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Recombinant Adenovirus Mediated Prostate-Specific Enzyme Pro-Drug Gene Therapy Regulated by Prostate-Specific Membrane Antigen (PSMA) Enhancer/Promoter

HAO ZENG^*,

RUI HUANG

NI CHEN

QIAO ZHOU^,

From the ^* Department of Urology, West China Hospital, Sichuan University Sichuan, People's Republic of China; and Laboratory of Cell Apoptosis & Signaling Transduction and Laboratory of Oncology, the State Key Laboratory of Biotherapy, Sichuan University Sichuan, People's Republic of China.

Correspondence to: Qiao Zhou, Department of Urology, West China Hospital, Sichuan University, 37 Guoxue Xiang St, Chendu, Sichuan, 610041, People's Republic of China (e-mail: kucaizeng{at}163.com).

Gene directed enzyme pro-drug therapy (GDEPT) is one of the adjuvant therapeutic regimens for advanced prostate adenocarcinoma, and this research intended to explore how to apply targeting therapy of prostate adenocarcinoma under the mediation of a promoter/enhancer of prostate-specific membrane antigen (PSMA_EP) as a specific regulatory element. Recombinant adenoviruses (Ad-PSMA_E-P–enhanced green fluorescent protein [EGFP], Ad-CMV-EGFP, Ad-PSMA_E-P–CD, and Ad-CMV-CD) were constructed and could express cytosine deaminase (CD) or the EGFP reporter gene driven by a PSMA_EP or cytomegalovirus (CMV) promoter. LNCaP, CL-1, MCF-7, and A549 were infected with CD-produced recombinant adenoviruses and treated with pro-drug 5-fluorocytosine (5-FC) in vivo and vitro; then, the growth inhibition of the cells and the cell cycle variation were assessed by an [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay and flow cytometry. Growth suppression of the xenograft tumor was also adopted to evaluate the efficiency of the suicide system. Morphologic changes after treatment in vivo were assessed with hematoxylin and eosin staining. In the 4 examined cancer cell lines, PSMA-positive prostate cancer cells LNCap and CL-1 were exclusively sensitive to the Ad-PSMA_E-P–CD/5-FC system. The S phase of cell cycle arrest was thought to be involved in the cytotoxicity of 5-fluorouracil (5-FU) converted from 5-FC by CD. CL-1 implanted Athymic BALB/c mice showed growth inhibition of tumors when they were treated with the Ad-PSMA_E-P–CD/5-FC system without systemic conversion toxicity. The PSMA-based, CD-produced adenovirus, deserving further investigation in the future, might be a good candidate for targeting gene therapy of prostate adenocarcinoma.

     Key words: Cytosine deaminase, prostate adenocarcinoma