title: Enhancement of the sensitivity of renal cell carcinoma cells to fas-mediated cytotoxicity and apoptosis by the selective cyclooxygenase-2 inhibitor JTE-522.
abstract: BACKGROUND
  Cyclooxygenase-2 (COX-2) is a key enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in a variety of cancer cells. We reasoned that combination treatment of renal cell carcinoma (RCC) cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 synergizes with anticancer agents in cytotoxicity and apoptosis against RCC cells.
  
  
  METHODS
  The cytotoxicity of the selective COX-2 inhibitor JTE-522 and other anticancer agents against the RCC cell lines and the normal renal cell line was determined by the microculture tetrazolium dye assay.
  
  
  RESULTS
  JTE-522 was cytotoxic against the Caki-1 RCC cell line. JTE-522 and anti-Fas monoclonal antibody (CH-11) exhibited a synergistic cytotoxic effect against Caki-1 cells. In contrast, JTE-522 in combination with 5-fluorouracil, adriamycin, cis-diamminedichloroplatinum, or interferon-alpha, all commonly used clinically, resulted in an additive cytotoxic effect. Synergy achieved in cytotoxicity with JTE-522 and CH-11 was shown to be due to apoptosis.
  
  
  CONCLUSIONS
  The present study demonstrated that the selective COX-2 inhibitor JTE-522 had a cytotoxic effect on RCC and that synergistic cytotoxicity against RCC was obtained with JTE-522 in combination with anti-Fas monoclonal antibody. These results suggest that selective COX-2 inhibitors in combination with immunotherapy may be useful in treating patients with RCC.
authors.affiliation: Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan. sato.n@ayabe-hsp.or.jp
authors.forename: Nodoka
authors.initials: N
authors.lastname: Sato
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizutani
authors.forename: Yong Nan
authors.initials: YN
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Fujiwara
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ishida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Toiyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Abe
authors.forename: Issei
authors.initials: I
authors.lastname: Hayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawauchi
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D010080:Oxazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D052246:Cyclooxygenase 2 Inhibitors; D010080:Oxazoles; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C411023:anti-Fas monoclonal antibody