Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies.

Abstract

The fragile histidine triad gene (FHIT) encompasses a human common fragile site, FRA3B, that is susceptible to environmental carcinogens. Deletion and inactivation of FHIT have been seen in a number of human premalignant and malignant lesions. To review and evaluate preclinical studies of cancer therapy using the FHIT tumor suppressor gene and related studies involving Fhit protein expression. A MEDLINE search of articles published from 1996 to June 2001 was performed; article reference lists were used to retrieve additional relevant articles. Immunohistochemical studies of primary tumors or relevant lesions were selected to evaluate Fhit expression in premalignant or malignant stages. Preclinical studies on antitumorigenic or therapeutic introduction 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 studies were included that analyzed at least 4 cases. For studies of FHIT introduction, 9 published studies were included. Using primary data from each of the studies, we assessed the rationale and potential contribution of FHIT cancer therapy. Data was independently abstracted by 2 authors and study quality was assessed by 2 other authors. Overall, 60% (1162/1948 cases) of primary tumors showed absent or markedly reduced Fhit protein expression in cancer cells. Studies of preneoplastic lesions or early-stage cancer showed absence or marked reduction of Fhit protein expression in 0% to 93% of samples (overall, 31% [127/408 cases]). Preclinical studies using 26 cancer-derived cell lines from human lung, head and neck, esophageal, gastric, cervical, pancreatic, and kidney cancers, showed that reintroduction of FHIT resulted in inhibition of in vitro tumor cell growth or of in vivo tumorigenicity in 17 (57%) of 30 cell line experiments. Model systems for human preventive cancer therapy suggested that oral introduction of viral vector-mediated FHIT into Fhit-deficient mice may prevent carcinogen-induced tumor development in some cases. These findings show that FHIT gene therapy may potentially be clinically useful for treatment of cancer and also prevention of carcinogen-induced tumor development, suggesting a rationale for further research involving FHIT introduction.