Abstract
Selective expression of a therapeutic gene in tumors contributes to the efficacy and the safety of cancer therapy. Regulatory regions of genes that are preferentially expressed in tumors have been examined. The regions of the survivin gene exhibited the greatest activity in human hepatocellular carcinoma cells. Deletion of the survivin regulatory region from the 5'-side demonstrated that the 0.5 kb and the 1.4 kb fragments possessed a strong promoter activity with relative tumor specificity. Human tumors transfected with the herpes simplex virus-thymidine kinase gene, that was powered by the survivin region, became susceptible to a prodrug, ganciclovir. Although survivin gene expression was up-regulated in the G2/M-phase of the cell cycle, taxol or vincristine treatment, which induce cell cycle arrest at the M-phase, did not enhance the transcriptional activity of the survivin promoter. These data collectively suggest that the survivin regulatory region induces the expression of an exogenous gene in tumors, but the transcriptional activity is not directly linked with M-phase induction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Line, Tumor
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Cyclooxygenase 2 / genetics
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Ganciclovir / pharmacokinetics
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Ganciclovir / pharmacology*
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Gene Expression Regulation, Neoplastic
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Genetic Therapy / methods*
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Genetic Vectors / genetics
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Humans
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Inhibitor of Apoptosis Proteins
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics*
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Neoplasms / drug therapy
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Neoplasms / genetics*
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Neoplasms / metabolism
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Neoplasms / therapy*
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Paclitaxel / pharmacology
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology*
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Promoter Regions, Genetic
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Simplexvirus / enzymology
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Simplexvirus / genetics
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Survivin
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Telomerase / genetics
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Thymidine Kinase / genetics
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Thymidine Kinase / metabolism
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Transcriptional Activation
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Vincristine / pharmacology
Substances
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Prodrugs
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Survivin
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Vincristine
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Cyclooxygenase 2
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Thymidine Kinase
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TERT protein, human
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Telomerase
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Paclitaxel
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Ganciclovir