Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats

Epidemiological studies have shown that nonsteroidal anti-inflammatory drug s (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, urinar y bladder, skin, and breast. In these studies, we evaluated the COX-2 inhib itor 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 fell urinary bladder cancers, many of which grew rapidly and caused substantial morbidity that required sacrifice of the mi ce. Groups of mice received various daily doses of celecoxib in the diet (1 250, 500, or 200 mg/kg of diet) beginning 7 days before the initiation of 1 2 weekly doses of OH-BBN, Mice were checked weekly for the presence of palp able urinary bladder masses. The study was terminated at 8 months following the initial treatment with OH-BBN. The percentage of mice with large palpa ble bladder lesions, which necessitated sacrifice of the mice, was 40% in t he OH-BBN control group, In contrast, only 10% of all celecoxib-treated mic e required sacrifice before the scheduled termination of the experiment, im plying that all three doses of celecoxib inhibited the formation of large p alpable lesions. Celecoxib did not significantly alter the incidence of pre neoplastic bladder lesions, but did dose-dependently decrease the total num ber 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, respe ctively. In the second model, female Fischer-344 rats were administered OI- I-BBN twice/week fur a period of 8 necks. After 8 months, all rats develope d preneoplastic lesions, whereas roughly 60% of the rats developed relative ly small urinary bladder ranters. Rats were treated continually with celeco xib in the diet (500 or 1000 mg/kg of diet) beginning either 1 week prior t o the initial OA-BBN treatment or beginning 1 week following the last ON-BB N treatment, Neither celecoxib treatment regimen significantly altered the number of preneoplastic lesions. Whereas celecoxib treatment initiated prio r to OH-BBN administration decreased ranter incidence roughly 65%, celecoxi b treatment initiated beginning 1 week after the last dose of OH-BBN profou ndly decreased cancer incidence (>95%). Celecoxib did not alter the body we ights of the mice or rats, or cause other signs of toxicity at any of the d oses 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 developmen t of urinary bladder cancers in the rat model even when administered follow ing 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.