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Antitumor activity of Ad-IU2, a prostate-specific replication-competent adenovirus encoding the apoptosis inducer,
1Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
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.
Insights
This study demonstrates Ad-IU2, a novel adenovirus, effectively targets and eliminates androgen-independent prostate cancer cells by delivering tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). It shows significant preclinical antitumor efficacy and potential for clinical application.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Molecular oncology
Background:
- Prostate cancer, particularly androgen-independent forms, presents a significant therapeutic challenge.
- Developing targeted therapies that selectively eliminate cancer cells while sparing normal tissues is crucial.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising pro-apoptotic agent.
Purpose of the Study:
- To evaluate the preclinical efficacy of Ad-IU2, a prostate-specific replication-competent adenovirus (PSRCA) engineered to deliver TRAIL.
- To assess the selective tumor-killing ability and potential for overcoming TRAIL resistance in prostate cancer models.
- To investigate the in vivo antitumor activity of Ad-IU2 against androgen-independent prostate cancer xenografts.
Main Methods:
- Ad-IU2 was designed with prostate-specific enhancing sequences (PSES) for transcriptional control of adenoviral genes and TRAIL expression.
- Apoptosis induction and viral replication were assessed in prostate-specific antigen (PSA)/prostate-specific membrane antigen (PSMA)-positive and negative cell lines.
- In vitro cytotoxicity, TRAIL resistance reversal, and bystander effects were evaluated.
- In vivo antitumor efficacy was determined using subcutaneous CWR22rv xenografts in mice.
Main Results:
- Ad-IU2 demonstrated a fivefold greater induction of apoptosis in PSA/PSMA-positive prostate cancer cells compared to an oncolytic adenoviral control.
- The agent reversed TRAIL resistance in LNCaP cells and showed superior killing efficiency at lower doses in targeted cells.
- Ad-IU2 exhibited a TRAIL-mediated bystander effect and significantly suppressed tumor growth in vivo (3.1-fold vs 17.1-fold growth).
- Cytotoxic effects were specific to prostate cancer cells, with no observed toxicity in non-prostatic cells.
Conclusions:
- Ad-IU2 exhibits significant preclinical antitumor efficacy against androgen-independent prostate cancer.
- The engineered PSRCA effectively delivers TRAIL selectively to prostate cancer cells, overcoming resistance mechanisms.
- Ad-IU2 holds promise as a potential clinical therapeutic agent for prostate cancer treatment.
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