Enhanced inhibitive effects of combination of rofecoxib and octreotide on the growth of human gastric cancer

Abstract

Our previous studies indicated that cyclooxygenase-2 inhibitor or octreotide could suppress the proliferation of gastric adenocarcinoma in vitro or in vivo. The present study was aimed to find whether rofecoxib combined with octreotide could enhance the inhibitive effects on the growth of gastric cancer. The effect of rofecoxib or octreotide on proliferation of gastric cancer cell line was determined by 3 H-thymidine ribotide incorporation. The TdT-mediated dUTP nick endlabeling assay was used to detect the apopotosis. To determine their synergic antineoplastic effects, the interaction between rofecoxib and octreotide on SGC-7901 cell was evaluated by the median effect plot. After orthotopical implantion of xenografts of human gastric cancer in stomach, nude mice were given rofecoxib plus octreotide for 8 weeks. Cyclooxygenase-2 in gastric cancer tissues was measured by immunohistochemistry. Combination of rofecoxib and octreotide presented synergistic effect (combination index < 1) in the majority of responses. The inhibitory rate for xenografts in nude mice was 89.7% in rofecoxib group. Combination of rofecoxib and octreotide enhanced inhibitory rate to 98.8%. The combination greatly increased the apoptotic index (78.20% ؎ 6.45%) of the xenografts as compared with that of using rofecoxib alone (46.60% ؎ 3.42%); the difference was very significant (p < 0.001). Rofecoxib could inhibit the activity of cyclooxygenase-2 in the tissue of gastric adenocarcinomas of nude mice. Our results indicate that combination of rofecoxib and octreotide significantly enhances the antiproliferative effect in gastric adenocarcinoma, which might have potential therapeutic value. © 2004 Wiley-Liss, Inc. Key words: rofecoxib; octreotide; gastric adenocarcinoma; cyclooxygenase-2The poor prognosis of unresectable gastric adenocarcinoma and the various disappointing therapeutic modalities make further investigation of new therapeutic approach for advanced gastric cancer of primary importance. Accumulative evidence has shown that overexpression of cyclooxygenase-2 (COX-2) in gastric adenocarcinoma might play a crucial role in invasive tumor growth and offer a new strategy against cancer by the use of COX-2 inhibitors. [1][2][3][4] The inhibitive effect of aspirin or rofecoxib, a higher selective COX-2 inhibitor 5 on the proliferation of gastric cancer, has been observed in our previous studies. 6,7 Various studies have demonstrated that the growth of normal cells and malignant tumor may be regulated by gut peptides. 8,9 In the stomach, besides the known inhibitory function of somatostatin (SST) on acid secretion, it has been suggested that the analogues of SST could be candidates for arresting the growth of gastric adenocarcinoma. Previous data from the literature have shown that the mean tumor volume in nude mice treated with octreotide, an analogue of SST, was significantly lower than that of control group with an inhibitory rate of 60.6%. 6,10 The antineoplastic action of octreotide is thought to be mediated through the receptors for S...

Clinical Significance of Protein Expression of Cyclooxygenase-2 and Somatostatin Receptors in Gastroenteropancreatic Neuroendocrine Tumors

“…Furthermore, rofecoxib and octreotide were found to have synergic antineoplastic effects in vitro in SGC-7901 cells (a gastric cancer cell line) and in xenografts in nude mice [17], and human gastric adenocarcinoma growth was found to be inhibited preoperatively by a combination of celecoxib and octreotide [18]. …”

Peptide Receptor Targeting in Cancer: The Somatostatin Paradigm

“…Octreotide reduced gastric carcinoma cell line proliferation in vitro interfering with Akt and telomerase activity [210], an effect that was dependent on the expression of sst3. The COX2 inhibitor rofecoxib, administered with octreotide in a gastric cancer xenograft model, caused an almost total tumor growth suppression due to induction of apoptosis [211]. These in vitro results were confirmed in clinical studies in which octreotide potentiated celecoxib effect in gastric carcinoma patients, increasing both necrosis and apoptosis and inhibiting angiogenesis [212].…”

Preoperative growth inhibition of human gastric adenocarcinoma treated with a combination of celecoxib and octreotide

“…The hypothetically synergistic inhibition of the combination of 2 types of non-cytotoxic agents, rofecoxib and octreotide, on the growth of gastric cancer has also been confirmed in both in vitro and in vivo animal studies [13] . However, whether this regime could be beneficial for human gastric cancer treatment is still unknown.…”

“…The inhibitive effects of the combination of non-cytotoxic drugs (COX-2 inhibitor and SST analogue) on gastric cancer in vitro or in vivo have been reported in animal experiments [9,13] . In the present study, more necrosis was detected in gastric adenocarcinomas of patients treated with celecoxib and octreotide for 1 week.…”