[醫(yī)藥衛(wèi)生]藥物的致癌性-文庫(kù)吧資料
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【正文】 mical pounds in vitro Combining pathwayassociated gene expression with metabolic proiles generated in vitro, 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 pound in vivo. Furthermore, toxicogenomicsbased assays may outperform currently available tests for genotoxicity, as well as for genotoxic and nongenotoxic 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. 研究動(dòng)向 An in vitro screening test for predicting the tumor promoting potential of chemicals based on gene expression Maeshima et al. established an in vitro realtime 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 accuracy, sensitivity, and specificity of the assay of %, % and %, respectively. These results indicate that the tumor promoting activity assay, based on the expression of 22 marker genes, will bee a valuable tool for rapid screening of potential tumor promoters. List of 22 markers for tumor promoting activity An enhanced 13week bioassay: An alternative to the 2year bioassay to screen for human carcinogenesis 謝謝大家！ 。 CD 1, 1CRCr: CD 1 mice。 S D, Sprague– Dawley rats。在細(xì)胞惡變以前，細(xì)胞存在著多階段的癌前病變。同時(shí)暴露于幾種致癌物，可發(fā)生聯(lián)合作用。 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 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(guò)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
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