State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
Previous studies have shown that Herpes Simplex Virus thymidine kinase (HSV-tk)/ganciclovir (GCV) were the most commonly used suicide gene therapy for prostate cancer with modest results. 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) was deliveried by prostate-specific, rat probasin-based promoter, ARR2PB. Following infection of various cell lines with ADV.ARR2 PB-PNP and administration of androgen analog, R1881, expression of PNP mRNA was detected; in vivo the antitumor effect of ARR2 PB-PNP/Fludara system as well as animal survival were monitored and analyzed.
After in vitro infection with ADV.ARR2 PB-PNP (MOI = 10), LNCaP cells were more sensitive to lower concentration Fludara (LD50 , ~0.1μg/ml) in the presence of R1881. Further, robust bystander effects following R1881/Fludara treatment were observed in LNCaP cells following 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 control groups, and the mice treated with our system had significantly prolonged survival with three of eight mice surviving up to the 160-day termination point as well as no systemic toxicity.
The ARR2 PB-PNP/Fludara system induced massive tumor cell death and prolonged life span without systemic cytotoxicity, therefore it might be a more attractive strategy for suicide gene therapy of prostate cancer.
Written by:
Xie X, Guo J, Kong Y, Xie GX, Li L, Lv N, Xiao X, Tang J, Wang X, Liu P, Yang M, Xie Z, Wei W, Xie X. Are you the author?
Reference: J Gene Med. 2011 Oct 18. Epub ahead of print.
doi: 10.1002/jgm.1620
PubMed Abstract
PMID: 22009763
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