Abstract
Immunotoxin therapy is a promising molecular cancer treatment strategy. Its main advantage is seletive cytotoxicity towards tumor cells and minimal toxicity in normal tissues. However, a short half-life and rapid clearance severely hampers its clinical application. We report here a novel genetic approach in which a recombinant adenovirus vector was used to deliver an immunotoxin gene e23(scFv)-PE40 targeted to the oncogene c-erbB-2 (also known as Her2/neu). This vector, when combined with a low dose of a conditionally replicative adenovirus vector (CRAd), has enhanced tumor-killing ability either alone or in combination with the chemotherapeutic agent etoposide. Our data show that low-dose CRAd facilitated the replication of replication-deficient Ad-e23(scFv)-PE40 up to 6–20 times and the transcription of e23(scFv)-PE40 gene up to 12 times. Moreover, etoposide increased the e23(scFv)-PE40 transcription up to 8.5 times. Furthermore, we show that systemic application of Ad-e23(scFv)-PE40 and enhanced expression of the immunotoxin gene was well tolerated as determined by serum biochemical markers and histological examination of most vital organs. Taken together, our data support a novel genetic immunotoxin delivery approach that may yield enhanced efficacy against a variety of Her2/neu-expressing tumors.
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Abbreviations
- Ad:
-
adenovirus
- CRAd:
-
conditionally replicative competent adenovirus
- FBS:
-
fetal bovine serum
- MOI:
-
multiplicity of infection
- PE:
-
Pseudomonas exotoxin
- scFv:
-
single-chain fragment variable
- TUNEL:
-
terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.
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Acknowledgements
We thank Dr Siyi Chen for the provision of e23(scFv)-PE40-bearing plasmids and Dr Aǹgang Yang for the provision of SK-BR-3 and SGC-7901cell lines. We are grateful for the technical assistant by Fang Wei, Xiafang Chen, Miaoying Yi, Yuhua Tian, Ping Xu, Kuangchen Xie and Yuanshan Lu in First People's Hospital, Shanghai Jiaotong University, for the statistic analyses by Yongbing Xiang and Yuting Tan in the Cancer Institute of Shanghai Jiaotong University. This work was supported by Grant of National Basic Research Project of China (2004CB518804), National Natural Science Foundation for Outstanding Youth (30325043, 30428015).
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Supplementary Information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt)
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Liu, X., Wu, J., Zhang, S. et al. Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy. Cancer Gene Ther 16, 861–872 (2009). https://doi.org/10.1038/cgt.2009.30
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DOI: https://doi.org/10.1038/cgt.2009.30