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


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 gamma-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.
Liu
Chunyan
C
James Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-2101, USA.
Zhang
Yonggang
Y
Liu
Minzhi Maggie
MM
Zhou
Haoming
H
Chowdhury
Wasim
W
Lupold
Shawn E
SE
Deweese
Ted L
TL
Rodriguez
Ronald
R
D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000727:Androgen-Binding Protein / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000502:physiology / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D006657:Histones / Q000378:metabolism; D008297:Male; D050130:Oncolytic Virotherapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy* / Q000821:virology; D011829:Radiation Dosage; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013997:Time Factors; D014779:Virus Replication / Q000502:physiology
D017500:Adenovirus E1A Proteins; D000727:Androgen-Binding Protein; D006657:Histones; D011944:Receptors, Androgen; C027519:probasin