Journal of Andrology
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Published-Ahead-of-Print May 23, 2007, DOI:10.2164/jandrol.107.002519

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Recombinant adenovirus mediated prostate specific enzyme pro-drug gene therapy regulated by prostate specific membrane antigen PSMAEP enhancer/promoter

Hao Zeng , qiang wei , rui huang , ni chen , qiang dong , yuru yang , and qiao zhou *

* To whom correspondence should be addressed. E-mail: kucaizeng{at}163.com.

Purpose Gene directed enzyme pro-drug therapy(GDEPT) is one of adjuvant therapeutic regimens for advanced prostate adenocarcinoma, and this research intended to explore how to apply targeting therapy of prostate adenocarcinoma under mediation of promoter/enhancer of prostate-specific membrane antigen(PSMAEP ) as specific regulatory element. Materials and Methods Recombinant adenoviruses (Ad-PSMAE-P"CEGFP, Ad-CMV-EGFP, Ad-PSMAE-P"CCD and Ad-CMV-CD) were constructed and could express cytosine deaminase (CD) or EGFP reporter gene driven by PSMAEP 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 cells growth inhibition and cell-cycle variation were assessed by using MTT assay and flow cytometry. Growth suppression of xenograft tumor was also adopted to evaluate the efficiency of the suicide system. Morphological changes after treatment in vivo were assessed by using hematoxylin and eosine staining. Results In the four examined cancer cell lines, PSMA positive prostate cancer cells LNCap and CL-1 were exclusively sensitive to Ad-PSMAE-PCCD/5-FC system. S-phase of cell cycle arrest was considered to be involved in cytotoxicity of 5-fluorouracil (5-FU) converted from 5-FC by CD. CL-1 implanted Athymic BALB/c mice showed growth inhibition of tumor when they were treated with Ad-PSMAE-PCCD/5-FC system without systemic conversion toxicity. Conclusions 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: Hormone • Prostate • Adenovirus • Cytosine deaminase • Prostate-specific membrane antigen promoter/enhancer






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Copyright © 2007 by The American Society of Andrology.