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首页> 外文期刊>Mutation Research, E. Environmental Mutagenesis and Related Subjects >DEVELOPMENT OF A SENSITIVE IN VITRO METHOD FOR IDENTIFYING TUMOR PROMOTERS
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DEVELOPMENT OF A SENSITIVE IN VITRO METHOD FOR IDENTIFYING TUMOR PROMOTERS

机译：识别肿瘤启动子的体外敏感方法的开发

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摘要

The identification and characterization of nongenotoxic carcinogens represents a significant challenge to toxicologists. In vitro methods for identifying tumor promoters with suitable sensitivity and specificity have been particularly elusive. Experiments are described which suggest that the human promyelocytic leukemia cell line HL-60 provides a sensitive indicator of promoter-induced changes to gene regulation and expression. As a result of differentiation these cells undergo a transition from a non-phagocytic suspension culture to an attached fibroblast-like culture which exhibits high phagocytic activity. Fluorescent latex particles were used as sensors to highlight the phagocytic phenotype and permitted the use of flow cytometry to automatically quantitate particle internalization. To evaluate specificity, HL-60 cells were treated with a series of phorbol esters covering a range of in vivo tumor promoting activity. Results indicate that this family of compounds induces HL-60 cells to differentiate in proportion to their in vivo promoting activity. To closely assess the sensitivity of the phagocytic endpoint, HL-60 cells were treated with picogram levels of 12-O-tetradecanoyl phorbol-13-acetate (TPA), whereupon increments as low as 50 pg of TPA per mi caused statistically significant increases in phagocytic activity. The experiments described herein suggest that in vitro differentiation of HL-60 cells may reflect the promoter-dependent modifications to gene expression that are observed in vivo during the promotion phase of carcinogenesis. The described method may represent a sensitive promoter screening assay which is both rapid and economical.
机译：非遗传毒性致癌物的鉴定和表征对毒理学家提出了重大挑战。鉴定具有合适敏感性和特异性的肿瘤启动子的体外方法特别难以捉摸。描述了实验，这些实验表明人早幼粒细胞白血病细胞系HL-60提供了启动子诱导的基因调节和表达变化的敏感指示。作为分化的结果，这些细胞经历了从非吞噬性悬浮培养物向附着的成纤维细胞样培养物的转变，该培养物表现出高吞噬活性。荧光乳胶颗粒用作传感器，以突出吞噬表型，并允许使用流式细胞仪自动定量颗粒内在化。为了评估特异性，用覆盖一系列体内肿瘤促进活性的一系列佛波酯处理HL-60细胞。结果表明该化合物家族诱导HL-60细胞与其体内促进活性成比例地分化。为了密切评估吞噬终点的敏感性，用皮克水平的12-O-十四烷酰佛波醇13-乙酸盐（TPA）处理了HL-60细胞，其后每毫升TPA的增加低至50 pg导致统计学上显着的增加。吞噬活动。本文所述的实验表明，HL-60细胞的体外分化可能反映了在癌变促进阶段体内观察到的基因表达的启动子依赖性修饰。所描述的方法可以代表快速且经济的灵敏的启动子筛选测定。

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