Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: chemoprevention by budesonide and N-acetylcysteine.

Abstract

The FHIT gene has many hallmarks of a tumor-suppressor gene and is involved in a large variety of cancers. We treated A/J mice and (C57BL/6J x 129/SvJ)F1 (B6/129 F1) mice, either wild-type or FHIT+/-, with multiple doses of benzo[a]pyrene (B[a]P) by gavage. B[a]P caused a time-related increase of micronuclei in peripheral blood erythrocytes. Both A/J and B6/129 F1 mice, irrespective of their FHIT status, were sensitive to induction of forestomach tumors, whereas B[a]P induced glandular stomach hyperplasia and a high multiplicity of lung tumors in A/J mice only. Preneoplastic lesions of the uterus were more frequent in FHIT+/- mice. B6/129 F1 mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which were greatly accelerated either by FHIT heterozygosity or by B[a]P treatment, thus suggesting that FHIT plays a role in the pathogenesis of alopecia areata. The oral administration of either budesonide or N-acetyl-L-cysteine (NAC) inhibited the occurrence of this inflammatory skin disease. In addition, these agents prevented B[a]P-induced glandular stomach hyperplasia and decreased the size of both forestomach tumors and lung tumors in A/J mice. Budesonide also attenuated lung tumor multiplicity. In B6/129 F1 mice, NAC significantly decreased the proliferating cell nuclear antigen in lung tumors. Both budesonide and NAC inhibited B[a]P-induced forestomach tumors and preneoplastic lesions of the respiratory tract in B6/129 F1 mice. In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC.

• Authors: Roumen Balansky, Francesco D'Agostini, Gancho Ganchev, Alberto Izzotti, Barbara Di Marco, Ronald A Lubet, Nicola Zanesi, Carlo M Croce, Silvio De Flora
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 20 Pg. 7823-8 (May 16 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16672365 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Neoplasm Proteins
• fragile histidine triad protein
• Benzo(a)pyrene
• Budesonide
• Acid Anhydride Hydrolases
• Acetylcysteine

Topics

• Acetylcysteine (metabolism, therapeutic use)
• Acid Anhydride Hydrolases (genetics, metabolism)
• Alopecia Areata (chemically induced, prevention & control)
• Animals
• Anti-Inflammatory Agents (metabolism, therapeutic use)
• Benzo(a)pyrene (administration & dosage, metabolism, toxicity)
• Budesonide (metabolism, therapeutic use)
• Female
• Genes, Tumor Suppressor
• Lung (pathology)
• Mice
• Mice, Inbred Strains
• Neoplasm Proteins (genetics, metabolism)
• Neoplasms (chemically induced, prevention & control)
• Stomach (pathology)