Transcriptional regulatory regions of the survivin gene activate an exogenous suicide gene in human tumors and enhance the sensitivity to a prodrug.

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.

[1]  Fengzhi Li,et al.  Induction of Survivin Expression by Taxol (Paclitaxel) Is an Early Event, Which Is Independent of Taxol-mediated G2/M Arrest* , 2004, Journal of Biological Chemistry.

[2]  B. Liu,et al.  Transcriptional targeting of tumors with a novel tumor-specific survivin promoter , 2004, Cancer Gene Therapy.

[3]  S. Kyo,et al.  Telomerase-Specific Replication-Selective Virotherapy for Human Cancer , 2004, Clinical Cancer Research.

[4]  D. Altieri.  Survivin, versatile modulation of cell division and apoptosis in cancer , 2003, Oncogene.

[5]  M. Ebara,et al.  A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the α-fetoprotein promoter , 2003, British Journal of Cancer.

[6]  M. Tagawa,et al.  Regulatory regions of growth-related genes can activate an exogenous gene of the alpha-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells. , 2003, Anticancer research.

[7]  L. Philipson,et al.  Expression of the coxsackie and adenovirus receptor in human astrocytic tumors and xenografts , 2003, International journal of cancer.

[8]  M. Murphy,et al.  Activation of cancer-specific gene expression by the survivin promoter. , 2002, Journal of the National Cancer Institute.

[9]  R. Alemany,et al.  Characterization of the cyclooxygenase-2 promoter in an adenoviral vector and its application for the mitigation of toxicity in suicide gene therapy of gastrointestinal cancers. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  A. Nakagawara,et al.  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 , 2001, International journal of cancer.

[11]  D. Nettelbeck,et al.  Gene therapy: designer promoters for tumour targeting. , 2000, Trends in genetics : TIG.

[12]  D. Altieri,et al.  Transcriptional analysis of human survivin gene expression. , 1999, The Biochemical journal.

[13]  T. Evans,et al.  Cyclooxygenase-2 as a therapeutic target , 1998, Inflammation Research.

[14]  J. Shay,et al.  Telomerase activity in human cancer. , 1996, Current opinion in oncology.

[15]  H. Nakabayashi,et al.  A position-dependent silencer plays a major role in repressing alpha-fetoprotein expression in human hepatoma , 1991, Molecular and cellular biology.