Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis.
OBJECTIVE
To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model.


METHODS
The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips.


RESULTS
The incidence of carcinoma, confirmed microscopically, was: control 14/20 (70%); high-dose gefitinib, 7/20 (35%); low-dose gefitinib, 7/20 (35%); high-dose meloxicam 7/21 (33%); and low-dose meloxicam, 12/20 (60%). The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects.


CONCLUSIONS
Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects.
Department of Urology, University of Tsukuba, Tsukuba, Japan. kazhat@iuhw.ac.jp
Kazunori
K
Hattori
Katsuyuki
K
Iida
Akira
A
Joraku
Sadamu
S
Tsukamoto
Hideyuki
H
Akaza
Ryoichi
R
Oyasu
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000077156:Gefitinib; D008297:Male; D000077239:Meloxicam; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D011916:Rats, Inbred F344; D013843:Thiazines / Q000008:administration & dosage* / Q000009:adverse effects; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013843:Thiazines; D013844:Thiazoles; D002085:Butylhydroxybutylnitrosamine; D000077156:Gefitinib; D000077239:Meloxicam