SKIN CANCER--IMMUNOTOXIC MECHANISMS

皮肤癌——免疫毒性机制

• 批准号: 3192702
• 负责人: Craig A Elmets
• 金额: $ 8.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-06-01 至 1992-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3192702
• 关键词: benzopyrenes; carbopolycyclic compound; chemical carcinogen; chemical carcinogenesis; clone cells; cutaneous papilloma; cyclic compound; cytochrome P450; delayed hypersensitivity; disease /disorder model; enzyme mechanism; epoxides; immune tolerance /unresponsiveness; immunoregulation; immunotoxicity; laboratory mouse; phorbols; receptor; skin hypersensitivity; skin neoplasms; toxin metabolism; tumor promoters

There is an increasing awareness that the induction of skin cancer is a multistep process requiring both initiating and promoting substances for full development of the malignant tumor. Most strategies examining immunological influences on this process have focused on immune responses to tumors. This, however, represents an investigation of such interactions at a rather late stage in the pathway. The objective of this proposal will be to examine immunological influences on skin carcinogenesis at an early stage in the pathway. This will be accomplished by inducing a contact dermatitis reaction in mice to two polyaromatic hydrocarbons, 7,12- dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (BP). These compounds have been widely employed to investigate mechanisms of skin cancer formation. Animals will be immunized to these agents by epicutaneous application of the compound. Five days later the response will be elicited by challenging their ears with the sensitizing compound and measuring the subsequent ear swelling response. Using this model system, participation of the Ah locus in contact hypersensitivity responses both in strains of mice with high an with low affinity Ah receptors. The role of cytochrome P450 dependent enzyme metabolism in induction of contact hypersensitivity to these agents will be assessed by pre-treating animals with pharmacologic agents which induce or inhibit cytochrome P450 activity. Also, various carcinogenic and non- carcinogenic metabolites of BP and non-carcinogenic PAH analogues will be tested for their immunogenicity by determining their ability to initiate and elicit contact hypersensitivity responses. Attempts will be made to induce immunological tolerance to DMBA and BP by utilizing methods of tolerance induction which have been successfully employed for other antigens. DMBA and BP-specific T cell clones will be developed to more fully evaluate the influence of antigen specific T lymphocytes on the tumorigenic activity of these compounds. Finally, the influence of contact immunization to DMBA and BP on the induction of tumors by these agents will be examined in skin carcinogenesis experiments. Knowledge obtained from these studies may help to define the influence of cell-mediated immunity on skin carcinogenesis and may offer new immunodermatologic approaches for the prevention and therapy of this type of skin cancer.

人们越来越认识到皮肤癌的诱发 是一个多步骤的过程，需要启动和促进 促进恶性肿瘤充分发展的物质。 最多 检查免疫学对该过程影响的策略 重点关注对肿瘤的免疫反应。 然而，这代表 在相当晚的阶段对这种相互作用的调查 途径。 该提案的目的是审查 免疫学对早期皮肤癌发生的影响 在路径中。 这将通过诱导接触来完成 小鼠对两种多环芳烃 7,12- 的皮炎反应 二甲基苯并(a)蒽(DMBA)和苯并(a)芘(BP)。 这些 化合物已被广泛应用于研究机制 皮肤癌的形成。 动物将对这些药物进行免疫 通过经皮施用该化合物。 五天后 通过用以下声音挑战他们的耳朵来引发反应 敏化化合物并测量随后的耳肿胀 回复。 使用该模型系统，Ah 基因座的参与 在接触性超敏反应中，小鼠品系 高 an 与低亲和力 Ah 受体。 细胞色素的作用 诱导接触过程中 P450 依赖性酶代谢 对这些药物的过敏反应将通过预处理进行评估 具有诱导或抑制药物作用的动物 细胞色素 P450 活性。 此外，各种致癌和非 BP 的致癌代谢物和非致癌性 PAH 类似物 将通过确定它们的免疫原性来测试它们 启动和引起接触超敏反应的能力。 将尝试诱导对 DMBA 的免疫耐受和 通过利用耐受诱导方法来控制血压 已成功用于其他抗原。 DMBA 和 BP 特定 T细胞克隆将被开发以更全面地评估 抗原特异性T淋巴细胞对肿瘤发生的影响 这些化合物的活性。 最后，接触的影响 DMBA 和 BP 免疫对诱导肿瘤的影响 将在皮肤致癌实验中检查药剂。 从这些研究中获得的知识可能有助于定义 细胞介导的免疫对皮肤癌发生的影响，可能 提供新的免疫皮肤病学方法来预防和 治疗此类皮肤癌。