经塞来昔布治疗后 Pirc（F344/NTac-Apc）大鼠结肠 PGE 水平的急性变化作为疗效的生物标志物。

Acute changes in colonic PGE levels as a biomarker of efficacy after treatment of the Pirc (F344/NTac-Apc ) rat with celecoxib.

机构信息

Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States.

Safety Assessment and Laboratory Animal Resources, Merck & Co., West Point, PA, 19486, USA.

出版信息

Inflamm Res. 2020 Jan;69(1):131-137. doi: 10.1007/s00011-019-01300-5. Epub 2019 Dec 3.

DOI:10.1007/s00011-019-01300-5

PMID:31797003

Abstract

OBJECTIVE

This study sought to evaluate short-term treatment with COX-2 inhibitors and acute changes in colonic PGE2 levels as predictors of long-term efficacy in a genetic model of colorectal cancer.

METHODS

Celecoxib oral suspension (40 mg/kg BID) was dosed to Apc-mutant Pirc (F344/NTac-Apcam1137) rats for 4 days (short-term group), or the equivalent dose of 1500 ppm celecoxib was administered in the diet for 4 months (long-term group). Percent inhibition of colonic PGE2 was calculated, and the reduction in colonic PGE2 was assessed in relation to suppression of adenomatous colon polyps.

RESULTS

Colonic mucosa PGE2 was fourfold higher in Pirc than in F344 wild-type rats (21 vs. 5.6 pg/mg epithelial tissue), due at least in part to higher COX-2 expression, and this was confirmed by elevated PGE2-d11 levels in Pirc colonic S9 incubations. In the 4-day study, dose-dependent reductions in PGE2 were observed in colonic epithelium (-33% (P>0.05) and -57% (P=0.0012)), after low- and high-dose celecoxib treatments of 4 mg/kg and 40 mg/kg (bid), respectively. In the 4-month study, 1500 ppm celecoxib suppressed colonic epithelium PGE2 by 43.5%, and tumor multiplicity by 80% (P<0.0015). Suppression of plasma 6-keto PGF1α also was corroborated following long-term treatment with 1500 ppm celecoxib (P<0.05).

CONCLUSIONS

Acute changes in colonic mucosa PGE2 provided a rapid means of predicting long-term chemopreventive effects from celecoxib, and might be useful for screening of new COX-2 inhibitor compounds.

摘要

目的

本研究旨在评估 COX-2 抑制剂短期治疗和结肠 PGE2 水平的急性变化，作为结直肠癌遗传模型中长期疗效的预测指标。

方法

将塞来昔布口服混悬液（40mg/kg，bid）给 Apc 突变 Pirc（F344/NTac-Apcam1137）大鼠灌胃 4 天（短期组），或在饮食中给予相当于 1500ppm 塞来昔布的剂量 4 个月（长期组）。计算结肠 PGE2 的抑制百分率，并评估结肠 PGE2 的减少与腺瘤性结肠息肉的抑制有关。

结果

Pirc 结肠黏膜 PGE2 是 F344 野生型大鼠的四倍（21 比 5.6pg/mg 上皮组织），至少部分原因是 COX-2 表达升高，这在 Pirc 结肠 S9 孵育中升高的 PGE2-d11 水平中得到证实。在 4 天的研究中，低剂量（4mg/kg，bid）和高剂量（40mg/kg，bid）塞来昔布治疗后，结肠上皮的 PGE2 呈剂量依赖性减少（-33%（P>0.05）和-57%（P=0.0012））。在 4 个月的研究中，1500ppm 塞来昔布抑制结肠上皮 PGE2 达 43.5%，肿瘤多发性达 80%（P<0.0015）。长期用 1500ppm 塞来昔布治疗后，血浆 6-酮-PGF1α 的抑制也得到证实（P<0.05）。