【正文】 B6C3F1, mice, (C57BL/6N+C3H/HeN)F1。具有這類(lèi)作用的化學(xué)物質(zhì)稱(chēng)為 化學(xué)致癌物(chemical carcinogen). 化學(xué)致癌研究的重要?dú)v史事件 1761, J Hill 提出使用鼻煙可能會(huì)誘發(fā)鼻咽癌 1775, P Pott 提出掃煙囪男童陰囊癌與煤煙過(guò)度暴露有關(guān) 1895 , L Rehn 首次報(bào)道從事苯胺染料生產(chǎn)的工人發(fā)生膀胱癌 1914, T Boveri 提出惡性腫瘤起源于存在染色體異常的單個(gè)細(xì)胞 （ 這就是著名的癌癥 體細(xì)胞突變理論 和 腫瘤單細(xì)胞克隆起源學(xué)說(shuō) ） 1915, Yamagiwa, K Ichikawa 通過(guò)長(zhǎng)期給兔耳涂煤焦油成功地誘發(fā)皮膚癌 （ 實(shí)驗(yàn)性化學(xué)致癌研究的開(kāi)端 ） 19321938， 先后給雄性小鼠注射雌激素誘發(fā)乳腺癌 、 通過(guò)慢性飼喂偶氮染料 O－氨基偶氮甲苯誘發(fā)出大鼠肝癌 、 使用 β－萘胺誘發(fā)狗膀胱癌成功 19411944,首次提出 啟動(dòng) (Initation)和 促進(jìn) (Promotion)的概念 , 根據(jù)多次使用巴豆油能促進(jìn)苯并芘誘發(fā)小鼠皮膚癌提出 小鼠皮膚癌兩階段致癌模型 。 致癌試驗(yàn)仍是目前評(píng)價(jià)藥物致癌作用最可靠和最有意義的方法 已評(píng)價(jià)的致癌物中有 93%(515/554)至少在三項(xiàng)標(biāo)準(zhǔn)遺傳毒性試驗(yàn)中有一項(xiàng)呈陽(yáng)性 , 表明在檢測(cè)致癌物（敏感性）是成功的；然而鑒定非致癌物的能力（特異性）較差 ， 183種在大、小鼠致癌試驗(yàn)中為陰性的物質(zhì) 80% 以上有體外遺傳毒性陽(yáng)性的資料。藥物致癌性的研究 現(xiàn)狀和動(dòng)態(tài) 第二軍醫(yī)大學(xué)藥物安全性評(píng)價(jià)中心 第二軍醫(yī)大學(xué)衛(wèi)生毒理學(xué)教研室 張?zhí)鞂? 藥物致癌性研究的必要性 腫瘤是一類(lèi)嚴(yán)重影響人類(lèi)健康和生命的疾病 腫瘤已成為人類(lèi)死亡的第 1或 2位原因，每年約有 700萬(wàn)人死于癌癥。 The European Centre for the Validation of Alternative Methods (ECVAM) A recent analysis of nearly 1000 chemicals for which data have been published has highlighted the strikingly imprecise nature of in vitro geic toxicology tests in discriminating noncarcinogens from carcinogens. When the standard battery of two or three in vitro genotoxicity tests was performed, at least 80% of the 177 noncarcinogenic pounds tested gave a false positive result in at least one test. The false positive rate was highest in mammalian cell tests such as those to detect chromosomal Aberrations or micronucleus in Chinese hamster cells, or Mutations in the mouse lymphoma assay. A similar oute was obtained in analysis by the . FDA of an even larger database of chemicals. Performance of individual genotoxic tests in detecting rodent carcinogens as analyzed by Kirkland et al. (2022). Ames MLN MN Sensitivity (%) Specificity (%) Ames+ MLA Ames + MN MLA + MN Ames + MLA + MN Sensitivity (%) Specificity (%) Performance of simultaneous testing batteries of genotoxic tests in detecting rodent carcinogens as analyzed In vitro genotox testing: the problem …poor specificity 大多數(shù)致癌物在組合試驗(yàn)中呈陽(yáng)性 －－ Good! 大多數(shù)非致癌物在組合試驗(yàn)中也呈陽(yáng)性 －－ Bad! 特異性 敏感性 Ames MLA Ames MN MN Indomethacin(吲哚美鋅 ) tested negative for in vivo cytogeic assays in the regulatory tests, but was reported positive for the induction of DNA adducts in the literature. Halothane(氟烷 ) and pyrazinamide(吡嗪酰胺 ) were also in vivo positive for et test in human lymphocytes and induction of sperm head abnormalities in mice, respectively, which are considered nonregulatory tests. 某些藥物是非遺傳毒性的致癌物 用遺傳毒性試驗(yàn)無(wú)法檢出 很多管理機(jī)構(gòu)都提出了致癌試驗(yàn)的要求 日本 (1990)， 如果臨床預(yù)期連續(xù)用藥 6個(gè)月或更長(zhǎng)時(shí)間，則需要進(jìn)行致癌試驗(yàn)。 1949 Foulds提出 腫瘤演進(jìn) (Progression) 概念 19711981, C Peraino等 , 發(fā)現(xiàn)小鼠皮膚癌兩階段致癌理論同樣適用于大鼠肝癌的發(fā)生情況；隨后建立了適用于各種臟器腫瘤的多階段癌變理論 1984, A Balmain, 首次報(bào)道在化學(xué)致癌物誘發(fā)的小鼠皮膚乳頭狀瘤中的 cHaras基因被激活；隨后發(fā)現(xiàn)多種致癌物可使不同的癌基因活化 和 抑癌基因失活 Initiating Event Cell Proliferation (clonal expansion) Progression Cell Proliferation Cell Proliferation Malignancy Initiation Promotion Stages of Carcinogenesis Cellular and Molecular Mechanisms in Multistage Carcinogenesis: INITIATION Initiating event involves cellular genome – MUTATIONS Target genes: oncogenes/tumor suppressor genes signal transduction cell cycle/apoptosis regulators “Simple” geic changes Gentic and Epigeic Models of The Cancer Initiation Epigeically reprogrammed cells Mutator phenotype cells Endogenous Environmental ALTERATIONS IN CELLULAR EPIGENOME Normal cells Cancer cells Clonal selection and expression of initiated cells Mutator phenotype cells Endogenous Environmental ACQUISITION OF ADDITIONAL RANDOM MUTATIONS Normal cells Cancer cells Cellular and Molecular Mechanisms in