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)

In adult mice of the transgenic strain TG66.19, in which expression of herpes simplex type 1 virus thymidine kinase (HSVI-TK) is driven in thyrocytes from the thyroglobulin promoter, the drug Ganciclovir causes the death (ablation) of thyrocytes. Ablation occurred in the absence of thyrocyte proliferation or nuclear DNA synthesis, but was accompanied by transient expression of proliferating cell nuclear antigen and the dying thyrocytes exhibited the ultrastructural features of apoptosis. Control experiments show that the apoptosis is a result of the production of Ganciclovir phosphates in thyrocytes that express HSV1-TK. However, cell death was not dependent upon the presence of a functional copy of the oncosuppressor gene p53. We conclude that the apoptosis is probably not mediated by induction of DNA damage and occurs via a pathway that is independent of p53. The fact that Ganciclovir phosphate can kill cells by a p53-independent apoptotic pathway is encouraging in relation to tumour ablation by methods based on transfection with HSV1-tk genes and administration of Ganciclovir.
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PMID:Ganciclovir-induced ablation non-proliferating thyrocytes expressing herpesvirus thymidine kinase occurs by p53-independent apoptosis. 870 May 54

In rats with diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC), we studied in vivo gene transfer efficiency using intraportal injections of recombinant adenovirus carrying the lacZ reporter gene (AdCMVlacZ) and the therapeutic efficacy of adenovirus-mediated transfer of the thymidine kinase gene of the herpes simplex virus (HSV-tk) followed by ganciclovir (GCV) administration. DENA was very effective in inducing HCC but also stimulated nontumor cell replication, as shown by proliferating cell nuclear antigen (PCNA) staining. The study of in vivo gene transfer efficiency in tumor-bearing rats showed that nontumor tissue and small tumor nodules were transduced effectively whereas a poor transduction rate was noted in large tumor nodules. Concerning therapeutic efficacy, three groups of rats with established HCC were studied: group A and B received intraportally recombinant adenovirus carrying HSV-tk (AdCMVtk) or AdCMVlacZ, respectively, and 2 days after GCV was given intraperitoneally for 9 days; group C received only saline. Of the rats from groups B and C, 100% and 93% respectively, exhibited multiple HCC tumor nodules at end of the study. In contrast, a complete regression of tumor was observed in 63% of animals from group A. This group showed significant elevation of serum transaminases and a diffuse hepatotoxic lesion in liver tissue; histological signs of regeneration were observed in surviving animals. Nine out of 19 rats from group A died during the treatment period. We conclude that (i) in the DENA model of HCC, tumoral cells can be destroyed in vivo by the HSV-tk/GCV system despite poor transduction of large tumor nodules, suggesting that toxic metabolites generated by nontumor cells may exert a bystander effect on tumor tissue; (ii) significant hepatoxicity and a high mortality rate occurred in HSV-tk/GCV-treated rats; these side effects appear to be due to the fact that in DENA-treated livers enhanced cell proliferation was present not only in tumor nodules but also in nontumor parenchyma, leading to GCV sensitization of both tissues; (iii) our results have implications concerning the efficacy and potential risks of the HSV-tk/GCV system in the treatment of human HCC.
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PMID:Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. 904 2

Epidermal growth factor (EGF), a mitogen in vitro for hepatocytes, produces in various cell lines changes similar to those observed very rapidly in hepatocytes after partial hepatectomy (PH). These changes include ion movements, membrane hyperpolarization and proto-oncogene expression. A stimulatory effect of EGF on liver regeneration can therefore tentatively be associated with the events occurring within the first 3 hours after a PH, sometimes referred to as the "priming phase." To assess this hypothesis, we examined in Wistar rats the effect of EGF deprivation produced by sialoadenectomy (SX) performed before or after a PH of 70%. SX at the time of PH significantly decreased the 3H-thymidine uptake in the DNA 24 hours later (147 +/- 14 DPM per microgram of DNA, mean +/- SE) compared with a simple PH (322 +/- 16; P < .01), but also compared with results obtained when PH is combined with a sham sialoadenectomy (SSX) or in rats pair-fed with the sialoadenectomized rats. This incomplete inhibition was confirmed by a decreased rise in thymidine kinase (TK) activity and by reduced proliferating cell nuclear antigen (PCNA) labeling and mitotic indices 30 hours after PH. By contrast, SX did not inhibit the early expression of c-jun and c-fos, or of c-myc, 30 or 120 minutes after PH, respectively. A reduction of DNA synthesis was also obtained when SX was performed 3 hours after PH (127 +/- 15 DPM per microgram of DNA vs. 350 +/- 21 in SSX; P < .001) but not when SX was delayed until the 6th or the 17th hour after PH. It was sufficient to administer EGF (40 microg) from the third to the ninth hour to correct the reduction of [3H]thymidine uptake in rats sialoadenectomized before PH. These results indicate that the diminished EGF availability following SX decreases or at least delays liver regeneration, and that the effect of EGF on liver regeneration does not seem related to the early changes of proto-oncogene expression, but rather to events occuring later, at the time of reported internalization and binding of EGF to its nuclear receptors.
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PMID:Effect of sialoadenectomy and epidermal growth factor administration on liver regeneration after partial hepatectomy. 904 6

1. The purpose of this study was to determine whether the commercially available forms of granulocyte-colony-stimulating factor exert the same beneficial effect on hepatic regeneration after 70% partial hepatectomy in rats. Adult male Wistar rats received either the two commercially available forms of granulocyte-colony-stimulating factor (Filgrastim or Lenograstim), or saline, simultaneously with partial hepatectomy. Hepatic regeneration was documented by determining [3H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity, mitotic index and proliferating cell nuclear antigen immunostaining, at various time points after partial hepatectomy. 2. DNA biosynthesis, liver thymidine kinase activity and mitotic index of hepatocytes were not only enhanced (P < 0.001) in rats that received 150 micrograms of Filgrastim or Lenograstim/kg of body weight, but occurred earlier than in saline-treated partially hepatectomized rats. The administration of both forms of granulocyte-colony-stimulating factor, at the dose of 15 micrograms/kg of body weight, did not affect liver proliferative capacity, compared with observations in simply partially hepatectomized rats. High mitotic and proliferating cell nuclear antigen indices appeared earlier than those estimated in simply partially hepatectomized rats, when 150 micrograms of Filgrastim or Lenograstim/kg of body weight were administered. 3. These findings suggest that both pharmacologically available forms of granulocyte-colony-stimulating factor at a dose of 150 micrograms/kg of body weight are able to augment liver regenerative capacity, to the same extent, in this animal model of controlled hepatic proliferation.
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PMID:Effect of two forms of granulocyte-colony-stimulating factor on hepatic regeneration after 70% partial hepatectomy in rats. 909 13

Liver regeneration is an essential component of the reparative process following liver injury and surgical resection. It can be assessed by different tissue-based tests such as liver weights, mitotic counts, DNA contents and synthesis rates, immunohistochemical staining of nuclear antigens, gene expressions and certain protein levels or various serum-based tests that largely consist of specific enzyme determinations or documentation of certain proliferation markers. Although the simplest tissue-based test of liver regeneration is measurement of liver weights, these determinations are influenced by the extent of deposition of various materials not directly related to regeneration, such as lipids, glycogen and blood volumes. Because mitosis constitutes a very short segment of the cell cycle, mitotic counts are infrequently observed by light microscopy. Thymidine and BrdU incorporation into DNA are the reference tools for studying DNA synthesis, but their use requires pre-injection with radioactive isotopes or nucleotides which render them impractical for human studies. Flow cytometry is an accurate and objective method of monitoring hepatic regenerative activity but requires sophisticated equipment that is not generally available in many laboratories. Immunohistochemical staining for nuclear antigens (Ki-67, proliferating cell nuclear antigen [PCNA], DNA polymerase alpha and nucleolar organizer region [NOR] proteins) are acceptable and commonly used methods of monitoring regenerative activity but are subject to inter- and intra-observer variability. Gene expression rates such as Histone-3 mRNA abundance are hampered by the relatively low rates of gene transcription and the need for recombinant DNA technology. Protein and enzyme levels in liver tissues, such as putrescine, ornithine decarboxylase and thymidine kinase, are not precise and are confounded by the nutritional status of the host. While PCNA protein levels measured by immunoblot hold promise as a simple, accurate and reproducible marker of liver regeneration, additional studies are required to determine if this is a valid marker of regenerative activity in various models of hepatic injury and in humans. Of the serum-based determinations: thymidine kinase, ornithine decarboxylase, fibronectin, alpha fetoprotein, and early pregnancy factor offer practical and non-invasive tools to monitor liver regeneration, but the sensitivity and specificity of these tests have yet to be determined. In conclusion, many tissue and serum-based methods have been employed in clinical and experimental studies to assess liver regeneration; however, a gold standard has yet to be identified. Because of the disadvantages inherent in each method, and until a new, more accurate marker is identified, clinicians and scientists should incorporate a minimum of two independent markers in studies of liver regeneration.
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PMID:Liver regeneration: methods for monitoring and their applications. 912 13

Expression of simian virus 40 T antigen (Tag) in the rod photoreceptors of transgenic mice leads to cell death that is completed by the end of the third week of postnatal development. To understand the mechanistic link between Tag expression and the death of the expressing photoreceptors, cell cycle activity was followed in a transgenic mouse family that expresses Tag directed by the mouse opsin promoter. Tag-expressing photoreceptors also expressed rhodopsin suggesting that these cells were differentiated. The presence of Tag in the photoreceptors induced the expression of both proliferating cell nuclear antigen (PCNA) and thymidine kinase (TK). The abnormally high levels of PCNA and TK continued until the complete disappearance of the cells expressing Tag. Photoreceptor cell death was also associated with continued DNA synthesis that ceased shortly after postnatal day 16. The specific loss of the rod photoreceptors that re-entered the cell cycle accounted entirely for the loss of photoreceptors from the outer nuclear layer. The antiproliferative nature of the mature retina is directly involved in the apoptotic death of photoreceptors expressing Tag.
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PMID:Unscheduled DNA replication precedes apoptosis of photoreceptors expressing SV40 T antigen. 922 76

The liver is of central importance in the metabolism of essential and toxic metals such as cadmium. Cadmium pretreatment suppressed the liver regenerative response to partial hepatectomy, due to the inhibition of the enzymatic activity of thymidine kinase. Exogenous putrescine administration has been reported to stimulate liver regeneration in animal models of acute liver failure. The purpose of this study was to document whether the administration of this polyamine enhances the impaired regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats. The intraperitoneal administration of putrescine (1 or 10 mg/kg body weight), at the time of surgery and at 4 and 8 hr postoperatively partly restored the suppressed hepatocyte deoxyribonucleic acid (DNA) biosynthesis and thymidine kinase activity in cadmium-pretreated partially hepatectomized rats. Mitotic activity and the percentage of hepatocytes positive for proliferating cell nuclear antigen nuclei were in accordance with the liver proliferative status. Our results showed that exogenous putrescine administration is able to improve diminished liver regeneration after partial hepatectomy in this animal model of acute hepatic injury.
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PMID:Putrescine administration reverses cadmium-associated inhibition of liver regeneration. 972 61

The effects of the energy and purine content in the diet on mucosal cell mitosis, function, and apoptosis in the small intestine of pigs were investigated in two experiments. In experiment I, three groups of five pigs were first fed a commercial diet that contained 9.1 MJ metabolizable energy (ME) per kilogram dry matter (DM) and 16.4% crude protein. It was followed by the experimental diets for 5 days each starting with an energy deficit (5.8 MJ ME/kg DM; 7% crude protein) followed by a high-energy diet with low purine content (14.1 MJ ME/kg DM; 13.6% crude protein; 460 mg purines/kg), or alternatively an isocaloric high-purine diet (2,160 mg purines/kg). During experimental periods, blood samples were drawn daily through catheters for insulin-like growth factor-I (IGF-I) determination. The animals were killed at the end of the corresponding feeding period and gut tissue samples were collected. In tissue samples, IGF-I and parameters for the characterization of mitosis (thymidine kinase [TK], proliferating-cell nuclear antigen [PCNA]) and differentiation (RNA content, alkaline phosphatase, sucrase) were measured. The degree of apoptosis was determined histologically. In experiment II, five pigs were fitted with simple T-cannula at the distal jejunum. They were fed the three experimental diets consecutively for 7 days each and sucrase and alkaline phosphatase were measured in digesta (four samples daily). IGF-I in blood but not in tissue clearly responded to the energy content of the diet with a decrease during the deficit and an increase in the two high-energy groups. However, purines had no additional effect on IGF-I. TK, PCNA, and gut weight showed an energy effect on mitosis, which was paralleled by increased peripheral IGF-I. Purines led to a further increase of mitosis, but IGF-I and gut weight were not increased. The degree of mitosis was correlated with higher activities of sucrase and alkaline phosphatase and also with the number of apoptotic cells. The enzyme activity increased from the deficit to the high-energy group and was further elevated due to purines. The results from experiment II also confirm these effects of energy and purines, because the activities of the enzymes in digesta decreased during energy deficit, but increased due to energy and in addition to purines.
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PMID:Effects of energy and purines in the diet on proliferation, differentiation, and apoptosis in the small intestine of the pig. 975 Dec 40

This report describes the evolution of hepatocytes isolated from 21-day fetuses and transplanted into spleens of Nagase analbuminemic rats which have negligible serum albumin levels due to a mutation affecting albumin mRNA processing. Albumin and alpha-fetoprotein expression, in addition to other parameters related to cellular proliferation status (thymidine kinase and proliferating cell nuclear antigen expression) were studied as indicative of the behavior and evolution of the cells. In recipient rats, only a few clusters of hepatocytes could be observed in the red pulp of the spleen 24 h after transplantation. The fetal hepatocytes migrated to the liver and could be seen in portal branches immediately after transplantation. Fifteen days later, albumin mRNA was detected in recipient livers and was expressed throughout the entire 3-month study. Alpha-fetoprotein was not detected. Cell proliferation was not relevant, although 3 months after transplantation, the proliferation rates appeared to show a tendency to increase. These data demonstrate that fetal hepatocytes transplanted into spleen migrate to liver, settle there and acquire an adult phenotype free of malignant transformation. Our study is a first step towards the thorough understanding of fetal hepatocyte transplantation. The next steps will involve in-depth studies of the possibilities of genetic manipulation to achieve a high degree of repopulation/expression, employing the least possible number of donor cells, and of how the cells reach the liver parenchyma, overcoming the endothelial barrier.
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PMID:Liver gene expression and increase in albumin synthesis by fetal hepatocytes transplanted into analbuminemic rats. 1106 65

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


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