Both investigators contributed equally and should be considered as senior authors.
Targeted expression of Escherichia coli purine nucleoside phosphorylase and Fludara® for prostate cancer therapy
Article first published online: 22 DEC 2011
Copyright © 2011 John Wiley & Sons, Ltd.
The Journal of Gene Medicine
Volume 13, Issue 12, pages 680–691, December 2011
How to Cite
Xie, X., Guo, J., Kong, Y., Xie, G. X., Li, L., Lv, N., Xiao, X., Tang, J., Wang, X., Liu, P., Yang, M., Xie, Z., Wei, W. and Xie, X. (2011), Targeted expression of Escherichia coli purine nucleoside phosphorylase and Fludara® for prostate cancer therapy. J. Gene Med., 13: 680–691. doi: 10.1002/jgm.1620
- Issue published online: 22 DEC 2011
- Article first published online: 22 DEC 2011
- Accepted manuscript online: 18 OCT 2011 07:11AM EST
- Manuscript Accepted: 10 OCT 2011
- Manuscript Revised: 20 SEP 2011
- Manuscript Received: 26 JUL 2011
- Major Program of National Natural Science Foundation of China. Grant Number: 31030061
- Doctoral Fund of Ministry of Education of China. Grant Number: 20090171110078
- Natural Science Foundation of Guangdong Province, China. Grant Number: 9151008901000124
Vol. 14, Issue 3, 217, Article first published online: 20 MAR 2012
- E. coli PNP;
- prostate cancer;
- probasin promoter;
- transcriptional targeting
Previous studies have shown that Herpes Simplex Virus thymidine kinase (HSV-tk)/ganciclovir (GCV) comprised the most commonly used suicide gene therapy for prostate cancer, with modest results being obtained. However, novel suicide genes, such as Escherichia coli purine nucleoside phosphorylase (PNP), have been utilized to demonstrate more potent tumor killing and an enhanced bystander effect on local, non-expressing cells compared to HSV-tk.
PNP/fludarabine (Fludara®; fludarabine phosphate; Berlex Labs, Richmond, CA, USA) was deliveried by prostate-specific, rat probasin-based promoter, ARR2PB. After infection of various cell lines with ADV.ARR2PB-PNP and administration of androgen analog, R1881, expression of PNP mRNA was detected; in vivo, the antitumor effect of the ARR2PB-PNP/Fludara system was monitored and analyzed, as well as animal survival.
After in vitro infection with ADV.ARR2PB-PNP (multiplicity of infection = 10), LNCaP cells were more sensitive to a lower concentration Fludara (LD50, approximately 0.1 µg/ml) in the presence of R1881. Furthermore, robust bystander effects after R1881/Fludara treatment were observed in LNCaP cells after infection with bicistronic vector ADV.ARR2PB/PNP-IRES-EGFP in contrast to a much weaker effect in cells treated with ADV.CMV-HSV-tk/GCV. In vivo, tumor size in the ADV.ARR2PB-PNP/Fludara treatment group was dramatically smaller than in the control groups, and the mice treated with our system had a significantly prolonged survival, with three of eight mice surviving up to the 160-day termination point, as well as no systemic toxicity.
The ARR2PB-PNP/Fludara system induced massive tumor cell death and a prolonged life span without systemic cytotoxicity; therefore, it might be a more attractive strategy for suicide gene therapy of prostate cancer. Copyright © 2011 John Wiley & Sons, Ltd.