title: The human survivin promoter: a novel transcriptional targeting strategy for treatment of glioma.
abstract: OBJECTIVE
  Malignant brain tumors have been proved to be resistant to standard treatments and therefore require new therapeutic strategies. Survivin, a recently described member of the inhibitor of apoptosis protein family, is overexpressed in several human brain tumors, primarily gliomas, but is downregulated in normal tissues. The authors hypothesized that the expression of tumor-specific survivin could be exploited for treatment of gliomas by targeting the tumors with gene therapy vectors.
  
  
  METHODS
  Following confirmation of survivin expression in glioma cell lines, an adenoviral vector containing the survivin promoter and the reporter gene luciferase was tested in established and primary glioma cells, normal astrocytic cells, and normal human brain tissues. High levels of reporter gene expression were observed in established tumor and primary tumor cell lines and low levels of expression in astrocytes and normal human brain tissue. To test oncolytic potency, the authors constructed survivin promoter-based conditionally replicative adenoviruses (CRAds), composed of survivin promoter-regulated E1 gene expression and an RGD-4C capsid modification. These CRAds could efficiently replicate within and kill a variety of established glioma tumor cells, but were inactive in a normal human liver organ culture. Finally, survivin promoter-based CRAds significantly inhibited the growth of glioma xenografts in vivo.
  
  
  CONCLUSIONS
  Together these data indicate that the survivin promoter is a promising tumor-specific promoter for transcriptional targeting of adenovirus-based vectors and CRAds for malignant gliomas. The strategy of using survivin-CRAds may thus translate into an experimental therapeutic approach that can be used in human clinical trials.
authors.affiliation: Department of Neurosurgery, VU Universiteit Medische Center, Amsterdam, The Netherlands.
authors.forename: Winan J
authors.initials: WJ
authors.lastname: Van Houdt
authors.forename: Yosef S
authors.initials: YS
authors.lastname: Haviv
authors.forename: Baogen
authors.initials: B
authors.lastname: Lu
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rivera
authors.forename: Ilya V
authors.initials: IV
authors.lastname: Ulasov
authors.forename: Martine L M
authors.initials: ML
authors.lastname: Lamfers
authors.forename: Daniel
authors.initials: D
authors.lastname: Rein
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Clemens M F
authors.initials: CM
authors.lastname: Dirven
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Zeng B
authors.initials: ZB
authors.lastname: Zhu
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000077022:Survivin; D014158:Transcription, Genetic / Q000235:genetics*; D014183:Transplantation, Heterologous; D014779:Virus Replication / Q000235:genetics
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin