【正文】 Multistage Carcinogenesis: PROMOTION Reversible enhancement/repression of gene expression: increased cell proliferation inhibition of apoptosis No direct structural alteration in DNA by agent or its metabolites Cellular and Molecular Mechanisms in Multistage Carcinogenesis: PROGRESSION ? Irreversible enhancement/repression of gene expression ? Complex geic alterations (chromosomal translocations, deletions, gene amplifications, rebinations, etc.) ? Selection of neoplastic cells for optimal growth genotype/ phenotype in response to the cellular environment “Complex” geic changes 致癌過程不同階段的特征 Initiation DNA modification, Mutation, Genotoxic One cell division necessary to lock in mutation Modification is not enough to produce cancer Nonreversible, Single treatment can induce mutation Promotion No direct DNA modification, Nongenotoxic, No direct mutation Multiple cell divisions necessary, Threshold Clonal expansion of the initiated cell population Increase in cell proliferation or decrease in cell death (apoptosis) Reversible, Multiple treatments (prolonged treatment) necessary Progression DNA modification, Genotoxic event? Mutation, chromosome disarrangement , Irreversible Changes from preneoplasia to neoplasia benign/malignant Number of treatments needed with pound unknown 遺傳毒物對 DNA和非 DNA相互作用的機(jī)制 正常細(xì)胞 遺傳改變 （突變） 遺傳改變的細(xì)胞 癌細(xì)胞 異倍體細(xì)胞 表遺傳 干擾 遺傳毒性致癌物 非遺傳毒性致癌物 遺傳毒性和非遺傳毒性致癌 物在多階段致癌中的區(qū)別 遺傳毒性和非遺傳毒性致癌物作用機(jī)制的比較 遺傳毒性致癌物 非遺傳毒性致癌物 遺傳毒性測試 陽性 陰性 多階段致癌作用 遺傳改變 表遺傳改變 第一階段 基因突變 細(xì)胞增殖 染色體畸變 再生 生長因子刺激 過氧化物酶體增殖 細(xì)胞間間隙連接通訊 基因組印記 以后階段 遺傳或表遺傳改變 遺傳或表遺傳改變 低劑量的劑量－反應(yīng)關(guān)系 無致癌性閾值 線性劑量－反應(yīng)曲線 致癌性閾值 S型劑量－反應(yīng)曲線 化學(xué)致癌的生物學(xué)特征 致癌物多數(shù)具有遺傳毒性，遺傳毒性致癌物盡管化學(xué)結(jié)構(gòu)和性質(zhì)不盡相同，但有一共同的特點(diǎn)，即皆為親電子劑。 CD 1, 1CRCr: CD 1 mice。 S D, Sprague– Dawley rats。 存在潛在致癌的擔(dān)憂因素 1）已有證據(jù)顯示此類藥物具有與人類相關(guān)的潛在致癌性； 2）其構(gòu)效關(guān)系提示致癌的風(fēng)險； 3）重復(fù)給藥毒性試驗(yàn)中有癌前病變的證據(jù)； 4）導(dǎo)致局部組織反應(yīng)或其它病理生理變化的化合物或其代謝產(chǎn)物在組織內(nèi)長期滯留 內(nèi)源性肽類、蛋白類物質(zhì)及其類似物 對于替代治療的內(nèi)源性物質(zhì)（濃度在生理水平），尤其是當(dāng)同類產(chǎn)品（如動物胰島素、垂體來源的生長激素和降鈣素）已有臨床使用經(jīng)驗(yàn)時，通常不需要進(jìn)行致癌試驗(yàn) 1）其生物活性與天然物質(zhì)明顯不同； 2）與天然物質(zhì)比較顯示修飾后結(jié)構(gòu)發(fā)生明顯改變 3）藥物的暴露量超過了血液或組織中的正常水平 化學(xué)致癌的過程及其機(jī)制 化學(xué)致癌 (chemical carcinogenesis) 化學(xué)物質(zhì)引起或增進(jìn)正常細(xì)胞發(fā)生惡性轉(zhuǎn)化并發(fā)展成為腫瘤的過程。 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)暴露評價技術(shù)更有意義。據(jù)