title: Regression of upper gastric cancer in mice by FHIT gene delivery.
abstract: Fhit expression is reduced in most cancers, and Fhit replacement by FHIT expression viruses in lung, esophageal, pancreatic, and cervical cancers induces apoptosis in the cancer cells. Mice carrying one or two inactivated Fhit alleles are hypersensitive to development of N-nitrosomethylbenzylamine (NMBA)-induced forestomach tumors. In the present study, we investigated the kinetics and mechanism of tumor reversal and intervention by oral delivery of FHIT expression viruses. Tumor analysis showed that: a) by 37 days post-NMBA, control mice showed approximately 7 tumors and by 84 days approximately 10 tumors/forestomach; b) mice receiving FHIT virus at 2 or 42 days post-NMBA showed significantly reduced tumor burdens; c) Fhit was still expressed at 82 days postinfection; d) control viral infection had no effect on tumor development; and e) reduced Bcl2, increased Bax expression, and increased TUNEL-positive apoptotic nuclei characterized the restored epithelia of FHIT transduced forestomachs. Thus, FHIT viral gene delivery prevents or retards development of carcinogen-induced forestomach tumors and reverses development of established tumors by 60-70% through an apoptotic pathway. This dramatic reduction in tumor burden emphasizes the efficacy of targeting the FHIT apoptotic pathway for tumor eradication.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Sai
authors.initials: S
authors.lastname: Yendamuri
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
authors.forename: Louise Y Y
authors.initials: LY
authors.lastname: Fong
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D017766:Acid Anhydride Hydrolases; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D005753:Gastric Mucosa / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics*; D013270:Stomach / Q000033:anatomy & histology / Q000473:pathology; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D014780:Viruses / Q000235:genetics; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D004128:Dimethylnitrosamine; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C014707:nitrosobenzylmethylamine