A novel targeting modality to enhance adenoviral replication by vitamin D(3) in androgen-independent human prostate cancer cells and tumors.
We report the development of a novel replication-competent adenoviral vector, Ad-hOC-E1, containing a single bidirectional human osteocalcin (hOC) promoter to drive both the early viral E1A and E1B gene. This vector selectively replicated in OC-expressing but not non-OC-expressing cells, with viral replication enhanced at least 10-fold on vitamin D(3) exposure. Both the artificial TATA-box and hOC promoter element in this bidirectional promoter construct were controlled by a common OC regulatory element which selectively activated OC expression in cells. The expression ofE1A and E1B gene by Ad-hOC-E1 can be markedly induced by vitamin D(3). Unlike Ad-sPSA-E1, an adenoviral vector with viral replication controlled by a strong super prostate-specific antigen (sPSA) promoter which only replicates in PSA-expressing cells with androgen receptor (AR), Ad-hOC-E1 retarded the growth of both androgen-dependent and androgen-independent prostate cancer cells irrespective of their basal level of AR and PSA expression. A single i.v. administration of 2 x 10(9) plaque-forming units of Ad-hOC-E1 inhibited the growth of previously established s.c. DU145 tumors (an AR- and PSA-negative cell line). Viral replication is highly enhanced by i.p. administration of vitamin D(3). Ultimately, enhancing Ad-hOC-E1 viral replication by vitamin D(3) may be used clinically to treat localized and osseous metastatic prostate cancer in men.
Hsieh
Chia-Ling
CL
Department of Urology, Molecular Urology and Therapeutics Program, Emory University School of Medicine, Atlanta, GA 30322, USA. chsieh2@emory.edu
Yang
Ling
L
Miao
Li
L
Yeung
Fang
F
Kao
Chinghai
C
Yang
Hua
H
Zhau
Haiyen E
HE
Chung
Leland W K
LW
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002762:Cholecalciferol / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy / Q000821:virology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects*
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D012333:RNA, Messenger; D015675:Osteocalcin; D002762:Cholecalciferol