title: Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression.
abstract: OBJECTIVE
  Sorafenib, a multikinase and tyrosine-kinase inhibitor, has anti-tumor activity in patients with advanced renal cell carcinoma (RCC). Recently, we reported that S-1 was active and well tolerated for the treatment of cytokine-refractory metastatic RCC. Therefore, we hypothesized that S-1 might be a good candidate for combination therapy with molecular targeting agents. In this study, we examined the mechanisms underlying for the synergism between S-1 and Sorafenib for RCC treatment in vitro and in tumor-bearing murine models.
  
  
  METHODS
  Human RCC cell lines were used for the in vitro cell proliferation assay. ACHN and 786-O tumors were subcutaneously transplanted into NCr-nu/nu-mice. Mice were treated with S-1 and/or Sorafenib, and tumor growth and side effects were monitored.
  
  
  RESULTS
  Synergistic anti-proliferative effects of Sorafenib and S-1 were clearly demonstrated in ACHN and 786-O cell lines in vitro due to the suppression of TS and E2F-1 expression. In the NCr-nu/nu model, the synergistic anti-tumor effects of S-1 and Sorafenib were again clearly seen, indicating direct synergistic effects of each drug on tumor growth.
  
  
  CONCLUSIONS
  Our results demonstrate the synergistic activity of S-1 and Sorafenib and provided the rationale for combination therapy with S-1 and Sorafenib for the treatment of patients with advanced RCC.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kuroiwa
authors.forename: Keijiro
authors.initials: K
authors.lastname: Kiyoshima
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004338:Drug Combinations; D004357:Drug Synergism; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives; D010094:Oxonic Acid / Q000494:pharmacology*; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D000077157:Sorafenib; D005641:Tegafur / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D004338:Drug Combinations; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010671:Phenylurea Compounds; D011725:Pyridines; D012333:RNA, Messenger; C079198:S 1 (combination); D005641:Tegafur; D009536:Niacinamide; D010094:Oxonic Acid; D000077157:Sorafenib; D013940:Thymidylate Synthase; D005472:Fluorouracil