Potential cancer therapy with the fragile histidine triad gene - Review ofthe preclinical studies

Context The fragile histidine triad gene (FHIT) encompasses a human common fragile site, FRA3B, that is susceptible to environmental carcinogens. Dele tion and inactivation of FHIT have been seen in a number of human premalign ant and malignant lesions. Objective To review and evaluate preclinical studies of cancer therapy usin g the FHIT tumor suppressor gene and related studies involving Fhit protein expression. Data Sources A MEDLINE search of articles published from 1996 to June 2001 was performed; article reference lists were used to retrieve additional rel evant articles. Study Selection Immunohistochemical studies of primary tumors or relevant l esions were selected to evaluate Fhit expression in premalignant or maligna nt stages. Preclinical studies on antitumorigenic or therapeutic introducti on of FHIT were reviewed for the effects of exogenous Fhit expression. For the immunohistochemical analyses, 26 studies were included that analyzed at least 15 cases of a single type of tumor. For precancerous lesions, 9 stud ies were included that analyzed at least 4 cases. For studies of FHIT intro duction, 9 published studies were included. Data Extraction Using primary data from each of the studies, we assessed th e rationale and potential contribution of FHIT cancer therapy. Data was ind ependently abstracted by 2 authors and study quality was assessed by 2 othe r authors. Data Synthesis Overall, 60% (1162/1948 cases) of primary tumors showed abse nt or markedly reduced Fhit protein expression in cancer cells. Studies of preneoplastic lesions or early-stage cancer showed absence or marked reduct ion of Fhit protein expression in 0% to 93% of samples (overall, 31% [127/4 08 cases]). Preclinical studies using 26 cancer-derived cell lines from hum an lung, head and neck, esophageal, gastric, cervical, pancreatic, and kidn ey cancers, showed that reintroduction of FHIT resulted in inhibition of in vitro tumor cell growth or of in vivo turnorigenicity in 17 (57%) of 30 ce ll line experiments. Model systems for human preventive cancer therapy sugg ested that oral introduction of viral vector-mediated FHIT into Fhit-defici ent mice may prevent carcinogen-induced tumor development in some cases. Conclusion These findings show that FHIT gene therapy may potentially be cl inically useful for treatment of cancer and also prevention of carcinogen-i nduced tumor development, suggesting a rationale for further research invol ving FHIT introduction.