ROLE OF DNA-BINDING IN SKIN TUMOR INITIATION

人类不断地接触到各种各样的化学物质， 其中一些可以作为引发剂、促进剂、共致癌物质 和/或完全致癌物质。目前的证据表明 DNA的共价修饰在整个过程中起着核心作用 多种致癌物质致癌机制的研究进展 助剂包括多环芳烃(PAH)。 然而，仍有待确定哪些DNA加合物是 最重要的是：DNA加合物是被有效去除还是 从而在DNA中引入错误；或者DNA- 加合物必须在DNA中持续很长时间 肿瘤的起源。拟议的研究旨在进一步 研究多环芳烃DNA加合物的去除和持久性的作用 与小鼠皮肤肿瘤的发生有关。老鼠皮是一口井 已知的多环芳烃的靶组织，是一个被广泛研究的模型系统 治疗皮肤癌。这项建议的具体目标如下 下面是。形成的数量化关系 特定的碳氢化合物DNA加合物(特别是DAO加合物)和 皮肤肿瘤的起始性将被确定。范围和时间 多种细胞因子诱导的非程序性DNA合成过程 将对多环芳烃进行检测。我们还将研究 脱除特定DNA加合物(特别是DAO加合物) 与皮肤肿瘤引发能力的关系。此外，我们还将 继续探索形成、清除和持续 中国人表皮亚群中的烃类DNA加合物 DNA加合物在小鼠体内双相消失的关系 表皮。我们将进一步研究DNA复制的作用 在肿瘤开始时通过测定数量 特异性加合物的形成与抑制作用的关系 表皮DNA合成及通过利用DNA合成 抑制剂。最后，为了了解更多关于生物学的知识， 特定多环芳烃DNA加合物的生物化学和分子效应， 我们将从抗BPDE中制备位点定向的DAO加合物 被整合到细菌载体中。这种方法将使我们能够 为了检验特定的碳氢化合物DNA加合物是 在皮肤肿瘤启动申请后的早期需要。

Humans are continually exposed to a wide variety of chemicals, some of which may act as initiators, promoters, cocarcinogens and/or complete carcinogens. Current evidence suggests that covalent modification of DNA plays a central role in the mechanism of tumor initiation by diverse classes of carcinogenic agents including polycyclic aromatic hydrocarbons (PAH). However, it remains to be determined which DNA-adducts are most important; whether DNA-adducts are removed efficiently or inefficiently thus introducing errors in the DNA; or whether DNA- adducts must persist in the DNA for long periods of time for tumor initiation. The proposed research is designed to further investigate the role of PAH DNA-adduct removal and persistence in relation to skin tumor initiation in mice. Mouse skin is a well known target tissue for PAH and is a widely studied model system for skin carcinogenesis. The specific aims of the proposal are as follows. The quantitative relationship between the formation of specific hydrocarbon DNA-adducts (especially dAdo adducts) and skin tumor-initiation will be determined. The extent and time course of unscheduled DNA synthesis induced by a variety of PAHs will be examined. We will also examine the rates of removal of specific DNA-adducts (especially dAdo adducts) in relation to skin tumor-initiating potency. Furthermore, we will continue to explore the formation, removal, and persistence of hydrocarbon DNA-adducts in epidermal subpopulations in relation to the biphasic disappearance of DNA-adducts in mouse epidermis. We will further examine the role of DNA replication at the time of tumor initiation by determining the quantitative relationship between specific adduct formation and inhibition of epidermal DNA synthesis and through the use of DNA synthesis inhibitors. Finally, to learn more about the biological, biochemical and molecular effects of specific PAH DNA-adducts, we will prepare site directed dAdo adducts from anti BPDE to be incorporated into a bacterial vector. This approach will allow us to test the hypothesis that specific hydrocarbon DNA-adducts are required early after application for skin tumor initiation.