Regression of upper gastric cancer in mice by FHIT gene delivery.
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.
Ishii
Hideshi
H
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Zanesi
Nicola
N
Vecchione
Andrea
A
Trapasso
Francesco
F
Yendamuri
Sai
S
Sarti
Manuela
M
Baffa
Raffaele
R
During
Matthew J
MJ
Huebner
Kay
K
Fong
Louise Y Y
LY
Croce
Carlo M
CM
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
D017766:Acid Anhydride Hydrolases; D004128:Dimethylnitrosamine; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C014707:nitrosobenzylmethylamine