title: Oncolytic virotherapy for osteosarcoma using midkine promoter-regulated adenoviruses.
abstract: Oncolytic virotherapy using adenoviruses has potential therapeutic benefits for a variety of cancers. We recently developed MOA5, a tumor-specific midkine promoter-regulated oncolytic vector based on human adenovirus serotype 5 (Ad5). We modified the binding tropism of MOA5 by replacing the cell-binding domain of the Ad5 fiber knob with that from another adenovirus serotype 35 (Ad35); the resulting vector was designated MOA35. Here we evaluated the therapeutic efficacies of MOA5 and MOA35 for human osteosarcoma. Midkine mRNA expression and its promoter activity was significantly high in five human osteosarcoma cell lines, but was restricted in normal cells. Very low levels of adenovirus cellular receptor coxsackievirus/adenovirus receptor (CAR) (Ad5 receptor) expression were observed in MNNG-HOS and MG-63 cells, whereas high levels of CAR expression were seen in the other osteosarcoma cell lines. By contrast, CD46 (Ad35 receptor) was highly expressed in all osteosarcoma cell lines. Infectivity and in vitro cytocidal effect of MOA35 was significantly enhanced in MNNG-HOS and MG-63 cells compared with MOA5, although the cytocidal effects of MOA5 were sometimes higher in high CAR-expressing cell lines. In MG-63 xenograft models, MOA35 significantly enhanced antitumor effects compared with MOA5. Our findings indicate that MOA5 and MOA35 allow tailored virotherapy and facilitate more effective treatments for osteosarcoma.
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takagi-Kimura
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamano
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tagawa
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kubo
mesh_terms: D000257:Adenoviridae Infections / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000235:genetics; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000078792:Midkine; D009414:Nerve Growth Factors / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010006:Osteoblasts / Q000821:virology; D012516:Osteosarcoma / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; C066254:MDK protein, human; D009414:Nerve Growth Factors; D011991:Receptors, Virus; C085301:adenovirus receptor; D000078792:Midkine