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

Abstract

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 tumorbearing 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. ' 2007 Wiley-Liss, Inc.

Apricoxib, a Novel Inhibitor of COX-2, Markedly Improves Standard Therapy Response in Molecularly Defined Models of Pancreatic Cancer

“…COX-2 expression correlates with VEGF levels in patient tumor samples and COX-2 inhibition can modulate VEGF production (27, 34). VEGF levels in plasma and tumor samples collected from mice tumor-bearing mice were measured by ELISA.…”

“…Apricoxib is a novel, selective COX-2 inhibitor currently in phase II studies for NSCLC and pancreatic cancer. Apricoxib has showed significant antitumor effects in xenograft models of lung and colorectal cancer and seems more potent than previous COX-2 inhibitors (23, 27, 28). In this study, we characterized the baseline expression and activity of EGFR and COX-2 in commonly employed pancreatic cancer cell lines as well as functional responses to inhibition of each pathway.…”

Effects of cyclooxygenase inhibitors on survival time in ovarian cancer xenograft-bearing mice

“…In a phase 2 trial, celecoxib treatment improved overall survival in patients who suffered from COX-2-positive esophageal and gastroesophageal junction cancer (11). In colorectal adenocarcinoma, CS-706, a novel COX-2 selective inhibitor, was demonstrated to have potent life-prolonging activity in tumor-bearing mice (12). In ovarian cancer, Xin et al (13) identified that meloxicam, categorized as a selective COX-2 inhibitor, prolonged survival in vivo when administered alone.…”

“…Few studies have also concluded that COX-1 inhibitors are able to reduce tumor growth by decreasing cell proliferation and accelerating apoptosis (6,10). Additionally, COX-2 inhibitors have demonstrated potent life-prolonging effects in patients with esophageal and gastroesophageal junction cancer (11) and in various animal models of cancer (12,13).…”

Efficient synthesis of apricoxib, CS-706, a selective cyclooxygenase-2 inhibitor, and evaluation of inhibition of prostaglandin E2 production in inflammatory breast cancer cells

“…14, 15 Clinical studies demonstrated potent analgesic activity 16, 17 and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. 18 As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models 19 and colorectal carcinoma, 20 and Recamp et al 21 recently reported a Phase I trial of 1 in combination with erlotinib in lung cancer.…”