Oncolytic virotherapy for prostate cancer by E1A, E1B mutant adenovirus.
OBJECTIVE
To report our therapeutic results in prostate cancer using double-mutated adenovirus AxdAdB-3, which has a mutation of E1A and deletion of E1B 55KD. Advanced prostate cancer can harbor multiple genetic alterations, including p53 and Rb/E2F/p16, and is often refractory to hormonal ablation. Virotherapy has been used to target these genetic abnormalities using mutant oncolytic adenovirus for the management of other cancers.


METHODS
The cytopathic effects of AxdAdB-3 were examined in human prostate carcinoma cell lines (DU145, PC3, and LNCaP) and human normal prostate-derived cell lines (PrEC and PrSC) with AxE1AdB and dl922-947 by crystal violet staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The therapeutic efficacy of AxdAdB-3 for the treatment of prostate cancer was investigated in an orthotopic prostate cancer model established with DU145 in severe combined immunodeficiency (SCID) mice.


RESULTS
AxdAdB-3 induced potent cytopathic effects in the prostate cancer cell lines tested. AxdAdB-3 showed no cytotoxicity in the normal prostate-derived cell lines PrEC and PrSC. In vivo, AxdAdB-3 showed apparent antitumor effect in the orthotopic prostate cancer model and significantly improved survival.


CONCLUSIONS
These results suggest that AxdAdB-3 could be a promising tool for virotherapy against prostate cancer in patients with disease resistant to hormonal therapy.
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003588:Cytopathogenic Effect, Viral; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D050130:Oncolytic Virotherapy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy*; D011991:Receptors, Virus / Q000032:analysis
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus