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

The Ohio State University, Columbus, Ohio, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2006; 103(20):7823-8. DOI: 10.1073/pnas.0601412103
Source: PubMed


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.

Download full-text


Available from: Roumen Mirtchev Balansky, Jul 24, 2014
24 Reads
  • Source
    • "Seven out of 77 total mice were found to have lesions (hyperplasias, adenomas, carcinomas, or in combination) in tissues of the stomach, pancreas, and ovaries. These observations are consistent with those previously documented in which B[a]P induced injection site tumors and tumors in the abdomen and pancreas of mice injected i.p. (Hecht et al. 1994, Balansky et al. 2006). As there were so few mice observed to have these lesions, no analysis was performed to examine the effect of radiation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Low-dose ionizing radiation (LDR) may lead to suppression of smoking-related lung cancer. We examined the effects of a known cigarette smoke carcinogen Benzo[a]pyrene (B[a]P) alone or in combination with fractionated low-dose gamma radiation (60 - 600 mGy total dose) on the induction of lung neoplasms in the A/J mouse. Our results show that 600 mGy of gamma radiation delivered in six biweekly fractions of 100 mGy starting 1 month after B[a]P injection significantly inhibits the development of lung adenomas per animal induced by B[a]P. Our data also indicated that the six biweekly doses suppressed the occurrence of spontaneous hyperplastic foci in the lung, although this suppression failed to reach statistical significance when analyzed as average foci per lung possibly related to the small sample sizes used for the control and test groups.
    Dose-Response 12/2012; 10(4):516-26. DOI:10.2203/dose-response.12-040.Bruce · 1.22 Impact Factor
  • Source
    • "The first generation of the cross between C57BL/6J and 129/SvJ strains (B6/129 F1) underwent spontaneous alopecia areata, an inflammatory skin disease, and hair bulb cell apoptosis. This phenotype was greatly accelerated by FHIT heterozygosity, suggesting that FHIT may play a role in the pathogenesis of alopecia areata [40] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS.
    BioMed Research International 01/2011; 2011(1110-7243):984505. DOI:10.1155/2011/984505 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A CFAR adaptive polarimetric generalized likelihood ratio test (GLRT) detector is proposed for the coherent detection of radar targets against a Gaussian background and its performance is fully characterized. A model based version of such a detector is also derived by applying a similar GLRT approach to a structured covariance matrix. This latter detector is shown to reduce the adaptivity losses and thus to reduce the homogeneous region, which is required to estimate the clutter covariance matrix. The application to live radar data demonstrates the performance improvement achievable in practice by exploiting the polarimetric information. In particular adding the HV channel to the two co-polarized channels can provide a sensible performance increase with respect to the HH and VV only. This is especially true for man-made targets having cross-polarized response higher than the clutter. When the target has a lower cross-polarized return than the clutter, a much lower improvement is available but there is not a sensible adaptivity loss and the CFAR characteristic is always enforced against the Gaussian background
    Radar Conference, 2000. The Record of the IEEE 2000 International; 02/2000
Show more