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

Abstract

In this study, we investigated 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), expression of TRAIL as well adenoviral replication was limited to prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA)-positive cells. Ad-IU2 induced 5-fold 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 exhibited superior killing efficiency in PSA/PSMA-positive prostate cancer cells at doses 5- to 8-fold lower than required by a PSRCA to produce a similar effect. This cytotoxic effect was not observed in non-prostatic cells, however. 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 to a PSRCA at six weeks post-treatment (3.1- vs. 17.1-fold growth of tumor). This study demonstrates the potential clinical utility of a PSRCA armed with an apoptosis-inducing ligand.