Early loss of Fhit in the respiratory tract of rodents exposed to environmental cigarette smoke

Francesco D'Agostini, Alberto Izzotti, Roumen Balansky, Nicola Zanesi, Carlo M. Croce, Silvio De Flora

Research output: Contribution to journalArticlepeer-review


The Fhit gene, encompassing the most active common human chromosomal fragile region, FRA3B, has been shown to act as a tumor suppressor. Several studies have shown significant Fhit alterations or Fhit protein loss in lung cancers from smokers compared with lung cancers from nonsmokers. To evaluate the role of Fhit under controlled experimental conditions, we exposed rodents to environmental cigarette smoke (ECS) and evaluated Fhit expression or Fhit protein in the respiratory tract. After 14 days of exposure to ECS, loss of Fhit protein in the bronchial/bronchiolar epithelium affected half of the tested B6-129(F1) mice, either wild type or Fhit+/-. After 28 days, it affected the vast majority of the tested SKH-1 hairless mice and of A/J mice and all (UL53-3 × A/J)F1 mice, either wild type or P53+/-. In Sprague-Dawley rats, exposure to ECS for up to 30 days caused a time-dependent loss of Fhit in pulmonary alveolar macrophages. Moreover, ECS downregulated Fhit expression and significantly decreased Fhit protein in the rat bronchial epithelium. The oral administration of N-acetylcysteine attenuated the ECS-related loss of Fhit, whereas oltipraz, 5,6-benzoflavone, phenethyl isothiocyanate, and indole 3-carbinol, and their combinations had no significant effect. Parallel studies evaluated a variety of molecular, biochemical, and cytogenetic alterations in the respiratory tract of the same animals. In conclusion, there is unequivocal evidence that Fhit is an early, critical target in smoke-related lung carcinogenesis in rodents, and that certain chemopreventive agents can attenuate the occurrence of this gene alteration.

Original languageEnglish
Pages (from-to)3936-3941
Number of pages6
JournalCancer Research
Issue number7
Publication statusPublished - Apr 1 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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