Yáñez Jaime A, Teng Xiao Wei, Roupe Kathryn A, Fariss Marc W, Davies Neal M
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6534, USA.
J Pharm Pharm Sci. 2003 Sep-Dec;6(3):308-14.
The gastrointestinal damage induced by xenobiotics is occurring more frequently and with greater toxicological significance than previously thought. Although there are some preliminary clinical studies and reports, there does not appear to be an extensive examination of gastrointestinal toxicity of various chemotherapeutic agents in the rat. This study was undertaken to examine the suitability of a rat model to detect the gastrointestinal damage after administration of various anti-neoplastic agents including etoposide, teniposide, melphalan, 5-fluorouracil, methotrexate and cisplatin.
Acute toxic doses of indomethacin and chemotherapeutic agents were administered to rats. The urinary excretion of orally administered sucrose and 51(Cr)-EDTA were measured as markers of gastroduodenal and intestinal permeability, respectively. Cyclooxygenase-2 messenger RNA and mitochondrial DNA damage were measured as toxicological endpoints.
Each anti-neoplastic agent examined induced appreciable and significant dose-dependent increase in gastrointestinal permeability that correlated with gross toxicological and pathological changes to the gastrointestinal tract including ulceration and bleeding. COX-2 mRNA was upregulated > 2 fold in intestinal mucosa with enteropathy and dose-dependent mitochondrial oxidative damage was apparent in gastric and intestinal mucosa. After administration of each drug, the rats presented with histological evidence of drug-induced gastroenteropathy, ulceration and increased cecal hemoglobin.
The rat appears to be a suitable model to study gastrointestinal toxicity of chemotherapeutic agents and non-steroidal anti-inflammatory drugs. Damage to mitochondrial DNA occurs in both the gastric and intestinal epithelium after the administration of these agents and may be an important factor in the pathogenesis and resolution of gastrointestinal toxicity.
异生物素引起的胃肠道损伤比之前认为的更为频繁，且具有更大的毒理学意义。尽管有一些初步的临床研究和报告，但似乎没有对大鼠体内各种化疗药物的胃肠道毒性进行广泛研究。本研究旨在检验大鼠模型对于检测包括依托泊苷、替尼泊苷、美法仑、5-氟尿嘧啶、甲氨蝶呤和顺铂在内的各种抗肿瘤药物给药后胃肠道损伤的适用性。
向大鼠给予消炎痛和化疗药物的急性中毒剂量。分别测量口服蔗糖和51（铬）-乙二胺四乙酸的尿排泄量，作为胃十二指肠和肠道通透性的标志物。测量环氧合酶-2信使核糖核酸和线粒体DNA损伤作为毒理学终点。
所检测的每种抗肿瘤药物均引起胃肠道通透性明显且显著的剂量依赖性增加，这与胃肠道的大体毒理学和病理学变化相关，包括溃疡和出血。在患有肠病的肠黏膜中，环氧合酶-2信使核糖核酸上调超过2倍，在胃和肠黏膜中明显存在剂量依赖性线粒体氧化损伤。给予每种药物后，大鼠呈现出药物诱导的胃肠病、溃疡和盲肠血红蛋白增加的组织学证据。
大鼠似乎是研究化疗药物和非甾体抗炎药胃肠道毒性的合适模型。给予这些药物后，胃和肠上皮细胞均发生线粒体DNA损伤，这可能是胃肠道毒性发病机制和恢复过程中的一个重要因素。
