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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Correlation of individual papilloma latency time with DNA adducts, 8-hydroxy-2'-deoxyguanosine, and the rate of DNA synthesis in the epidermis of mice treated with 7,12-dimethylbenz(alpha)anthracene.
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Correlation of individual papilloma latency time with DNA adducts, 8-hydroxy-2'-deoxyguanosine, and the rate of DNA synthesis in the epidermis of mice treated with 7,12-dimethylbenz(alpha)anthracene.

机译:个体乳头状瘤潜伏时间与DNA加合物,8-羟基-2'-脱氧鸟苷和经7,12-二甲基苯并α-蒽处理的小鼠表皮中DNA合成速率的相关性。

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The question was addressed whether the risk of cancer of an individual in a heterogeneous population can be predicted on the basis of measurable biochemical and biological variables postulated to be associated with the process of chemical carcinogenesis. Using the skin tumor model with outbred male NMRI mice, the latency time for the appearance of a papilloma was used as an indicator of the individual cancer risk. Starting at 8 weeks of age, a group of 29 mice was treated twice weekly with 20 nmol of 7,12-dimethylbenz[alpha]anthracene (DMBA) applied to back skin. The individual papilloma latency time ranged from 13.5 to 25 weeks of treatment. Two weeks after the appearance of the first papilloma in each mouse, an osmotic minipump delivering 5-bromo-2'-deoxyuridine was s.c. implanted and the mouse was killed 24 hr later. Levels of DMBA-DNA adducts, of 8-hydroxy-2'-deoxyguanosine, and various measures of the kinetics of cell division were determined in the epidermis of the treated skin area. The levels of 8-hydroxy-2'-deoxyguanosine and the fraction of cells in DNA replication (labeling index for the incorporation of 5-bromo-2'-deoxyuridine) were significantly higher in those mice that showed short latency times. On the other hand, the levels of DMBA-DNA adducts were lowest in animals with short latency times. The latter finding was rather unexpected but can be explained as a consequence of the inverse correlation seen for the labeling index: with each round of cell division, the adduct concentration is reduced to 50% because the new DNA strand is free of DMBA adducts until the next treatment. Under the conditions of this bioassay, therefore, oxygen radical-related genotoxicity and the rate of cell division, rather than levels of carcinogen-DNA adducts, were found to be of predictive value as indicators of an individual cancer risk.
机译:提出了一个问题,即是否可以根据假定与化学致癌过程相关的可测量生化和生物学变量来预测异质人群中个体的癌症风险。使用具有远交雄性NMRI小鼠的皮肤肿瘤模型,乳头状瘤出现的潜伏时间被用作个体癌症风险的指标。从8周龄开始,一组29只小鼠每周两次用20nmol施用于背部皮肤的7,12-二甲基苯并蒽(DMBA)治疗。单个乳头状瘤的潜伏期为13.5至25周。在每只小鼠中出现第一个乳头状瘤后两周,一个经皮渗透输送5-溴-2'-脱氧尿苷的微型泵是皮下注射。植入后24小时将小鼠杀死。在治疗的皮肤区域的表皮中测定DMBA-DNA加合物的水平,8-羟基-2'-脱氧鸟苷的水平以及细胞分裂动力学的各种量度。在那些表现出短潜伏时间的小鼠中,8-羟基-2'-脱氧鸟苷的水平和DNA复制中细胞的比例(结合5-溴-2'-脱氧尿苷的标记指数)明显更高。另一方面,在短潜伏期的动物中,DMBA-DNA加合物的水平最低。后一个发现是相当意外的,但是可以解释为标记指数呈负相关的结果:在每轮细胞分裂中,加合物的浓度降低到50%,因为新的DNA链不含DMBA加合物,直到下次治疗。因此,在这种生物测定的条件下,发现氧自由基相关的基因毒性和细胞分裂的速率,而不是致癌物-DNA加合物的水平,具有预测价值,可作为个体癌症风险的指标。

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