Author Affiliations: Kimmel Cancer Institute and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pa.
Context 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
Objective To review and evaluate preclinical studies of cancer therapy using 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 relevant articles.
Study Selection 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.
Data Extraction 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.
Data Synthesis 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.
Conclusion 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.
Ishii H, Dumon KR, Vecchione A, Fong LYY, Baffa R, Huebner K, Croce CM. Potential Cancer Therapy With the Fragile Histidine Triad GeneReview of the Preclinical Studies. JAMA. 2001;286(19):2441-2449. doi:10.1001/jama.286.19.2441