CS-706, a novel cyclooxygenase-2 selective inhibitor, prolonged the survival of tumor-bearing mice when treated alone or in combination with anti-tumor chemotherapeutic agents.
The potent chemopreventive activity of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated in a number of preclinical studies, but their potency in antitumor activity is still in dispute. In this report, we demonstrate the potent antitumor activity of a novel COX-2 inhibitor, CS-706 in mouse colorectal adenocarcinoma colon 26 tumor-bearing mice treated with or without antitumor chemotherapeutic agents. Daily oral administration of CS-706 at doses of 3-100 mg/kg from the day of tumor inoculation (Day 0) inhibited tumor growth dose-dependently, and the maximal inhibition was 67% at a dose of 100 mg/kg. In contrast, celecoxib, a well-known COX-2 inhibitor, did not inhibit tumor growth at doses up to 100 mg/kg. Furthermore, CS-706 at a dose of 1 mg/kg or above markedly prolonged the survival time of tumor-bearing mice. Administration of 30 mg/kg CS-706 from Day 7 combined with a single intravenous treatment of 10 mg/kg cisplatin on Day 7 completely regressed the tumors in all tumor-bearing mice examined, whereas only in 1 of 10 mice tumor was regressed with cisplatin treatment. Similar combination effects were observed with 10 mg/kg CS-706 and 60 mg/kg 5-fluorouracil (5-FU). Moreover, 10 mg/kg CS-706 significantly inhibited angiogenesis induced by implanted chambers with colon 26 cells in a dorsal air sac assay in mice. Collectively, these results suggest that CS-706 is a potent antitumor agent, especially in combination with conventional chemotherapeutic agents, and that the anti-angiogenic activity of CS-706 may contribute at least in part to its marked antitumor activity.
Senzaki
Michiyo
M
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. senzaki.michiyo.hf@daiichisankyo.co.jp
Ishida
Saori
S
Yada
Ayumi
A
Hanai
Masaharu
M
Fujiwara
Kosaku
K
Inoue
Shin-Ichi
S
Kimura
Tomio
T
Kurakata
Shinichi
S
D000230:Adenocarcinoma / Q000188:drug therapy*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011758:Pyrroles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C514354:apricoxib; D002945:Cisplatin; D005472:Fluorouracil