Evaluation of continuous low dose rate versus acute single high dose rate radiation combined with oncolytic viral therapy for prostate cancer

Abstract

Purpose: Conditionally Replicative Adenovirus (CRAd) has been previously demonstrated to augment the activity of radiation, resulting in synergy of cell kill. However, previous models combining radiation with CRAd have not focused on the methods of radiation delivery.

Materials and methods: We model the combination of a novel prostate-specific CRAd, Ad5 PSE/PBN E1A-AR (Ad5: adenovirus 5; PSE: prostate-specific enhancer; PBN: rat probasin promoter; E1A: early region 1A; AR: androgen receptor), with radiation delivered both acutely and continuously, in an effort to better mimic the potential clinical modes of prostate cancer radiotherapy.

Results: We demonstrate that pre-treatment of cells with acute single high dose rate (HDR) radiation 24 hours prior to viral infection results in significantly enhanced viral replication and virus-mediated cell death. In addition, this combination causes increased level of γ-H2AX (Phosphorylated histone protein H2AX on serine 139), a marker of double-stranded DNA damage and an indirect measure of nuclear fragmentation. In contrast, continuous low dose rate (LDR) radiation immediately following infection of the same CRAd results in no enhancement of viral replication, and only additive effects in virus-mediated cell death.

Conclusions: These data provide the first direct assessment of the real-time impact of radiation on viral replication and the first comparison of the effect of radiation delivery on the efficacy of CRAd virotherapy. Our data demonstrate substantial differences in CRAd efficacy based on the mode of radiation delivery.

Keywords:

• adenocarcinoma of prostate
• radiosensitisation
• oncolytic viral therapy
• prostate-specific conditionally replicative adenovirus
• acute single high dose rate radiation
• continuous low dose rate radiation

Acknowledgements

The authors would like to thank Marikki Laiho, MD, PhD, Danny Song, MD, and Gary Ketner, PhD (The Johns Hopkins University School of Medicine) for helpful discussions and advices, and Tarana Kudrolli, MS, and Nasir Hoti, PhD (The Johns Hopkins University School of Medicine) for technical assistance during the course of these studies. This project has been supported in whole or in part through the Prostate Cancer SPORE (5 P50 CA58236), DOD, Prostate Cancer Consortium (DAMD17-03-2-033), and Prostate Cancer Foundation (private philanthropy).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.