Abstract
A new modality is necessary to prevent recurrence of superficial bladder cancer after complete transurethral resection (TUR) because of the high recurrence rate even with current prophylaxis protocols. Prostaglandins (PGs) are known to be produced more in transitional cell carcinoma, and etiologically bladder cancer risk is negatively associated with the intake of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), the rate-limiting enzyme of the PG production. We have shown the chemopreventive effect of piroxicam, an NSAID, on the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder cancer model. To avoid gastrointestinal side effects of regular NSAIDs, we also showed the chemopreventive effect of nimesulide, a selective inhibitor of the second isoform of COX, COX-2, which does not affect COX-l house-keeping activity in gastrointestinal mucosa on the same model. We also observed induction of COX-2 protein in the rat bladder tumor. In this study, we screened COX-2 protein expression in primary superficial bladder cancer tissues, to elucidate if COX-2 selective inhibitors can be a candidate chemopreventive agent for bladder cancer recurrence. Five and 6 samples of superficial bladder cancer cases with and without recurrence after complete TUR were examined by immunohistochemical analysis. We found more COX-2 protein positive samples in the cases with recurrence than in cases without recurrence. Even though the number of cases examined is small, this result supports our hypothesis that COX-2 contributes to superficial bladder cancer recurrence, thus, selective COX-2 inhibitors can be a candidate chemopreventive agent for the recurrence.
Key words
Prostagalandin endoperoxide synthase - bladder neoplasm - recurrence - chemoprevention
References
1
Lee C, Park M S.
Prophylactic treatment of superficial bladder tumor.
Int J Urol.
1998;
5
511-520
2
Droller M J, Lindgren J A, Claessen H E, Perlmann P.
Production of prostaglandin E2 by bladder tumor cells in tissue culture and a possible mechanism of lymphocyte inhibition.
Cell Immunol.
1979;
47
261-273
3
Cohen S M, Zenser T V, Murasaki G, Fukushima S, Mattammal M B, Rapp N S, Davis B B.
Aspirin inhibition of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced lesions of the urinary bladder correlated with inhibition of metabolism by bladder prostaglandin endoperoxide synthetase.
Cancer Res.
1981;
41
3355-3359
4
Castelao J E, Yuan J M, Gago-Dominguez M, Yu M C, Ross R K.
Non-steroidal anti-inflammatory drugs and bladder cancer prevention.
Br J Cancer.
2000;
82
1364-1369
5
Gwyn K, Sinicrope F A.
Chemoprevention of colorectal cancer.
Am J Gastroenterol.
2002;
97
13-21
6
Levi M S, Borne R F, Williamson J S.
A review of cancer chemopreventive agents.
Curr Med Chem.
2001;
8
1349-1362
7
Earnest D L, Hixson L J, Alberts D S.
Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention.
J Cell Biochem Suppl.
1992;
161
156-166
8
Kurata Y, Asamoto M, Hagiwara A, Masui T, Fukushima S.
Promoting effects of various agents in rat urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.
Cancer Lett.
1986;
32
125-135
9
Sakata T, Hasegawa R, Johansson S L, Zenser T V, Cohen S M.
Inhibition by aspirin of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide initiation and sodium saccharin promotion of urinary bladder carcinogenesis in male F344 rats.
Cancer Res.
1986;
46
3903-3906
10
Hasegawa R, St John M, Murasaki G, Fukushima S, Cohen S M.
Effect of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced epithelial proliferation in the urinary bladder and forestomach of the rat.
Cancer Lett.
1984;
21
269-275
11
Cohen S M, Hasegawa R, Sakata T, Johansson S L.
Effect of aspirin on urinary bladder carcinogenesis initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide in rats.
Cancer Res.
1989;
49
372-377
12
Okajima E, Ozono S, Endo T, Majima T, Tsutsumi M, Fukuda T, Akai H, Denda A, Hirao Y, Okajima E, Nishino H, Nir Z, Konishi Y.
Chemopreventive efficacy of piroxicam administered alone or in combination with lycopene and beta-carotene on the development of rat urinary bladder carcinoma after N-butyl-N-(4-hydroxybutyl)nitrosamine treatment.
Jpn J Cancer Res.
1997;
88
543-552
13
Kennedy B P, Chan C C, Culp S A, Cromlish W A.
Cloning and expression of rat prostagiandin endoperoxide synthase (cyclooxygenase)-2 cDNA.
Biochem Biophys Res Commun.
1993;
197
494-500
14
Appleby S B, Ristimaki A, Neilson K, Narko K, Hla T.
Structure of the human cyclo-oxygenase-2 gene.
Biochem J.
1994;
302
723-727
15
Jones D A, Carlton D P, McIntyre T M, Zimmerman G A, Prescott S M.
Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines.
J Biol Chem.
1993;
268
9049-9054
16
Hla T, Neilson K.
Human cyclooxygenase-2 cDNA.
Proc Natl Acad Sci USA.
1992;
89
7384-7388
17
Okajima E, Denda A, Ozono S, Takahama M, Akai H, Sasaki Y, Kitayama W, Wakabayashi K, Konishi Y.
Chemopreventive effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on the development of rat urinary bladder carcinomas initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.
Cancer Res.
1998;
58
3028-3031
18
Kitayama W, Denda A, Okajima E, Tsujiuchi T, Konishi Y.
Increased expression of cyclooxygenase-2 protein in rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.
Carcinogenesis.
1999;
20
305-310
19
Mohammed S I, Knapp D W, Bostwick D G, Foster R S, Khan K N, Masferrer J L, Woerner B M, Snyder P W, Koki A T.
Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of the urinary bladder.
Cancer Res.
1999;
59
5647-5650
20
Komhoff M, Guan Y, Shappell H W, Davis L, Jack G, Shyr Y, Koch M O, Shappell S B, Breyer M D.
Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas.
Am J Pathol.
2000;
157
29-35
21
Ozono S, Hinotsu S, Tabata S, Takashima K, Fujimoto K, Okajima E, Hirao Y, Ohashi Y, Akaza H, Fukushima S.
Treated natural history of superficial bladder cancer.
Jpn J Clin Oncol.
2001;
31
536-540
Yoshihiko Hirao, M. D.
Department of Urology, · Nara Medical University
Shijo-cho 840
Kashihara
Nara 634-8522
Japan
Telefon: +81-744-22-3051 (Ext. 2338)
Fax: +81-744-22-9282
eMail: hiraoyos@nmu-gw.naramed-u.ac.jp