[醫(yī)藥衛(wèi)生]藥物的致癌性(已修改)
2025-04-26 00:34 本頁(yè)面
【正文】 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 腫瘤是一類嚴(yán)重影響人類健康和生命的疾病 腫瘤已成為人類死亡的第 1或 2位原因，每年約有 700萬(wàn)人死于癌癥。據(jù) 2022年 WHO資料 ,目前每年新增腫瘤 1000萬(wàn)人，其中男性 530萬(wàn)人，與 1990年相比，全球癌癥患者發(fā)病率增長(zhǎng) 19％， 死亡率增長(zhǎng)了 18％。 我國(guó)惡性腫瘤 (2022年 )在各種死因中排在第二位，城市已排在首位。每年新增腫瘤 200萬(wàn)人。據(jù)預(yù)測(cè)我國(guó) 2022年年發(fā)病數(shù) 220萬(wàn)， 2020年為 300萬(wàn)。 Ageadjusted Cancer Death Rates, by Site, US, 19302022 195 198 199 2022年我國(guó)城市主要疾病死因構(gòu)成比及死因順位 順 位 1957 1984 1999 2022 死 因 比例 (%) 死 因 比例 (%) 死 因 比例 (%) 死因 比例（ %） 1 呼吸系統(tǒng) 心臟病 腦血管病 惡性腫瘤 2 傳染病 腦血管病 惡性腫瘤 腦血管病 3 肺結(jié)核 惡性腫瘤 心臟病 心臟病 4 消化系統(tǒng) 呼吸系統(tǒng) 呼吸系統(tǒng) 呼吸系統(tǒng) 5 心臟病 消化系統(tǒng) 意外傷害 損傷中毒 特別嚴(yán)重的是 ,腫瘤是我國(guó)最佳勞動(dòng)人口的首要死因，在 35－59歲年齡人口中，所有年齡組的第一位死因都是腫瘤，只有到了 60歲以后腦血管或心血管疾病才上升為第 1位死因。 What may cause cancer ? ? Hereditary disorders ? Chemicals ? Viruses ? Chronic inflammation ? ??? WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monograph Evaluations LYON, FRANCE Slide courtesy of V. Cogliano (IARC) IARC (2022) ?Carcinogenic to humans (group 1) – 108 agents ?Probably carcinogenic to humans (group 2A) – 66 ?Possibly carcinogenic to humans (group 2B) – 248 ?Not classifiable as to its carcinogenicity to humans (group 3) – 515 ?Probably not carcinogenic to humans (group 4) – 1 IARC: IARC Group 1 – Carcinogenic to humans Medical drugs and treatments 24 Industrial processes 13 Infectious agents or processes 10 Physical agents 10 Industrial chemicals 7 Inhaled particulates 5 Metals and inanic salts 5 Lifestyle factors (incl. herbal remedies) 7 Other 8 Group 2A – 66 Medical drugs and treatments 12 Chemical Carcinogenesis in the 21st Century New perceptions of previously known carcinogens: Combined effects of multiple exposures Examples: o Alcohol drinking and aflatoxins o Alcohol drinking and HBV/HBC o Alcohol drinking and tobacco smoking o Tobacco smoking and asbestos/arsenic/radon 在研究藥物的潛在致癌作用中，致癌試驗(yàn)比現(xiàn)有遺傳毒性試驗(yàn)和系統(tǒng)暴露評(píng)價(jià)技術(shù)更有意義。 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。 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 te
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