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


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.
D'Arca
Domenico
D
Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
LeNoir
James
J
Wildemore
Bernadette
B
Gottardo
Fedra
F
Bragantini
Emma
E
Shupp-Byrne
Dolores
D
Zanesi
Nicola
N
Fassan
Matteo
M
Croce
Carlo M
CM
Gomella
Leonard G
LG
Baffa
Raffaele
R
D017766:Acid Anhydride Hydrolases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D005260:Female; D007783:Lactones / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D011230:Precancerous Conditions / Q000517:prevention & control; D013450:Sulfones / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000517:prevention & control*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D009363:Neoplasm Proteins; D013450:Sulfones; D000099170:Bis(5'-adenosyl)triphosphatase; C116926:rofecoxib