Aragon Health Research Institute (IIS Aragon), University of Zaragoza School of Medicine, Department of Pharmacology and Physiology, C/Domingo Miral s/n, 50009 Zaragoza, Spain.
Int J Oncol. 2012 Feb;40(2):527-34. doi: 10.3892/ijo.2011.1219. Epub 2011 Oct 3.
Cyclooxygenase (COX) inhibition has been shown to prevent the development of esophageal adenocarcinoma (EAC). However, the potential of this approach for treatment of established cancer has been poorly investigated. Our objective was to determine whether non-selective or selective inhibition of the COX pathway affects the growth of esophageal adenocarcinoma xenografts in nude mice. A human esophageal adenocarcinoma xenograft model was established by subcutaneous inoculation of OE33 cells in nude mice. Small tumor slices harvested from four OE33 xenografts were implanted in the flanks of new mice that were randomized to different treatments (6 animals per group): indomethacin (3 mg/kg/day), parecoxib (0.11 and 0.22 mg/kg/day) or a selective prostaglandin E₂ receptor antagonist (AH-23848B, 1 mg/kg/day). For each treatment, a control group of 6 animals (vehicle) carrying xenografts from the same OE33 tumor was included. Tumor growth was measured twice a week. After 8 weeks mice were euthanized. Tumors were assessed by histological analysis, mRNA expression of COX isoenzymes, PGE₂ receptors and PGE₂ content. All OE33 tumors were poorly differentiated esophageal adenocarcinomas. Tumors expressed COX-2, EP₁, EP₂ and EP₄ receptor mRNA. Treatment with parecoxib, higher dose or indomethacin significantly inhibited tumor growth. Furthermore, indomethacin induced tumor regression (74 vs 582% in control animals; p<0.01). However, AH-23848B or parecoxib low dose failed to affect tumor growth significantly. PGE₂ content in tumors was significantly decreased by high-dose parecoxib and indomethacin. Indomethacin and parecoxib inhibit the growth of human esophageal adenocarcinoma xenografts in nude mice, which suggests a potential role for NSAIDs or selective COX-2 inhibitors for EAC chemotherapy.
环氧化酶（COX）抑制已被证明可预防食管腺癌（EAC）的发展。然而，这种方法治疗已确立的癌症的潜力尚未得到充分研究。我们的目的是确定非选择性或选择性 COX 途径抑制是否会影响裸鼠中食管腺癌异种移植物的生长。通过将 OE33 细胞皮下接种到裸鼠中建立人食管腺癌异种移植模型。从小鼠四个 OE33 异种移植物中收获的小肿瘤切片被植入新的随机分组接受不同治疗的小鼠（每组 6 只动物）：吲哚美辛（3mg/kg/天）、帕瑞昔布（0.11 和 0.22mg/kg/天）或选择性前列腺素 E₂ 受体拮抗剂（AH-23848B，1mg/kg/天）。对于每种治疗方法，还包括来自同一 OE33 肿瘤的 6 只携带异种移植物的对照动物（载体）。每周测量两次肿瘤生长情况。8 周后，处死小鼠。通过组织学分析、COX 同工酶、PGE₂ 受体和 PGE₂ 含量的 mRNA 表达评估肿瘤。所有 OE33 肿瘤均为低分化食管腺癌。肿瘤表达 COX-2、EP₁、EP₂ 和 EP₄ 受体 mRNA。帕瑞昔布高剂量或吲哚美辛治疗显著抑制肿瘤生长。此外，吲哚美辛诱导肿瘤消退（对照动物中为 74%比 582%；p<0.01）。然而，AH-23848B 或帕瑞昔布低剂量未能显著影响肿瘤生长。高剂量帕瑞昔布和吲哚美辛显著降低肿瘤中的 PGE₂ 含量。吲哚美辛和帕瑞昔布抑制裸鼠中人类食管腺癌异种移植物的生长，这表明 NSAIDs 或选择性 COX-2 抑制剂可能用于 EAC 化疗。
