Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The respective pretreatment prognostic impacts of the following markers were evaluated in 125 patients with small cell lung cancer (SCLC): lactic dehydrogenase (LDH), serum thymidine kinase (S-TK), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and tissue polypeptide antigen (TPA). More traditional clinical and serologic markers were also evaluated. Univariate analysis showed that all of the biochemical markers mentioned above, the Karnofsky index (KI) and the patient's sex were related to both the stage of disease (limited/extensive disease: LD/ED) and to survival. The strongest marker for the clinical stage was S-TK, whereas TPA showed the strongest relationship with survival. Multivariate analyses produced a model consisting of S-TK, CEA, NSE, and the patient's sex for determining the clinical stage. To compare the prognostic capacity of easily determined biochemical and simple clinical variables to the more resource-demanding variable of the clinical stage, three multivariate analyses in relation to survival were performed: (1) biochemical markers and simple clinical variables; (2) LD/ED and simple clinical variables; and (3) all available variables. The model obtained from the first analysis included TPA, KI, age, and the patient's sex; the model from the second analyses included LD/ED, patient's age, and KI; and the model from the third analysis, TPA, KI, age, sex, and LD/ED. Indices based on these three multivariate models were calculated for each patient and the prognostic capacity of these indices was compared. Pretreatment serum marker levels also had the capacity to predict both the grade and the duration of the response to therapy.
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PMID:Clinical and serologic markers of stage and prognosis in small cell lung cancer. A multivariate analysis. 216 41

Seven tumour markers, i.e. squamous cell carcinoma antigen (SCC), cancer antigen 125 (CA 125), tissue polypeptide antigen (TPA), neopterin, C-reactive protein (CRP), carcinoembryonic antigen (CEA) and deoxythymidine kinase (TK) were analysed in sera from 104 women with benign and 61 women with malignant gynecologic diseases, in order to create tumour marker panels for various gynecologic malignancies, for monitoring and prediction of disease development. The incidence of elevated tumour marker levels, in cervical carcinoma was 78% when SCC, CA 125 and CEA were used. In ovarian carcinoma one of the markers CA 125, TPA and CEA was elevated in 91% and for endometrial carcinoma the best combination of markers was SCC, CA 125 and CEA (57%). No individual marker was superior to the above combinations. However, in patients with a fatal outcome of their malignant gynecologic disease (mean survival time from serum sampling was 16 months), the incidence of death was highest among those who had TPA elevated (91%) followed by neopterin (86%) and CRP (76%). Although intercurrent diseases affected tumour marker levels the markers picked up a majority of patients with a poor prognosis. This demonstrates the importance of interpreting tumour marker results against a background of detailed clinical information.
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PMID:Evaluation of seven different tumour markers for the establishment of tumour marker panels in gynecologic malignancies. 262 71

The potential therapeutic effects of differentiating agents on leukemic and solid tumor cells are being evaluated worldwide. These effects can be followed by morphologic as well as biochemical parameters. The enzymatic profile of four enzymes and the level of carcinoembryonic antigen were studied in 24 human colorectal carcinoma specimens and their adjacent uninvolved mucosa. The enzymes studied were thymidine kinase and 6-phosphogluconate dehydrogenase as markers of proliferation, and alkaline phosphatase and gamma-glutamyl transpeptidase as markers of differentiation. A consistent finding was a marked increase in the activities of thymidine kinase and 6-phosphogluconate dehydrogenase in the tumor cells as compared with the adjacent normal mucosa. The activity of gamma-glutamyl transpeptidase was not significantly different between tumor and uninvolved colon tissue. Alkaline phosphatase activity was markedly reduced in the tumor specimens. A relationship between the degree of differentiation and the degree of penetration and CEA expression was demonstrated in the tumor specimens as well as in their surrounding uninvolved mucosa.
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PMID:Biochemical tissue markers of human colorectal carcinoma. 289 33

A carcinoembryonic antigen (CEA)-producing human lung cancer cell line (A549), a nonproducing human lung cancer cell line (CADO-LC9), and a human uterine cervical cancer (HeLa) were transfected with the herpes simplex virus thymidine kinase (HSV-TK) gene regulated by 445 nucleotides upstream from the translational start of CEA gene. Fifty % growth inhibitory concentration of ganciclovir (GCV) was 0.57 micron for HSV-TK-transfected A549; relative sensitivity to GCV was more than 1000 times higher compared to the 50% growth inhibitory concentration of the parental cell line. Both CADO-LC9 and HeLa transfected with HSV-TK were still resistant to GCV. There was no difference in either morphology or doubling time between HSV-TK-transfected and parental clones. Injections (i.p.) of GCV resulted in significant regression of HSV-TK-transfected A549 tumors in nude mice. These data show the possibility of gene therapy using the cell type-specific promoter of CEA gene against CEA-producing adenocarcinoma of the lung.
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PMID:Gene therapy for carcinoembryonic antigen-producing human lung cancer cells by cell type-specific expression of herpes simplex virus thymidine kinase gene. 792 50

Serological tumor markers may become widely used as inexpensive and non-invasive methods of cancer detection. Markers of current interest for small cell lung cancer (SCLC) comprise enzymes, peptides, proteins, and carbohydrates. None of the serological markers for SCLC have yet proven to be of diagnostic value and at present their use is limited to monitoring disease and indicating prognosis. However, whilst serological markers related to the metabolic state of SCLC cells, such as neuron-specific enolase, serum thymidine kinase and tissue polypeptide antigen, may only be used for monitoring patients and for estimating prognosis, the other serological markers under current investigation may be used to indicate new treatment forms. Several novel approaches, including interference in the autocrine growth-regulating loop of SCLC by either peptides or antibodies, have been tried, SCLC is a highly heterogeneous tumor with respect to antigen expression, regulation of growth, and differentiation state. It is therefore important that new interventions are directed against both antigen-positive and antigen-negative tumor cells. For instance, radioisotopes or enzymes coupled to antibodies may be effective by exerting toxicity at some distance from the target. Antigens expressed on SCLC cells, such as peptide receptors involved in growth regulation, carbohydrate antigens like Lewis antigens, carcinoembryonic antigen and the ganglioside fucosylGM1, provide potential targets for antibody-conjugated therapy.
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PMID:Serological tumor markers for small cell lung cancer and their therapeutic implications. 794 58

The clinical relevance of the carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, squamous cell carcinoma antigen (SCC), thymidine kinase (TK), and deoxythymidine-5'-triphosphatase (dTTPase) as tumor markers in the diagnosis and follow-up treatment of 26 patients with head and neck cancer is evaluated. Serum levels prior to treatment were found elevated just above the upper limit of normal in 46% (SCC), 15% (CEA), 12% (CA 19-9), 27% (TK), and 39% (dTTPase) of all patients. If all markers were taken into account, they were elevated in 73% of the untreated patients. However, only in a few cases were the tumor marker values elevated significantly (8%-12%). No significant correlation was detected between serum levels and tumor localization, staging, grading, or performance status for any of the markers. In the follow-up none of the markers tested revealed any disease-related information despite therapy variation. Patients with originally elevated marker levels showed decreasing and in some cases increasing values after primary therapy, although no tumor recurrence was detected. Even considering the results as preliminary due to the rather small sample size, they suggest that the routine assessment of CEA, CA 19-9, SCC, TK, and dTTPase serum levels is of limited practical value.
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PMID:Tumor markers in the diagnosis and follow-up of head and neck cancer: role of CEA, CA 19-9, SCC, TK, and dTTPase. 838 81

We analyzed the ability of a recombinant replication-defective adenovirus vector with the carcinoembryonic antigen (CEA) promotor to transfer the thymidine kinase gene of herpes simplex virus (HSVtk) into gastric cancer cells to confer sensitivity to ganciclovir (GCV). CEA-producing gastric cancer cell lines (MKN28 and MKN45), a CEA-nonproducing gastric cancer cell line (MKN1), and a human uterine cervical cancer cell line (HeLa) were infected with a recombinant adenovirus carrying lacZ reporter gene coupled to the CEA promoter (AdCEAlacZ). The efficiency of AdCEAlacZ-mediated gene transfer was correlated with the amount of CEA produced by each cell line. Furthermore, the 50% growth inhibitory concentrations (IC50) of GCV were 21 and 5.8 microm for MKN28 and MKN45, respectively, when infected with a recombinant adenovirus carrying the HSVtk gene coupled to the CEA promoter (AdCEAtk). However, MKN1 and HeLa cells infected with AdCEAtk remained resistant to GCV (IC50 > 300 microm of GCV). In addition, a bystander killing effect was demonstrated against MKN45 cells when only 20% of AdCEAtk-infected cells were mixed with uninfected cells. These data indicate the potential for targeted gene therapy using the cell type-specific promotor of the CEA gene against gastric cancers that produce CEA.
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PMID:Adenovirus-mediated prodrug gene therapy for carcinoembryonic antigen-producing human gastric carcinoma cells in vitro. 864 Aug 23

The carcinoembryonic antigen (CEA) is a glycoprotein which overexpressed in the majority of human gastric cancers. We demonstrated that recombinant adenoviral vector (AdCEAtk), containing the CEA promoter, could transfer the herpes simplex virus thymidine kinase (HSVtk) gene into CEA-producing gastric cancer cells to confer sensitivity to ganciclovir (GCV) in vivo. In an ex vivo experiment, the tumor growth was inhibited after GCV treatment when the tumor contained more than 20% of AdCEAtk infected cells, indicating an efficient bystander killing effect. With intra-tumoral injection of AdCEAtk, the HSVtk were selectively expressed in approximately 30% of CEA producing cancer cells. By AdCEAtk injection and GCV administration, the growth of tumors was significantly inhibited by 20% as compared to untreated tumors. It is hoped that these results provide a strategy of tumor specific gene transfer for CEA producing gastric cancers.
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PMID:Adenovirus-mediated gene therapy of gastric carcinoma using cancer-specific gene expression in vivo. 907 Aug 91

In recent years the idea of using gene therapy as a modality in the treatment of diseases other than genetically inherited, monogenic disorders has taken root. This is particularly obvious in the field of oncology where currently more than 100 clinical trials have been approved worldwide. This report will summarize some of the exciting progress that has recently been made with respect to both targeting the delivery of potentially therapeutic genes to tumor sites and regulating their expression within the tumor microenvironment. In order to specifically target malignant cells while at the same time sparing normal tissue, cancer gene therapy will need to combine highly selective gene delivery with highly specific gene expression, specific gene product activity, and, possibly, specific drug activation. Although the efficient delivery of DNA to tumor sites remains a formidable task, progress has been made in recent years using both viral (retrovirus, adenovirus, adeno-associated virus) and nonviral (liposomes, gene gun, injection) methods. In this report emphasis will be placed on targeted rather than high-efficiency delivery, although those would need to be combined in the future for effective therapy. To date delivery has been targeted to tumor-specific and tissue-specific antigens, such as epithelial growth factor receptor, c-kit receptor, and folate receptor, and these will be described in some detail. To increase specificity and safety of gene therapy further, the expression of the therapeutic gene needs to be tightly controlled within the target tissue. Targeted gene expression has been analyzed using tissue-specific promoters (breast-, prostate-, and melanoma-specific promoters) and disease-specific promoters (carcinoembryonic antigen, HER-2/neu, Myc-Max response elements, DF3/MUC). Alternatively, expression could be regulated externally with the use of radiation-induced promoters or tetracycline-responsive elements. Another novel possibility that will be discussed is the regulation of therapeutic gene products by tumor-specific gene splicing. Gene expression could also be targeted at conditions specific to the tumor microenvironment, such as glucose deprivation and hypoxia. We have concentrated on hypoxia-targeted gene expression and this report will discuss our progress in detail. Chronic hypoxia occurs in tissue that is more than 100-200 microns away from a functional blood supply. In solid tumors hypoxia is widespread both because cancer cells are more prolific than the invading endothelial cells that make up the blood vessels and because the newly formed blood supply is disorganized. Measurements of oxygen partial pressure in patients' tumors showed a high percentage of severe hypoxia readings (less than 2.5 mmHg), readings not seen in normal tissue. This is a major problem in the treatment of cancer, because hypoxic cells are resistant to radiotherapy and often to chemotherapy. However, severe hypoxia is also a physiological condition specific to tumors, which makes it a potentially exploitable target. We have utilized hypoxia response elements (HRE) derived from the oxygen-regulated phosphoglycerate kinase gene to control gene expression in human tumor cells in vitro and in experimental tumors. The list of genes that have been considered for use in the treatment of cancer is extensive. It includes cytokines and costimulatory cell surface molecules intended to induce an effective systemic immune response against tumor antigens that would not otherwise develop. Other inventive strategies include the use of internally expressed antibodies to target oncogenic proteins (intrabodies) and the use of antisense technology (antisense oligonucleotides, antigenes, and ribozymes). This report will concentrate more on novel genes encoding prodrug activating enzymes, so-called suicide genes (Herpes simplex virus thymidine kinase, Escherichia coli nitroreductase, E. (ABSTRACT TRUNCATED)
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PMID:Targeting gene therapy to cancer: a review. 940 37

In gene therapy for malignancy, the herpes simplex virus thymidine kinase (HSVtk)-ganciclovir (GCV) system has been widely used. For pancreatic cancer targeting, we estimated the therapeutic efficacy of gene transduction by an adenovirus-carrying HSVtk gene under the control of a carcinoembryonic antigen (CEA) promoter (AdCEAtk) followed by systemic administration of GCV. Four cell lines, CEA-producing Su.86.86. BxPC-3 (pancreatic cancer cells), MKN45 (gastric cancer cells) and CEA-nonproducing HeLa, were used for analysis of GCV sensitivity induced by adenoviral gene transduction. To evaluate the therapeutic efficacy of AdCEAtk and GCV administration in human CEA-positive pancreatic cancer in vivo, a subcutaneously implanted tumor-bearing nude mouse model was used. When the HSVtk gene was transduced with a ubiquitous promoter into these cells, increase of the GCV sensitivity was independent of CEA-production. In contrast, when the cells were transduced with a CEA promoter, the cell-killing effect of GCV was increased in only CEA-producing cells. For in vivo analysis, AdCEAtk was delivered into subcutaneously established tumors of Su.86.86 cells. Immunohistochemical staining of the tumor showed that HSVtk protein was expressed only in tumor cells, and tumor growth was markedly suppressed by administration of GCV. These results suggest that the adenovirus-mediated transfer of HSVtk gene with CEA promoter specifically increases the GCV sensitivity of CEA-producing pancreatic cancer cells in vitro and in vivo. This strategy may provide a useful tool for treating pancreatic cancer, especially CEA-producing tumor cells.
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PMID:In vivo adenovirus-mediated prodrug gene therapy for carcinoembryonic antigen-producing pancreatic cancer. 961 53


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