Antitumor activity of Ad-IU2, a prostate-specific replication-competent adenovirus encoding the apoptosis inducer, TRAIL

J. A. Jiménez, X. Li, Y. P. Zhang, K. H. Bae, Y. Mohammadi, P. Pandya, C. Kao, T. A. Gardner

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

In this study, we analyzed the preclinical utility and antitumor efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) delivered by Ad-IU2, a prostate-specific replication-competent adenovirus (PSRCA), against androgen-independent prostate cancer. Through transcriptional control of adenoviral early genes E1a, E1b and E4, as well as TRAIL by two bidirectional prostate-specific enhancing sequences (PSES), the expression of TRAIL and adenoviral replication was limited to prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA)-positive cells. Ad-IU2 induced fivefold greater apoptosis selectively in PSA/PSMA-positive CWR22rv and C4-2 cells than an oncolytic adenoviral control. Furthermore, prolonged infection with Ad-IU2 reversed TRAIL resistance in LNCaP cells. Ad-IU2 showed superior killing efficiency in PSA/PSMA-positive prostate cancer cells at doses five-to eight-fold lower than required by a PSRCA to produce a similar effect; however, this cytotoxic effect was not observed in non-prostatic cells. As an enhancement of its therapeutic efficacy, Ad-IU2 exerted a TRAIL-mediated bystander effect through direct cell-to-cell contact and soluble factors such as apoptotic bodies. In vivo, Ad-IU2 markedly suppressed the growth of subcutaneous androgen-independent CWR22rv xenografts compared with a PSRCA at 6 weeks after treatment (3.1-vs 17.1-fold growth of tumor). This study shows the potential clinical utility of a PSRCA armed with an apoptosis-inducing ligand.

Original languageEnglish (US)
Pages (from-to)180-191
Number of pages12
JournalCancer gene therapy
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2010

Keywords

  • Adenovirus
  • Prostate cancer
  • PSES
  • TRAIL

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

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