment of retroviral vector producer cells in three-dimensional alginate scaffolds for potential use in cancer gene therapy. 1668 Jul 30

Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.
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PMID:Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. 1796 76

The disseminated characteristics of human glioblastoma multiforme (GBM) make it a particularly difficult tumor to treat with long-term efficacy. Most preclinical models of GBM involve treatment of a single tumor mass. For therapeutic outcomes to translate from the preclinical to the clinical setting, induction of an antitumor response capable of eliminating multifocal disease is essential. We tested the hypothesis that expression of Flt3L (human soluble FMS-like tyrosine kinase 3 ligand) and TK (herpes simplex virus type 1-thymidine kinase) within brain gliomas would mediate regression of the primary, treated tumor mass and a secondary, untreated tumor growing at a distant site from the primary tumor and the site of therapeutic vector injection. In both the single-GBM and multifocal-GBM models used, all saline-treated control animals succumbed to tumors by day 22. Around 70% of the animals bearing a single GBM mass treated with an adenovirus expressing Flt3L (AdFlt3L) and an adenovirus expressing TK (AdTK + GCV) survived long term. Approximately 50% of animals bearing a large primary GBM that were implanted with a second GBM in the contralateral hemisphere at the same time the primary tumors were being treated with AdFlt3L and AdTK also survived long term. A second multifocal GBM model, in which bilateral GBMs were implanted simultaneously and only the right tumor mass was treated with AdFlt3L and AdTK, also demonstrated long-term survival. While no significant difference in survival was found between unifocal and multifocal GBM-bearing animals treated with AdFlt3L and AdTK, both treatments were statistically different from the saline-treated control group (p < 0.05). Our results demonstrate that combination therapy with AdFlt3L and AdTK can eradicate multifocal brain tumor disease in a syngeneic, intracranial GBM model.
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PMID:Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model. 1807 58

It is known that the concentration and activity of the DNA precursor enzyme thymidine kinase 1 (TK1) in serum is significantly elevated in patients with malignancies, as compared with levels in patients with benign tumours and those in healthy individuals. For the first time, the use of serum TK1 as a prognostic marker for patients with renal cell carcinoma (RCC) was examined. Serum TK1 protein (STK1p) concentration and serum TK1 activity (STK1a) were determined by a dot blot chemoluminescence assay and a radio enzyme assay, respectively. There was no correlation between STK1p and STK1a in the same sera from 27 RCC patients. Only one STK1p value as compared with 15 STK1a values was clearly above the cut-off values (2 pmol/l and 6 U/l, respectively) for healthy individuals. STK1a values did not correlate with the level of TK1 expression in tumour sections from the RCC patients, estimated by immunohistochemistry staining. However, there was a significant correlation between STK1a levels and the grade, stage and size of the RCC tumours. The discrepancy between the STK1p and the STK1a results is likely to be because of reduced ability of the TK1 antibody to recognize the STK1 in sera from RCC patients. We conclude that the activity of STK1 is a useful tool for evaluating the prognosis of patients with RCC.
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PMID:Thymidine kinase activity in serum of renal cell carcinoma patients is a useful prognostic marker. 1928 58

The herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) promoter contains elements involved in both constitutive and induced expression. We determined that phorbol 12-myristate 13-acetate (PMA) induces the HSV-1 TK promoter in HEK293 cells. However, PMA did not induce expression from the promoter in HeLa cells and did not result in a globally increased gene expression in HEK293 cells. Induction of HSV-1 TK promoter required activation of both of JNK and ERK pathways. However, activation of the two pathways alone was not sufficient for induction of HSV-1 TK promoter. By transiently transfecting into HeLa cells the adenoviral E1A gene, which exists as an integrant in HEK293 genome, we demonstrated that E1A proteins are necessary for induction of HSV-1 TK promoter by PMA. We propose mechanisms by which signaling pathways activated by the tumor-promoter PMA cooperate with the oncogene E1A to stimulate a eukaryotic promoter, namely the HSV-1 TK promoter.
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PMID:PMA induces expression from the herpes simplex virus thymidine kinase promoter via the activation of JNK and ERK in the presence of adenoviral E1A proteins. 1970 84

We have assessed the ability of bispecific fusion proteins to improve adenovirus-mediated transfer of therapeutic and marker transgenes. We constructed an expression vector that can be easily modified to synthesize a variety of fusion proteins for retargeting adenoviral gene therapy vectors to cell surface markers, which are differentially expressed between normal and cancer cells. Adenoviral transduction can be improved in a number of tumour cell lines which overexpress EGFR (epidermal growth factor receptor) or uPAR (urokinase-type plasminogen activator receptor), but which have only low levels of endogenous hCAR (human coxsackie B and adenovirus receptor) expression. Up to 40-fold improvement in beta-galactosidase transgene expression was seen using an EGFR retargeting protein, and up to 16-fold using a second fusion protein targeting uPAR. In vitro, our uPAR retargeting fusion protein improved the sensitivity to adenoviral herpes simplex virus thymidine kinase/ganciclovir by an order of magnitude, whereas in vivo, our EGFR retargeting protein is able to significantly delay tumour growth in rodent animal models in a dose-dependent manner. The 'cassette' design of our fusion protein constructs offers a flexible method for the straightforward synthesis of multiple adenoviral retargeting proteins, directed against a variety of tumour-associated antigens, for use in clinical trials.
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PMID:Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor. 2041 Sep 26

In this study we examine the use of the concentration of thymidine kinase 1 in serum (STK1) as a prognostic factor in routine clinical settings. For this purpose we used sera from patients with oesophageal (n=101) and cardial (n=39) carcinomas and nonsmall-cell lung carcinoma (NSCLC) (n=157). Sera from healthy individuals (n=95) were used as controls. STK1 was analysed by a chemiluminiscence dot blot assay. The mean STK1 concentrations and the STK1 positive rates of the patients with oesophageal and cardial carcinomas and with NSCLC were significantly higher as compared with healthy controls (P=0.01). The mean STK1 value of oesophageal carcinoma patients correlated with T-values (P=0.021) and with stage (P<0.005), but not with grade. The mean STK1 value of cardial carcinoma patients did not correlate with grade. No data on stage and T-values were available for these patients, due to advanced disease. The mean STK1 value of NSCLC patients with squamous cell carcinoma was significantly higher as compared with adenocarcinoma type (P=0.024). The mean STK1 value of the NSCLC patients correlated with clinical grade (P=0.006), T-values (P=0.001), stage (P=0.035) and to size of the tumour (P=0.030). The mean STK1 value and the number of STK1 positive patients were also higher in recurrent NSCLC patients. There was a tendency that stage I-II NSCLC patients with an STK1 level above 2 pmol/l showed a higher frequency of recurrence/death than patients below 1 pmol/l. Our results show that STK1 is a useful marker for prognosis in patients with oesophageal, cardial and lung carcinomas.
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PMID:Serological thymidine kinase 1 is a prognostic factor in oesophageal, cardial and lung carcinomas. 2047 45


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