title: Gene therapy for pancreatic cancer based on genetic characterization of the disease.
abstract: In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we analyzed the association of loss of heterozygosity (LOH) with the clinicopathological features of the disease. Based on these results, we are developing a new gene therapy that targets the genetic character of pancreatic cancer, using mutant adenoviruses that are selectively replication-competent in tumor cells. LOH of 30% or more was observed on chromosome arms 17p (47%), 9p (45%), 18q (43%), 12q (34%), and 6q (30%). LOH of 12q, 17p, and 18q showed significant association with poor prognosis. These data strongly suggest that mutations of the putative tumor suppressor genes, TP53 and SMAD4, play significant roles in the disease progression. Based on this rationale, we are developing a new gene therapy that targets tumors without normal TP53 function. The E1B-55kDa-deleted adenovirus can selectively replicate in TP53-deficient human tumor cells, but not in cells with functional TP53. We evaluated the therapeutic effect of this E1B-55kDa-deleted mutant adenovirus on pancreatic cancer without normal TP53 function. The growth of a human pancreatic tumor in a severe combined immunodeficiency (SCID) mouse model was markedly inhibited by consecutive injections of the E1B-55kDa-deleted adenovirus. Furthermore, the replication-competent adenovirus is not only a strong weapon itself but it is also a useful carrier of genes that possess antitumor activities, as a virus vector specific to tumors without normal TP53 function.
authors.affiliation: First Departments of Surgery, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamura
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yatsuoka
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kimura
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Abe
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inoue
authors.forename: Masaru
authors.initials: M
authors.lastname: Oonuma
authors.forename: Kazunori
authors.initials: K
authors.lastname: Takeda
authors.forename: Seiki
authors.initials: S
authors.lastname: Matsuno
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins; D000818:Animals; D016147:Genes, Tumor Suppressor / Q000502:physiology; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D011379:Prognosis; D016160:Retinoblastoma Protein; D016019:Survival Analysis
chemical_list: D017500:Adenovirus E1A Proteins; D016160:Retinoblastoma Protein