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Gene therapy reduces cancer in knockout mouse model
Stomach cancer in mice responds to doses of human tumor-suppressor gene
By Roberta Friedman

Researchers have used gene therapy to reduce the size and number of cancerous tumors in mice. After being exposed to cancer-causing chemicals, the mice received extra copies of a human gene that slows tumor growth in tissue cultures, FHIT. Normal mice have two copies of this tumor suppressor gene, but the animals in the study were bred to carry only one.

Carlo M. Croce, of Jefferson Medical College in Philadelphia, and colleagues delivered the human FHIT gene, packaged in virus vectors, directly into the stomach of the mice. The carcinogen, NMBA, was also given through the stomach. Neither the human or mouse anti-cancer gene was expressed in the tumor of one animal with cancer following treatment, suggesting an inadequate therapy.

Mutations in the FHIT gene result in a deficiency of the Fhit protein. Although this is not a hallmark of all tumors, the protein is defective or missing in many cancers, including stomach, esophageal, colon, breast and lung. Researchers first discovered mutations in the gene in 1979 by studying an Italian family prone to kidney cancer at a young age. Mutant mice that lack one or both copies of the FHIT gene have a higher incidence of spontaneous tumors and are more susceptible to cancer induced by a carcinogen.

More than 90 percent of adenocarcinomas of the esophagus in humans lack expression of FHIT. "It is therefore tempting to relate the observed effect in the well-established rodent NMBA model of esophageal and gastric cancer to the human condition," the researchers write in Proceedings of the National Academy of Sciences. The carcinogen NMBA has been linked to the rise in stomach cancers among populations in China and Iran.

Both the human and mouse genes sit astride a spot where the chromosome tends to break during cell division. These so-called fragile sites have been linked to cancers. FHIT is "the only example thus far of a frequently altered gene at a constitutive fragile region and shows hallmarks of a tumor suppressor gene," the researchers write.

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Dumon, K.R. et al. FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proc Natl Acad Sci USA, Early Edition (February 27, 2001).

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