title: Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs.
abstract: Although previous studies modified two components of conditionally replicating adenoviruses (CRAs), which selectively replicate in and kill cancer cells, the most accurate ways to achieve increased cancer specificity (that is, safety) without reducing the anticancer (that is, therapeutic) effects are unknown. Here, we generated two types of survivin-responsive m-CRAs (Surv.m-CRAs), Surv.m-CRA-CMVp and Surv.m-CRA-OCp, which use two and three different mechanisms to target cancer, that is, early region 1A (E1A) regulated by the survivin promoter and mutated E1BΔ55K regulated by the ubiquitously active cytomegalovirus promoter and cancer/tissue-specific osteocalcin promoter, respectively, and carefully examined their safety and anticancer effects. Endogenous osteocalcin mRNA was expressed and further enhanced by vitamin D(3) in all osteosarcoma and prostate cancer cell lines and human osteoblasts, but not in human fibroblasts. The osteocalcin promoter activity was weak even with vitamin D(3) treatment in these osteocalcin-expressing cancers, leading to low E1BΔ55K expression after Surv.m-CRA-OCp infection. Nevertheless, Surv.m-CRA-OCp had significantly increased cancer specificity without reduced anticancer effects in both in vitro and in vivo experiments. The unexpected but favorable fact that strong activity of an altered E1B promoter is unnecessary indicates that the majority of cancer/tissue-specific promoters may be used to generate ideal m-CRAs and will advance the development of m-CRA-based cancer therapies.
authors.affiliation: 1] Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Nagano
authors.forename: J
authors.initials: J
authors.lastname: Kamizono
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: S
authors.initials: S
authors.lastname: Komiya
authors.forename: K-i
authors.initials: KI
authors.lastname: Kosai
mesh_terms: D017501:Adenovirus E1B Proteins / Q000235:genetics* / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D000077022:Survivin; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D017501:Adenovirus E1B Proteins; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D000077022:Survivin; D015675:Osteocalcin