A fhit-ing end to tumor development

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Most gene therapy approaches to cancer to date have concentrated on the elimination of pre-existing tumor cells. However, as more genes are identified that when mutated predispose individuals to the development of cancer, alternative strategies are now being considered. Some of these strategies are based on the premise that a normal version of, for example, a tumor suppressor gene expressed in susceptible tissues, could prevent the development or proliferation of tumor cells. The feasibility of this approach has recently been shown by Dumon et al.1 Dumon K.R. et al. FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proc. Natl. Acad. Sci. USA. 2001; 98: 3340-3351 Crossref PubMed Scopus (150) Google Scholar using a knockout transgenic mouse model that shows an increased susceptibility to the formation of tumors as a result of inactivation of the tumor suppressor gene fhit. In humans FHIT maps to a common fragile site on chromosome 3. Chromosomal rearrangements effecting this region and thus the FHIT gene are present in many cancers including esophageal and gastric cancer. Fong and co-workers 2 Fong L.Y.Y. et al. Muir–Torre-like syndrome in Fhit-deficient mice. Proc. Natl. Acad. Sci. USA. 2000; 97: 4742-4747 Crossref PubMed Scopus (186) Google Scholar have previously shown that heterozygous mice defective for fhit show an increased predeposition to carcinogen-induced tumor development in the esophagus and forestomach compared with wild-type mice. To test whether FHIT expression could prevent the formation of tumors in Fhit-defective mice, adenovirus (Ad) and adeno-associated virus (AAV) vectors were used to deliver the human FHIT gene to the esophagus and forestomach of treated-Fhit heterozygous mice treated with the carcinogen N-nitrosomethylbenzylamine. Both the carcinogen and the viral vectors were administered via oral gavage. FHIT immunohistochemistry confirmed transduction of intestinal cells in the esophagus and forestomach by both the Ad–FHIT and AVV–FHIT vectors. Gross and histological examination of mice ten weeks after viral administration showed a reduction in the number of tumors and focal hyperplastic lesions in FHIT-treated animals compared with control animals. This reduction was particularly emphatic in the forestomach and the squamocolumnar junction region – a region corresponding to the human esophago-gastric junction. A reduction in cellular proliferation was also noted in the FHIT-treated animals. These data suggest that FHIT expression in susceptible cells of the esophago-gastric tract could be used to prevent the development of tumor cells. It will be interesting to see if this approach could also be applied to the prevention or treatment of other cancers associated with the loss of FHIT gene activity including lung cancer.