Comparative evaluation of survivin, midkine and CXCR4 promoters for transcriptional targeting of glioma gene therapy.
Cancer Biol Ther
; 6(5): 679-85, 2007 May.
Article
em En
| MEDLINE
| ID: mdl-17404502
ABSTRACT
OBJECTIVE:
Transcriptional targeting is a key strategy to enhance therapeutic efficacy of gene therapy applications. In the context of oncolytic virotherapy, transcriptional promoter elements are used from genes that are over expressed in a variety of malignant cancers. In the present study, we examined the feasibility of transcriptional targeting to glioma cells by comparing the activity of survivin, midkine, and CXCR4 tumor-specific promoters.METHODS:
To evaluate the expression level of several glioma related genes, we performed quantitative RT-PCR analyses on samples obtained from cell lines and patients. To determine specific level of gene expression mediated by selective promoter elements, we measured luciferase expression in glioma samples transduced with replication deficient adenoviral vectors. Finally, we incorporated the optimal promoters into a conditionally replicative adenoviral vector, CRAd-5/3, and examined the cytopathic effect in vitro.RESULTS:
The survivin promoter demonstrated the highest level of mRNA expression in primary tumor samples and cell lines. Transcriptional targeting was confirmed by infection of glioma cells with an adenovirus expression vector containing a surviving-driven luciferase reporter gene. Of the tested promoters, minimal level of survivin activity was detected in normal human liver and brain. A novel vector, CRAd-survivin5/3, with E1a under the control of the survivin promoter, exhibited enhanced cytopathic effect in vitro.CONCLUSIONS:
Our data demonstrate that the survivin promoter element is very active in glioma samples and has low activity in normal human brain and liver. A novel oncolytic virus, CRAd-survivin-5/3, was effective against a panel of glioma cell lines in vitro. Our results suggest that employing the survivin promoter element in the context of CRAd-5/3 may present a new opportunity for the development of glioma specific oncolytic vectors.
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Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
/
Terapia Genética
/
Citocinas
/
Regiões Promotoras Genéticas
/
Receptores CXCR4
/
Glioma
/
Proteínas Associadas aos Microtúbulos
/
Proteínas de Neoplasias
Tipo de estudo:
Evaluation_studies
Limite:
Humans
Idioma:
En
Revista:
Cancer Biol Ther
Assunto da revista:
NEOPLASIAS
/
TERAPEUTICA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos