DIBENZO(A,1)PYRENE--TUMOR INITIATION AND PROMOTION

二苯并[a，l]芘（DB [a，l] P）是最强的致癌物， 多环芳烃（pAH）。它的致癌性很高 小鼠皮肤中的活性伴随着PAH中特有的红斑。 红斑的时间过程是恒定的，并且与剂量无关，尽管 强度是剂量依赖性的，表明免疫诱导。 我们提出 对特定DB [a，l] P二醇环氧化物-蛋白的适应性免疫应答 加合物产生迟发性红斑， 表皮增生 DB [a，l] P是一个独特的研究模型 (1)通过确定肿瘤起始的结构， DB [a，l] P-DNA加合物及其在肿瘤发生中的意义;（2） DB（a，l] P诱导的炎症反应是肿瘤发生发展的关键因素 推广.这将通过完成以下具体工作来实现 目的：（1）完成稳定DNA的鉴定和定量 DB [a，l] P在体外通过辣根过氧化物酶（HRP）和3- 甲基胆蒽（MC）诱导的大鼠肝微粒体;（2）鉴定和 定量DB [a，l] P在细胞中形成的稳定和脱嘌呤DNA加合物， 在小鼠皮肤和大鼠乳腺中的体内;（3）鉴定和定量 DB [a，l] P-DNA脱嘌呤加合物经处理大鼠尿液排泄 用DB [a，l] P通过乳头内注射和用DB [a，l] P局部处理的小鼠 DB [a，l] P;（4）确定是否观察到皮肤的组织学变化 在用DB [a，l] P处理后的第5 - 7天也观察到 在剂量反应研究中使用DMBA、BP或11-甲基BP治疗后;（5） 评估DB [a，l] P诱导的炎症对细胞增殖的贡献。 DB [a，l] P诱导的小鼠皮肤肿瘤的发展， 地塞米松治疗对炎症和肿瘤产生的影响; 和（6）确定血清补体和CD4 + T细胞对 DB [a，l] P的促销活动。 体内形成的DB [a，l] P-DNA加合物将表明涉及的DNA损伤 在肿瘤发生中。建议的肿瘤促进研究将采取 组织学检查持续和相对较短的时间过程的优点 单次皮肤应用DB [a，l] P诱导的事件， 通常被认为是肿瘤促进的核心。这些研究将 确定（l）其他PAH致癌物可能诱导 （2）DB [a，l] P诱导的组织学变化 炎症与PAH致癌能力的关系，（3） 观察到的组织学事件对肿瘤产生的重要性和（4） 两种适应性免疫途径导致炎症和表皮 DB [a，l] P诱导的肿瘤促进。

Dibenzo(a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycyclic aromatic hydrocarbons (pAH). Its very high carcinogenic activity in mouse skin is accompanied by an erythema unique among PAH. The time course of erythema is constant and dose-independent, although the intensity is dose-dependent, suggesting an immune induction. We propose that an adaptive immune response to specific DB[a,l]P diol epoxide-protein adducts produces delayed erythema and contributes significantly to epidermal hyperplasia. DB[a,l]P represents a unique model for studying (1) the mechanism of tumor initiation by determining the structure of DB[a,l]P-DNA adducts and their significance in tumor initiation, and (2) DB(a,l]P-induced inflammation as a critical factor in the process of tumor promotion. This will be achieved by accomplishing the following specific aims: (1) Complete the identification and quantitation of stable DNA adducts formed by DB[a,l]P in vitro by horseradish peroxidase (HRP) and 3- methylcholanthrene (MC)induced rat liver microsomes; (2) Identify and quantify the stable and depurinating DNA adducts formed by DB[a,l]P in vivo in mouse skin and rat mammary gland; (3) Identify and quantify the DB[a,l]P-DNA depurinating adducts excreted in the urine of rats treated with DB[a,l]P by intramammillary injection and mice treated topically with DB[a,l]P; (4) Determine whether the histological changes in skin observed on days 5-7 after treatment with DB[a,l]P are also observed on days 5-7 after treatment with DMBA, BP or 11-methylBP in a dose-response study; (5) Assess the contribution of DB[a,l]P-induced inflammation to the development of DB[a,l]P-induced tumors in mouse skin by determining the effects of dexamethasone treatment on inflammation and tumor production; and (6) Determine the contribution of serum complement and CD4+ T cells to the promotional activity of DB[a,l]P. Determination of the structure of DB[a,l]P-DNA adducts formed in vivo will indicate the DNA lesions involved in tumor initiation. The proposed studies of tumor promotion will take advantage of the constant and relatively short time course of histological events induced by a single dermal application of DB[a,l]P that are generally considered central to tumor promotion. These studies will determine (l) the degree to which other PAH carcinogens may induce the same histological changes, (2) the contribution of DB[a,l]P-induced inflammation to the carcinogenic potency of this PAH, (3) the relationship of observed histological events to tumor production and (4) the importance of two adaptive immune pathways leading to inflammation and epidermal hyperplasia to DB[a,l]P-induced tumor promotion.