Targeted expression of Escherichia coli purine nucleoside phosphorylase and Fludara® for prostate cancer therapy

Authors

  • Xinhua Xie,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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    • Both investigators contributed equally and should be considered as senior authors.

  • Jiaoli Guo,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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    • Both investigators contributed equally and should be considered as senior authors.

  • Yanan Kong,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Gene Xianquan Xie,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Laishen Li,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Ning Lv,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Xiangsheng Xiao,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Jun Tang,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Xi Wang,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Peng Liu,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Mingtian Yang,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Zeming Xie,

    1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
    2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Weidong Wei,

    Corresponding author
    1. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
    • State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
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  • Xiaoming Xie

    Corresponding author
    1. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
    • State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Errata

This article is corrected by:

  1. Errata: Erratum: Targeted expression of Escherichia coli purine nucleoside phosphorylase and Fludara® for prostate cancer therapy Volume 14, Issue 3, 217, Article first published online: 20 March 2012

X. Xie or W. Wei, State Key Laboratory of Oncology in South China, Department of Breast Oncology, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, People's Republic of China.

E-mail: xiexm@sysucc.org.cn or weiwd@sysucc.org.cn

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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