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)

It is important to develop a system to express therapeutic genes in tumor cells with sufficient selectivity for cancer gene therapy. Midkine (MK) is a newly identified heparin-binding growth factor that is transiently expressed in the early stages of retinoic acid-induced differentiation of embryonal carcinoma cells. It has been reported that many human malignant tumors express high levels of MK mRNA or protein. However, no MK expression is detected in human or mouse liver. These interesting features of MK led us to examine the MK promoter as a candidate for tumor-specific gene expression. We thus developed new recombinant adenoviral (Ad) vectors containing either luciferase reporter gene (AdMKLuc) or herpes simplex thymidine kinase gene (AdMKTK) under the control of the human MK promoter. AdMKLuc achieved relatively high activity in Wilms' tumor (G-401) and neuroblastoma (SK-N-SH) cell lines. In addition, AdMKTK induced marked cell death in response to ganciclovir (GCV) in these same lines. Conversely, very low activity of the MK promoter was observed in mouse liver in vivo compared with the cytomegalovirus promoter. Importantly, AdMKTK + GCV did not induce liver toxicity, whereas substantial toxicity was seen with AdCMVTK + GCV treatment. On the basis of these findings, we conclude that the MK promoter is a candidate tumor-specific promoter for Wilms' tumor or neuroblastoma.
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PMID:Midkine promoter-based adenoviral vector gene delivery for pediatric solid tumors. 1096 65

A selective expression of suicide gene(s) in tumor cells should produce a preferential cytotoxic effect on tumors. Promoter region(s) of a gene that is expressed in tumors but not in normal tissues can be useful for tumor-specific transcription of a suicide gene. Midkine (MK), a growth/differentiation factor, is expressed predominantly in various types of human tumors, whereas its expression in adult normal tissues is highly restricted. In our study, we showed that a 2.3-kb fragment of genomic DNA in the 5' upstream region of the MK gene could activate transcription of a fused reporter gene in MK-positive cells but not in MK-negative cells. Efficiency of the cis-acting sequence to permit expression of an exogenous gene in tumor cells was comparable with that of the SV40 promoter. Regulated expression of the herpes simplex virus-thymidine kinase (HSV-TK) gene under the control of the MK promoter conferred increased sensitivity to ganciclovir (GCV) on MK-positive tumor cells. Administration of GCV into nude mice that were implanted with MK-positive tumor cells that expressed the HSV-TK gene under the control of the MK promoter could suppress the subsequent tumor growth. Expression of therapeutic genes restricted to tumors can be achieved by the use of the putative cis-acting MK promoter.
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PMID:Expression of herpes simplex virus-thymidine kinase gene controlled by a promoter region of the midkine gene confers selective cytotoxicity to ganciclovir in human carcinoma cells. 1126 87

Midkine (MK), a heparin binding growth factor, and cyclooxygenase-2 (COX-2), a key enzyme in the conversion of arachidonic acid to prostaglandin, are both up-regulated at the mRNA or protein level in many human malignant tumors. Here, we investigated the tumor specificity of both MK and COX-2 promoters in human pancreatic cancer, with the aim to improve the selectivity of therapeutic gene expression. We constructed recombinant adenoviral (Ad) vectors containing either the luciferase (Luc) reporter gene under the control of the COX-2 or MK promoter or the herpes simplex virus thymidine kinase (HSV Tk) gene under the control of the COX-2 promoter and compared the expression with the cytomegalovirus (CMV) promoter. AdMKLuc achieved moderate to relatively high activity upon infection to both primary and established pancreatic carcinoma cells. Of the two COX-2 promoter regions (COX-2M and COX-2L), both revealed a high activity in primary pancreatic carcinoma cells, whereas in the established pancreatic carcinoma cell lines, COX-2L has an approximately equal high activity compared to CMV. In addition, both AdCOX-2M Tk and AdCOX-2L Tk induced marked cell death in response to ganciclovir (GCV) in three of four established pancreatic carcinoma cell lines. From these results, and because it has been reported that AdMKTk and AdCOX-2L Tk in combination with GCV did not reveal significant liver toxicity, we conclude that the MK as well as the COX-2 promoters are promising tumor-specific promoters for Ad vector-based gene therapy of pancreatic cancer.
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PMID:Midkine and cyclooxygenase-2 promoters are promising for adenoviral vector gene delivery of pancreatic carcinoma. 1178 62

Midkine (MK) is preferentially expressed in a number of human tumors, while the expression in adult normal tissues is restricted. Previous studies showed that a 2.3-kb regulatory region of the human MK gene could selectively activate a linked suicide gene in tumors. In this study, we explored the minimal promoter region using genomic fragments deleted from the 5'-upstream side and analyzed the mechanism of the preferential activation in tumor cells. Luciferase assays showed that the 0.3-kb fragment from the transcription start site contained a cis-acting element(s) for the promoter activity. Expression of the herpes simplex virus-thymidine kinase gene under the control of the MK promoter followed by ganciclovir administration produced antitumor effects in vivo. Transfection of the wild-type p53 gene into the immortalized fibroblasts bearing mutated p53 and tumor cell lines, which induced cell cycle arrest, decreased the MK promoter-mediated transcription more effectively than the SV40 or the cytomegalovirus promoter-mediated transcription. The P53-mediated downregulation of the MK promoter activity was stronger in p53-defective tumors than in wild-type p53-bearing tumors. Moreover, the MK promoter-mediated luciferase activity was greater in p53-deficient mouse embryonic fibroblasts than in those bearing wild-type p53 gene. The transcriptional activity of the MK promoter could be regulated by cell growth and in part P53-dependent pathways.
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PMID:Cell growth- and P53-dependent transcriptional activity of the midkine promoter confers suicide gene expression in tumor cells. 1288 97