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Regression of upper gastric cancer in mice by FHIT gene delivery
Author(s) -
Ishii Hideshi,
Zanesi Nicola,
Vecchione Andrea,
Trapasso Francesco,
Yendamuri Sai,
Sarti Manuela,
Baffa Raffaele,
During Matthew J.,
Huebner Kay,
Fong Louise Y.Y.,
Croce Carlo M.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0241fje
Subject(s) - fhit , apoptosis , cancer research , cancer , tunel assay , biology , carcinogen , microbiology and biotechnology , tumor suppressor gene , carcinogenesis , genetics
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 ∼7 tumors and by 84 days ∼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.