title: Oncolytic virotherapy as a novel strategy for pancreatic cancer.
abstract: We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication-selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.
authors.affiliation: Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. msun-thk@umin.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.forename: Masaru
authors.initials: M
authors.lastname: Oonuma
authors.forename: Hisashi
authors.initials: H
authors.lastname: Abe
authors.forename: Yukoh
authors.initials: Y
authors.lastname: Saitoh
authors.forename: Toru
authors.initials: T
authors.lastname: Hoshida
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ottomo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Omura
authors.forename: Seiki
authors.initials: S
authors.lastname: Matsuno
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000818:Animals; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy*; D014779:Virus Replication
chemical_list: D017501:Adenovirus E1B Proteins