药物的致癌性PPT课件

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1、 肿 瘤 是 一 类 严 重 影 响 人 类 健 康 和 生 命 的 疾 病 Age-adjusted Cancer Death Rates, by Site, US, 1930-2005 1957、 1984、 1999、 2004年 我 国 城 市 主 要 疾 病 死 因构 成 比 及 死 因 顺 位顺位1957 1984 1999 2004死 因比例(%)死 因比例(%)死 因比例(%)死因比例（%）1呼吸系统16.86心脏病22.65脑血管病22.28恶性肿瘤27.232传染病7.93脑血管病21.13恶性肿瘤21.66脑血管病18.47 3肺结核7.51恶性肿瘤21.11心脏病16.

2、37心脏病17.234消化系统7.31呼吸系统8.79呼吸系统15.28呼吸系统12.775心脏病6.61消化系统4.32意外伤害6.52损伤中毒6.56 WORLD HEALTH ORGANIZATIONINTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC Monograph Evaluations LYON, FRANCE Slide courtesy of V. Cogliano (IARC) IARC (2009) - monographs. iarc. frCarcinogenic to humans (group 1) 108 agents

3、Probably carcinogenic to humans (group 2A) 66Possibly carcinogenic to humans (group 2B) 248Not classifiable as to its carcinogenicity to humans (group 3) 515 Probably not carcinogenic to humans (group 4) 1 IARC: IARC Group 1 Carcinogenic to humansMedical drugs and treatments 24Industrial processes 1

4、3Infectious agents or processes 10Physical agents 10Industrial chemicals 7Inhaled particulates 5Metals and inorganic salts 5Lifestyle factors (incl. herbal remedies) 7Other 8Group 2A 66 Medical drugs and treatments 12 Chemical Carcinogenesis in the 21st CenturyNew perceptions of previously known car

5、cinogens: Combined effects of multiple exposuresExamples:o Alcohol drinking and aflatoxinso Alcohol drinking and HBV/HBCo Alcohol drinking and tobacco smokingo Tobacco smoking and asbestos/arsenic/radon 致 癌 试 验 仍 是 目 前 评 价 药 物 致 癌 作 用 最 可靠 和 最 有 意 义 的 方 法 已 评 价 的 致 癌 物 中 有 93%(515/554)至 少 在 三 项标 准 遗

6、 传 毒 性 试 验 中 有 一 项 呈 阳 性 , 表 明 在 检 测致 癌 物 （ 敏 感 性 ） 是 成 功 的 ； 然 而 鉴 定 非 致 癌 物的 能 力 （ 特 异 性 ） 较 差 ， 183种 在 大 、 小 鼠 致 癌试 验 中 为 阴 性 的 物 质 80% 以 上 有 体 外 遗 传 毒 性 阳性 的 资 料 。 The European Centre for the Validation of Alternative Methods (ECVAM)A recent analysis of nearly 1000 chemicals for which data have

7、been published has highlighted the strikingly imprecise nature of in vitro genetic toxicology tests in discriminating non-carcinogens from carcinogens. When the standard battery of two or three in vitro genotoxicity tests was performed, The false positive rate was highest in mammalian cell tests suc

8、h as those to detect chromosomal Aberrations or micronucleus in Chinese hamster cells, or Mutations in the mouse lymphoma assay. A similar outcome was obtained in analysis by the U. S. FDA of an even larger database of chemicals. Performance of individual genotoxic tests in detecting rodent carcinog

9、ens as analyzed by Kirkland et al. (2005). Sensitivity (%) 58.8 73.1 78.7Specificity (%) 73.9 39.0 30.8Sensitivity (%) 81.0 85.9 87.0 90.7Specificity (%) 32.4 12.0 10.0 5.0Performance of simultaneous testing batteries of genotoxic tests in detecting rodent carcinogens as analyzed In vitro genotox te

10、sting: the problem Good!Bad!特异性敏感性 Ames MLA AmesMN MN Indomethacin(吲哚美锌) tested negative for in vivo cytogenetic 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 comet tes

11、t in human lymphocytes and induction of sperm head abnormalities in mice, respectively, which are considered non-regulatory tests.某 些 药 物 是 非 遗 传 毒 性 的 致 癌 物 -用 遗 传 毒 性试 验 无 法 检 出 很 多 管 理 机 构 都 提 出 了 致 癌 试 验 的 要 求日本(1990)，如 果 临 床 预 期 连 续 用 药 6个 月 或 更 长 时 间 ，则 需 要 进 行 致 癌 试 验 。 尽 管 连 续 用 药 少 于 6个 月 ，

12、 如 果存 在 潜 在 致 癌 性 因 素 ， 也 可 能 需 要 进 行 致 癌 试 验 。美国，一 般 药 物 使 用 3个 月 或 更 长 时 间 ， 需 要 进 行 致 癌试 验 。欧洲，规 定 长 期 应 用 的 药 物 ， 即 至 少 6个 月 的 连 续 用 药 ，或 频 繁 的 间 歇 性 用 药 以 致 总 的 暴 露 量 与 前 者 相 似 的 药 物需 要 进 行 致 癌 试 验 .2010年04月01日我国SFDA制定发布了药物致癌试验必要性的技术指导原则 药 物 致 癌 试 验 2010年04月01日SFDA制定发布了药物致癌试验必要性的技术指导原则 预 期 临 床

13、用 药 期 至 少 连 续 6个 月 的 药 物 一 般 应 进 行 。 连 续 用 药 没 有 6个 月 ， 但 以 间 歇 的 方 式 重 复 使 用 ，如 治 疗 慢 性 和 复 发 性 疾 病 (包 括 过 敏 性 鼻 炎 、 抑 郁 症和 焦 虑 症 )， 而 需 经 常 间 歇 使 用 的 药 物 ， 一 般 也 需 进行 。 某 些 可 能 导 致 暴 露 时 间 延 长 的 释 药 系 统 ， 也 应 考 虑进 行 致 癌 试 验 。 存 在 潜 在 致 癌 的 担 忧 因 素 1） 已 有 证 据 显 示 此 类 药 物 具 有 与 人 类 相 关 的 潜 在 致 癌 性 ；

14、 2） 其 构 效 关 系 提 示 致 癌 的 风 险 ； 3） 重 复 给 药 毒 性 试 验 中 有 癌 前 病 变 的 证 据 ； 4） 导 致 局 部 组 织 反 应 或 其 它 病 理 生 理 变 化 的 化 合 物 或 其 代谢 产 物 在 组 织 内 长 期 滞 留 内 源 性 肽 类 、 蛋 白 类 物 质 及 其 类 似 物 对于替代治疗的内源性物质（浓度在生理水平），尤其是当同类产品（如动物胰岛素、垂体来源的生长激素和降钙素）已有临床使用经验时，通常不需要进行致癌试验 1） 其 生 物 活 性 与 天 然 物 质 明 显 不 同 ； 2） 与 天 然 物 质 比 较 显 示

15、 修 饰 后 结 构 发 生 明 显 改 变 3） 药 物 的 暴 露 量 超 过 了 血 液 或 组 织 中 的 正 常 水 平 化学致癌 (chemical carcinogenesis) 化 学 物 质 引 起或 增 进 正 常 细 胞 发 生 恶 性 转 化 并 发 展 成 为 肿 瘤 的过 程 。 具 有 这 类 作 用 的 化 学 物 质 称 为化学致癌物(chemical carcinogen). 1761, J Hill 提 出 使 用 鼻 烟 可 能 会 诱 发 鼻 咽 癌1775, P Pott 提 出 扫 烟 囱 男 童 阴 囊 癌 与 煤 烟 过 度 暴 露 有 关18

16、95 , L Rehn 首 次 报 道 从 事 苯 胺 染 料 生 产 的 工 人 发 生 膀 胱 癌1914, T Boveri 提 出 恶 性 肿 瘤 起 源 于 存 在 染 色 体 异 常 的 单 个 细胞 （ 这 就 是 著 名 的 癌 症 体 细 胞 突 变 理 论 和 肿 瘤 单 细 胞 克 隆起 源 学 说 ） 1915, Yamagiwa, K Ichikawa 通 过 长 期 给 兔 耳 涂 煤 焦 油 成 功 地 诱 发皮 肤 癌 （ 实 验 性 化 学 致 癌 研 究 的 开 端 ）1932-1938，先 后 给 雄 性 小 鼠 注 射 雌 激 素 诱 发 乳 腺 癌 、

17、 通 过 慢 性饲 喂 偶 氮 染 料 O 氨 基 偶 氮 甲 苯 诱 发 出 大 鼠 肝 癌 、 使 用 萘 胺诱 发 狗 膀 胱 癌 成 功 1941-1944,首 次 提 出 启 动 (Initation)和 促 进 (Promotion)的 概 念 , 根 据多 次 使 用 巴 豆 油 能 促 进 苯 并 芘 诱 发 小 鼠 皮 肤 癌 提 出 小 鼠 皮 肤 癌两 阶 段 致 癌 模 型 ; 1949 Foulds提 出 肿 瘤 演 进 (Progression) 概 念 1971-1981, C Peraino等, 发 现 小 鼠 皮 肤 癌 两 阶 段 致 癌 理 论 同 样 适

18、用 于 大 鼠 肝 癌 的 发 生 情 况 ； 随 后 建 立 了 适 用 于 各 种 脏 器 肿 瘤 的多 阶 段 癌 变 理 论1984-, A Balmain, 首 次 报 道 在 化 学 致 癌 物 诱 发 的 小 鼠 皮 肤 乳 头 状瘤 中 的 c-Ha-ras基 因 被 激 活 ； 随 后 发 现 多 种 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) ProgressionCell ProliferationCell Proliferatio

19、n MalignancySecond Mutating EventN Mutating Event Initiation Promotion Cellular and Molecular Mechanisms in Multistage Carcinogenesis: INITIATIONInitiating event involves cellular genome MUTATIONSTarget genes: - oncogenes/tumor suppressor genes - signal transduction - cell cycle/apoptosis regulators

20、“Simple” genetic changes Gentic and Epigenetic Models of The Cancer InitiationEpigenetically reprogrammed cellsMutator phenotype cellsALTERATIONS IN CELLULAR EPIGENOMENormal cellsCancer cellsClonal selection and expression of initiated cellsMutator phenotype cellsACQUISITION OF ADDITIONAL RANDOM MUT

21、ATIONSNormal cellsCancer cells Cellular and Molecular Mechanisms in Multistage Carcinogenesis: PROMOTIONReversible enhancement/ repression of gene expression:- increased cell proliferation- inhibition of apoptosisNo direct structural alteration in DNA by agent or its metabolites Cellular and Molecul

22、ar Mechanisms in Multistage Carcinogenesis: PROGRESSION Irreversible enhancement/repression of gene expression Complex genetic alterations (chromosomal translocations, deletions, gene amplifications, recombinations, etc.) Selection of neoplastic cells for optimal growth genotype/ phenotype in respon

23、se to the cellular environment“Complex” genetic changes 致 癌 过 程 不 同 阶 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 mutationPromotion No direct DNA modifi

24、cation, 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) necessaryProgression DNA modification, Ge

25、notoxic event? Mutation, chromosome disarrangement , Irreversible Changes from preneoplasia to neoplasia benign/malignant Number of treatments needed with compound unknown 致 癌 作 用 依 赖 于 化 学 致 癌 物 的 剂 量 ,大 剂 量 的 致癌 物 可 增 强 肿 瘤 的 发 生 , 缩 短 潜 伏 期 .肿 瘤 的 产生 取 决 于 化 学 致 癌 物 的 总 剂 量 。 同 时 暴 露 于 几 种致 癌 物 ，

26、 可 发 生 联 合 作 用 。 The development of cancer is a multi-step process “Initiation” forms an early adenoma “Promotion” leads to a late adenoma “Progression” leads first to a cancer in situ, then on to “Malignant conversion,” which leads to true a carcinoma This set of processes often takes YEARS Genotox

27、ic carcinogens increase tumour frequency in animal cancer bioassay positive results from in vitro and in vivo genotoxicity tests either direct-acting or indirectly acting genotoxic carcinogensNon-genotoxic carcinogens usually act as tumor promoters positive in cancer bioassay in animals, but negativ

28、e in genotoxicity tests The mechanism of carcinogenicity may include the chronic injury and regeneration hormonal mechanisms increase in the cell proliferation or decrease in the cell death in target organ When one foreign chemical is suffient to cause cancer, either as a direct or indirect carcinog

29、en, it is said to be complete When it requires a tumor promoter to cause cancer, it is an incomplete carcinogen Promotors are compounds that induce cells, like the mutated cancer initiator cell, to grow and divide, making more DNA reactivity (covalent binding)Gene mutationChromosomal breakageAneuplo

30、idyEnzyme-mediated effects on DNA damage or repairEpigenetic effectsCell signaling: nuclear receptor-mediatedCell signaling: other than nuclear receptor-mediatedImmune response modulationInflammationCytotoxicity and compensatory cell proliferationMitogenicityChronic metabolic or physiologic overload

31、Nutrient deficiency related Interference with intercellular communication ICH Guideline S1B onTesting for Carcinogenicity of Pharmaceuticalschoosing one 2-year rodent carcinogenicity study (rat) plus one other study that supplements the 2-year study and providing additional information that is not r

32、eadily available from the 2-year study: either (1) a short- or medium-term in vivo rodent test system or (2) a 2-year carcinogenicity study in a second rodent species (mouse).the short- or medium-term models was intended to focus on the use of in vivo models providing insight into carcinogenic endpo

33、ints such as and models of carcinogenesis using or Stipulated Rationale for Choosing a Short- or Medium-Term Test System as Supplement to One 2- Year Bioassay The mechanism of carcinogenesis in the model should most likely be relevant to humans, and therefore the use of the model should be applicabl

34、e to human risk assessment. The use of the model should supplement the 2-yearcarcinogenicity study and it should provide additional information that is not readily available from the 2-yearstudy. Animal welfare, animal numbers, and overall economy of the carcinogenic evaluation process should be con

35、sidered. Two-year Carcinogenesis “Bioassay” Protocol Current Global Carcinogenicity Study Requirements Standard Tissue ListKidney Urinary bladder AortaHeart Trachea LungsLiver Gallbladder PancreasFat Salivary gland SpleenCervical lymph node Mesenteric lymph node ThymusTongue Esophagus StomachDuodenu

36、m Jejunum IleumCecum Colon Mammary glandSkin Skeletal muscle Sciatic nerveParathyroid Thyroid Adrenal glandPituitary Prostate Seminal vesiclesTestes Epididymides OvariesOviducts Uterine horns Uterine body Cervix Vagina BrainSpinal cord Sternum Rib/boneEyes Harderian glands BM smearNares Clitoral/pre

37、putial gland Zymbal s glandGross lesions 美国毒性病理学会（STP）建议致癌试验进行组织病理学检查的最基本的受检内容目录 Tumor - Bearing Animals in Control Groups from Rodent Studies Source : J. K. Haseman (unpublished summary of U.S. NTP data). Comparative Percent Incidence of Pertinent Neoplasia in Different Strains of Rats and Mice (10

38、4 Weeks Old) Note : F344, Fischer 244 rats; S- D, Sprague Dawley rats; B6C3F1, mice, (C57BL/6N+C3H/HeN)F1; CD- 1, 1CRCr: CD- 1 mice; NA, nonapplicable; the average number used by species/strain/gender was in excess of 750 animals Preclinical approaches for assessing carcinogenic potential Tumorigeni

39、city in humans, nonhuman primates and rodents Spontaneous tumor rates in the breeder and control animals Pietra et al. (1959).The neonatal mouse is one of the alternative in vivo models, for detecting the carcinogenic potential of pharmaceuticals. This is in agreement with the suggestions of ICH, wh

40、ich allows the use of one alternative study in place of one of the 2-year carcinogenicity studies.When treatment begins within the first 24 hours of life, the study design is described as “newbornmouse”. “neonatal mouse” includes test item administration at different timepoints from birth to three w

41、eeks of age.Fujii (1991) reported that the neonatal mouse assay showed a sensitivity of 85% and a positive prediction rate of 96% compared to the results of the adult mouse 2-year carcinogenicity study. Flammang et al. (1997) considered this model to have high sensitivity and specificity to detect g

42、enotoxic carcinogens as well as presenting advantages such as reduced test article requirements, decreased animal numbers and costs and a reduced completion time. McClain et al. (2001) reported that neonatal mice have been shown to have a reduced time for tumor induction, a higher multiplicity of in

43、duced tumors, a lower spontaneous tumor rate and an equivalent or higher sensitivity to carcinogens when compared to adult mice. This model also responds to a wide range of structurally dissimilar genotoxic compounds. Additionally, the neonatal mouse possesses the majority of the phase I and II biot

44、ransformation liver enzymes involved in the processes of activation and detoxification of carcinogens from different chemical classes. CD-1 mice 10 to 12 weeks of age. Mice were caged with 5 females per male and examined each day for the presence of a vaginal copulation plug. Females were isolated u

45、ntil delivery, 6 litters with 4 neonates / sex/ litter were assigned to each group during the first week after birth. Three or four dose levels, a vehicle and a positive control were used. Groups consisted of 24 animals/sex/group.They were dosed on the basis of their average bodyweight, on days 8 an

46、d 15 of age, using dose volumes of up to 100 and 200 l, respectively. Dose levels were selected on the basis of the results obtained in dose range finding studies, in which the MTD or the MFD (Maximum Feasible Dose) for neonatal mice, were determined. The pups were weaned around 22 days of age, hous

47、ed 4/sex/cage and then maintained until 1 year of age, when they were sacrificed. DEN (diethylnitrosamine) at a dosage of 2 mg/kg dissolved in water was used as the positive control. Tg.AC (v-Ha-ras) Transgenic Mouse89 weeks oldGroups of 15 mice/sex/dose were randomly assigned to the study groups.Th

48、e vehicles used for drugs and positive control agents were acetone, ethanol or DMSO. TPA (12-o-tetradecanoylphorbol-13-acetate) was the positive control compound26 weeks Hemizygous p53 +/ Knockout Mouse6 to 10 weeks old, Genotype analysis was recommended prior to assignment to dose groupsGroups of 1

49、5 mice/sex/group, Three dose levels, a vehicle and a positive control were used. Two additional groups of 15 wild-type mice/sex/group received the vehicle and the high dosage of the test compound.p-Cresidine at 400 mg/kg/day by gavage in corn oil (10ml/kg), or benzene at 100 mg/kg/day by gavage in c

50、orn oil (5 ml/kg) were recommended as positive controls.18 to 24 month bioassay Development of a high throughput genomics-based test for assessing genotoxic and carcinogenic properties of chemical compounds in vitroCombining pathway-associated gene expression with metabolic proiles generated in vitr

51、o, as is foreseen in carcinoGENOMICS, represents a highly innovative approach possibly leading to in silico models that may be used to predict the carcinogenic potential of a compound in vivo. Furthermore, toxicogenomics-based assays mayoutperform currently available tests for genotoxicity, as well

52、as for genotoxic and non-genotoxic carcinogenicity, without using animals. These in vitro methods may therefore play a major role under the new system of the Community regarding the REACH initiative. An in vitro screening test for predicting the tumor promoting potential of chemicals based on gene e

53、xpressionMaeshima et al. established an in vitro real-time PCR screening assay with BALB/c 3T3 cells for the assessment of the tumor promoting potential of chemicals.based on 22 marker genes, enables earlier assessment, and is easier to conduct than classical methods. 63 test chemicals showed an acc

54、uracy, sensitivity, and specificity of the assay of 96.8%, 97.0% and 96.7%, respectively. These results indicate that the tumor promoting activity assay, based on the expression of 22 marker genes, will become a valuable tool for rapid screening of potential tumor promoters. List of 22 markers for tumor promoting activity An enhanced 13-week bioassay: An alternative to the 2-year bioassay to screen for human carcinogenesis 谢谢大家！