【摘要】：目的:以靜脈給予食蟹猴抗表皮生長(zhǎng)因子受體(anti-EGFR)單克隆抗體長(zhǎng)期毒性研究作為個(gè)案分析,探討藥物毒性研究中應(yīng)激反應(yīng)造成多器官損傷的組織病理學(xué)特征。方法:將食蟹猴隨機(jī)分為4組,分別為溶媒對(duì)照組、低劑量組、中劑量組和高劑量組。靜脈推注給予EGFR單抗,每周1次,連續(xù)26周,停藥后8周的恢復(fù)期。中高劑量組因動(dòng)物狀態(tài)差處于瀕死狀態(tài)而提前至給藥22周解剖,進(jìn)入恢復(fù)期。本研究中10只動(dòng)物在給藥期間死亡,死亡動(dòng)物和其余動(dòng)物均進(jìn)行解剖和組織病理學(xué)檢查。通過(guò)免疫組織化學(xué)方法檢查所有動(dòng)物垂體的促腎上腺皮質(zhì)激素(ACTH)的表達(dá)。結(jié)果:本實(shí)驗(yàn)中給藥動(dòng)物出現(xiàn)不同程度腹瀉、稀便、皮膚發(fā)紅、脫毛、脫屑、潰爛。死亡動(dòng)物的免疫器官表現(xiàn)出明顯萎縮,包括胸腺、脾臟、淋巴結(jié)中淋巴細(xì)胞數(shù)目減少。死亡的雌性動(dòng)物子宮重量減低,組織病理學(xué)表現(xiàn)為子宮萎縮伴纖維組織增生。此外,中高劑量組死亡動(dòng)物腎上腺表現(xiàn)為皮質(zhì)束狀帶細(xì)胞肥大。中高劑量組動(dòng)物垂體ACTH的表達(dá)明顯高于溶媒對(duì)照組。結(jié)論:藥物毒性研究中應(yīng)激反應(yīng)誘導(dǎo)的免疫器官的萎縮,可伴有腎上腺皮質(zhì)束狀帶細(xì)胞肥大。采用權(quán)重法綜合分析所有數(shù)據(jù),并結(jié)合垂體促腎上腺皮質(zhì)激素的檢測(cè),這對(duì)于輔助性鑒別診斷應(yīng)激和直接免疫毒性具有一定的意義。
[Abstract]:Objective: to study the long term toxicity of monoclonal antibody against epidermal growth factor receptor (anti-EGFR) induced by intravenous administration of anti-epidermal growth factor receptor (anti-EGFR) in crab monkeys as a case study, and to investigate the histopathological characteristics of multiple organ damage caused by stress response in drug toxicity study. Methods: the monkeys were randomly divided into four groups: medium control group, low dose group, middle dose group and high dose group. EGFR McAb was given intravenously once a week for 26 weeks, 8 weeks after withdrawal. In the middle and high dose group, the animals were dissected for 22 weeks due to their poor state of state. In this study, 10 animals died during administration, and all the dead animals and other animals were examined by anatomy and histopathology. The expression of adrenocorticotropic hormone (ACTH) in pituitary of all animals was detected by immunohistochemical method. Results: diarrhea, dilute stool, redness, depilation, desquamation and ulceration were observed in this experiment. The immune organs of the dead animals showed significant atrophy, including a decrease in the number of lymphocytes in the thymus, spleen, and lymph nodes. The weight of the dead female uterus is reduced, and the histopathological features are uterine atrophy with fibrous tissue proliferation. In addition, the adrenal gland in the middle and high dose groups showed hypertrophy of cortical bundles. The expression of pituitary ACTH in the middle and high dose group was significantly higher than that in the solvent control group. Conclusion: the atrophy of immune organs induced by stress in the study of drug toxicity may be accompanied by hypertrophy of adrenal cortical bundles. The weight method was used to analyze all the data and combined with the detection of pituitary adrenocorticotropic hormone, which has a certain significance for the differential diagnosis of stress and direct immunotoxicity.
【作者單位】： 中國(guó)食品藥品檢定研究院國(guó)家藥物安全評(píng)價(jià)監(jiān)測(cè)中心;神州細(xì)胞工程有限公司;
【基金】：國(guó)家“重大新藥創(chuàng)制”科技重大專項(xiàng)資助項(xiàng)目(2015ZX09501007-004;2009ZX09102-216)
【分類號(hào)】：R96

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