TY - JOUR
T1 - The human survivin promoter
T2 - A novel transcriptional targeting strategy for treatment of glioma
AU - Van Houdt, Winan J.
AU - Haviv, Yosef S.
AU - Lu, Baogen
AU - Wang, Minghui
AU - Rivera, Angel A.
AU - Ulasov, Ilya V.
AU - Lamfers, Martine L.M.
AU - Rein, Daniel
AU - Lesniak, Maciej S.
AU - Siegal, Gene P.
AU - Dirven, Clemens M.F.
AU - Curiel, David T.
AU - Zhu, Zeng B.
PY - 2006/4/1
Y1 - 2006/4/1
N2 - Object. 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.
AB - Object. 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.
KW - Adenoviral vector
KW - Conditionally replicative adenovirus
KW - Survivin gene
KW - Transcriptional targeting
KW - Tumor-specific promoter
UR - http://www.scopus.com/inward/record.url?scp=33645552398&partnerID=8YFLogxK
U2 - 10.3171/jns.2006.104.4.583
DO - 10.3171/jns.2006.104.4.583
M3 - Article
C2 - 16619663
AN - SCOPUS:33645552398
SN - 0022-3085
VL - 104
SP - 583
EP - 592
JO - Journal of Neurosurgery
JF - Journal of Neurosurgery
IS - 4
ER -