The human survivin promoter: a novel transcriptional targeting strategy for treatment of glioma.
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.
Van Houdt
Winan J
WJ
Department of Neurosurgery, VU Universiteit Medische Center, Amsterdam, The Netherlands.
Haviv
Yosef S
YS
Lu
Baogen
B
Wang
Minghui
M
Rivera
Angel A
AA
Ulasov
Ilya V
IV
Lamfers
Martine L M
ML
Rein
Daniel
D
Lesniak
Maciej S
MS
Siegal
Gene P
GP
Dirven
Clemens M F
CM
Curiel
David T
DT
Zhu
Zeng B
ZB
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
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin