The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases
The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases
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DOI：
10.1016/s0016-5085(03)01061-8
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发表时间：
2003-09-01
期刊：
影响因子：
29.4
通讯作者：
Hull, MA
中科院分区：
文献类型：
--
作者：
Fenwick, SW;Toogood, GJ;Hull, MA
背景与目的：环氧化酶-2（cyclooxygenase-2，考克斯-2）是大肠癌（colorectal cancer，CRC）化疗的潜在靶点。我们在一项随机、双盲、安慰剂对照试验中，通过测量肿瘤生长和血管生成的替代标志物，检测选择性考克斯-2抑制剂罗非昔布对人CRC肝转移的抑制活性。研究方法：因转移性疾病接受肝切除手术的患者在手术前随机接受罗非昔布25 mg/d或安慰剂（持续时间>14天）。细胞凋亡指数（AI;采用免疫组化法检测转移瘤中的细胞增殖指数（PI; Ki-67）、微血管密度（MVD; CD 31）。研究罗非昔布对考克斯-2阳性HCA-7人结直肠癌细胞PGE（2）合成、增殖和凋亡的影响。结果：接受罗非昔布（n = 23）和安慰剂（n = 21）的患者在临床和转移特征方面匹配良好。罗非昔布治疗的平均（范围）持续时间为26（14-46）天。罗非昔布治疗转移瘤的MVD（平均值，25.1 [SEM，2.7]/hpf）比安慰剂治疗组织（32.5 [SEM，4.5]/hpf; P = 0.15）降低29%。Al（罗非昔布平均值，2.03% [SEM，0.43%] vs.安慰剂1.39% [SEM，0.39%]）或PI（罗非昔布54.7% [SEM，5.1%] vs.安慰剂52.6% [SEM，5.6%]）差异不大。罗非昔布诱导的HCA-7细胞生长停滞和凋亡仅在浓度（> 10 mumol/L）下发生，该浓度显著高于考克斯-2抑制的IC 50。结论：罗非昔布可能负性调节结直肠癌肝转移灶的血管生成。罗非昔布在体内对肝转移瘤中的上皮细胞没有显著的直接作用，这反映了在体外对人CRC细胞缺乏活性。
Background & Aims: Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial. Methods: Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib 25 mg daily or placebo before surgery (duration, >14 days). The apoptosis index (Al; neocytokeratin 18), proliferation index (PI; Ki-67), and microvessel density (MVD; CD31) were measured in metastases by immunohistochemistry. The effect of rofecoxib on COX-2-positive HCA-7 human CRC cell PGE(2) synthesis, proliferation, and apoptosis in vitro was also investigated. Results: Patients who received rofecoxib (n = 23) and placebo (n = 21) were well matched regarding clinical and metastasis characteristics. The mean (range) duration of rofecoxib therapy was 26 (14-46) days. Rofecoxib-treated metastases had a 29% decrease in MVD (mean, 25.1 [SEM, 2.7] per hpf) compared with placebo-treated tissue (32.5 [SEM, 4.5] per hpf; P = 0.15). There was little difference in Al (rofecoxib mean, 2.03% [SEM, 0.43%] vs. placebo 1.39% [SEM, 0.39%]) or PI (rofecoxib 54.7% [SEM, 5.1%] vs. placebo 52.6% [SEM, 5.6%]). Rofecoxib-induced growth arrest and apoptosis of HCA-7 cells occurred only at concentrations (> 10 mumol/L), which were significantly higher than the IC50 for COX-2 inhibition. Conclusions: Rofecoxib may negatively regulate angiogenesis in human CRC liver metastases. The absence of a significant, direct effect of rofecoxib on epithelial cells in liver metastases in vivo mirrors the lack of activity on human CRC cells at pharmacologically relevant concentrations in vitro.