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Celecoxib Inhibits N-Butyl-N-(4-hydroxybutyl)-nitrosamine-induced Urinary Bladder Cancers in Male B6D2F1 Mice and Female Fischer-344 Rats

Chemoprevention Center, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294 [C. J. G., D. L. H.]; Chemoprevention Branch, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [R. A. L., V. E. S., G. J. K.]; and G. D. Searle/Monsanto Company, St. Louis, Missouri 63167 [A. T. K., K. M. L., J. L. M., K. S.]

Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may have a role in the prevention of human cancers. A number of preclinical studies have also suggested that inhibition of cyclooxygenase (COX) with NSAIDs has an anticancer effect in animal models of colon, urinary bladder, skin, and breast. In these studies, we evaluated the COX-2 inhibitor celecoxib in two rodent models of urinary bladder cancer. Male B6D2F1 mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) developed transitional and squamous cell urinary bladder cancers, many of which grew rapidly and caused substantial morbidity that required sacrifice of the mice. Groups of mice received various daily doses of celecoxib in the diet (1250, 500, or 200 mg/kg of diet) beginning 7 days before the initiation of 12 weekly doses of OH-BBN. Mice were checked weekly for the presence of palpable urinary bladder masses. The study was terminated at 8 months following the initial treatment with OH-BBN. The percentage of mice with large palpable bladder lesions, which necessitated sacrifice of the mice, was 40% in the OH-BBN control group. In contrast, only 10% of all celecoxib-treated mice required sacrifice before the scheduled termination of the experiment, implying that all three doses of celecoxib inhibited the formation of large palpable lesions. Celecoxib did not significantly alter the incidence of preneoplastic bladder lesions, but did dose-dependently decrease the total number of urinary bladder cancers/mouse, palpable plus microscopic, by 77, 57, and 43% at dosages of 1250, 500, and 200 mg of celecoxib/kg of diet, respectively. In the second model, female Fischer-344 rats were administered OH-BBN twice/week for a period of 8 weeks. After 8 months, all rats developed preneoplastic lesions, whereas roughly 60% of the rats developed relatively small urinary bladder cancers. Rats were treated continually with celecoxib in the diet (500 or 1000 mg/kg of diet) beginning either 1 week prior to the initial OH-BBN treatment or beginning 1 week following the last OH-BBN treatment. Neither celecoxib treatment regimen significantly altered the number of preneoplastic lesions. Whereas celecoxib treatment initiated prior to OH-BBN administration decreased cancer incidence roughly 65%, celecoxib treatment initiated beginning 1 week after the last dose of OH-BBN profoundly decreased cancer incidence (>95%). Celecoxib did not alter the body weights of the mice or rats, or cause other signs of toxicity at any of the doses studied. Taken together these results demonstrate that: (a) celecoxib effectively inhibits tumor growth and enhances survival in the mouse model of urinary bladder cancer; and (b) celecoxib profoundly inhibits development of urinary bladder cancers in the rat model even when administered following the last dose of OH-BBN. Clinical trials will be necessary to determine whether COX-2 inhibitors will provide a clinical benefit in human bladder cancer.

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