Prevention of urinary bladder cancer in the FHIT knock-out mouse with Rofecoxib, a Cox-2 inhibitor

D'Arca, Domenico; LeNoir, James; Wildemore, Bernadette; Gottardo, Fedra; Bragantini, Emma; Shupp-Byrne, Dolores; Zanesi, Nicola; Fassan, Matteo; Croce, Carlo M.; Gomella, Leonard G.; Baffa, Raffaele

doi:10.1016/j.urolonc.2009.01.016

« Previous Next »Urologic Oncology: Seminars and Original Investigations
Volume 28, Issue 2 , Pages 189-194, March 2010

Prevention of urinary bladder cancer in the FHIT knock-out mouse with Rofecoxib, a Cox-2 inhibitor☆

Domenico D'Arca, Ph.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, University of Modena and Reggio Emilia, Modena, Italy
- These authors contributed equally to this work.
James LeNoir, Ph.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- These authors contributed equally to this work.
Bernadette Wildemore, M.D.
- Department of Pathology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- These authors contributed equally to this work.
Fedra Gottardo, M.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- These authors contributed equally to this work.
Emma Bragantini, M.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Current address: Department of Pathology, Anatomic Pathology Unit, University of Verona, Verona.
Dolores Shupp-Byrne, Ph.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Nicola Zanesi, M.D.
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
- NZ is a Kimmel Scholar.
Matteo Fassan, M.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Current address: Department of Diagnostic Sciences and Special Therapies, Pathology Unit, University of Padova, Padova.
Carlo M. Croce, M.D.
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
Leonard G. Gomella, M.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Raffaele Baffa, M.D.
- Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Current address: Department of Translational Sciences, Research, MedImmune, Gaithersburg, MD.
- Corresponding author. Tel.: +1-215-955-9072; fax: +1-215-503-2627

Received 13 June 2008; received in revised form 14 January 2009; accepted 15 January 2009. published online 17 April 2009.

Abstract

Objectives

Aberrant or increased expression of cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of many diseases, including cancer. However, the exact mechanism by which COX-2 may influence tumorigenesis has yet to be described. To investigate the chemopreventive role of a COX-2 inhibitor, rofecoxib, in the development of urinary bladder cancer, we studied the effect of this drug in heterozygous and nullizygous fragile histidine triad (FHIT) gene-deficient mice in a chemically induced carcinogenesis model.

Materials and methods

Two-hundred eight mice consisting of 50 FHIT +/+, 63 FHIT +/– and 95 FHIT –/–, were divided into five treatment groups and followed up for 15 weeks. Mice were treated with freshly prepared solution of 0.1% or 0.01% N-butyl-N-(-4-hydroxybutyl)-nitrosamine (BBN) in their drinking water and rofecoxib was administered in mouse chow at 150 parts per million concentration. Mice were sacrificed, and accurate histological analysis of the bladder was performed.

Results

Rofecoxib treatment significantly reduced the incidence of preneoplastic lesions/bladder tumors (P = 0.016). Comparing the incidence of neoplastic lesions in mice treated with rofecoxib and BBN (22/56, 39.3%) and mice treated only with BBN (32/57, 56.1%), a protective role of rofecoxib on the BBN tumor induction has been observed (P = 0.024). A similar result (P = 0.002) has been reached observing the incidence of mild and moderate dysplasia in mice treated with a lower concentration of BBN (8/16, 50.0% vs. 20/24, 83.3%).Moreover, as previously observed, a significant increase in neoplastic lesions in the FHIT +/– and FHIT –/– vs. FHIT +/+ mice after BBN treatment has been observed (P = 0.003).

Conclusions

These findings suggest that rofecoxib provides a therapeutic defense against bladder carcinogenesis in our model and confirmed that the FHIT knock-out mouse is a suitable system to study in vivo bladder carcinogenesis.

Keywords: Urinary bladder cancer, Rofecoxib, Cox-2, FHIT, Knock-out mouse