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

Cancer Gene Therapy volume 17, pages 180–191 (2010)Cite this article

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.

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Abbreviations

CMV:

cytomegalovirus

FACS:

fluorescence-activated cell sorting

HER:

human embryonic retinoblast

LDU:

lethal dose50 units

mRFP:

monomeric red fluorescent protein

PSA:

prostate-specific antigen

PSES:

prostate-specific enhancing sequence

PSMA:

prostate-specific membrane antigen

PSRCA:

prostate-specific replication-competent adenovirus

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

vp:

virus particles

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Acknowledgements

This work was supported by the following funding sources, NIH F31 CA106215-01 (JA Jiménez), NIH R01 CA074042 (C Kao) and DOD W81XWH-04-1-0168 (C Kao).

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Authors and Affiliations

  1. Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

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

  2. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    J A Jiménez, C Kao & T A Gardner

  3. Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA

    J A Jiménez, X Li, C Kao & T A Gardner

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  1. J A Jiménez
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  2. X Li
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Correspondence to C Kao.

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Jiménez, J., Li, X., Zhang, YP. et al. Antitumor activity of Ad-IU2, a prostate-specific replication-competent adenovirus encoding the apoptosis inducer, TRAIL. Cancer Gene Ther 17, 180–191 (2010). https://doi.org/10.1038/cgt.2009.62

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