CYCLOSPORIN A, POSSIBLE PROMOTOR OF LYMPHOMA INDUCTION

环孢菌素 A，淋巴瘤诱导的可能促进剂

• 批准号: 3173678
• 负责人: HISASHI SHINOZUKA
• 金额: $ 13.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173678
• 关键词: autoradiography; azathioprine; cellular immunity; chemical carcinogenesis; cyclosporines; drug adverse effect; drug related neoplasm /cancer; genetic strain; histochemistry /cytochemistry; hyperplasia; immunosuppressive; liver neoplasms; lymphatic tissue; lymphoma; nitrosourea; pathogenic diet; radiotracer; skin transplantation; transplantation; tumor promoters

The proposal is aimed at clarifying the mechanism of lymphoreticular tumor development in patients undergoing immunosuppressive treatment. There is increasing evidence that cancer development in many organ systems is a multistep process, broadly divisible into initiation and promotion. Immunosuppressive agents currently in clinical use, such as cyclosporin A (CyA) are nono-genotoxic and, thus, are not likely to be an initiator of carcinogenesis, but rather they may act as a tumor promoter. In this proposal, we will first determine whether CyA and Azathioprine act as a promoter of induction of lymphoreticular neoplasms in experimental animals initiated with a subcarcinogenic dose of methylnitrosourea. In the preliminary study, we have demonstrated that the dietary administration of CyA induces atypical B cell proliferation in the lymphoid tissues of rats. Through our investigation on the mechanism of tumor promotion in the liver, we postulated that liver tumor promotion involves possible two components, a selective stimulation of the growth of initiated cells and a suppression of the surrounding non-initiated cells. The creation of differential growth environment will lead to amplification of the growth of initiated cell population. We will test this notion by demonstrating that immunosuppressants which act as a tumor promoter suppress the growth of subsets of lymphoid cells and selectively stimulate the proliferation of initiated cell populations leading to the development of lymphoreticular tumors. Whether or not the promoting potency of immunosuppressive agents correlates with their immunosuppressive effects on the hosts will be analyzed. We will further determine whether or not CyA and Azathioprine induce similar pathological lesions in the lymphoid tissue, and whether CyA-induced atypical lymphoid hyperplasia is reversible or progresses to neoplasia. The distinction of the stages of neoplastic development in lymphoma induction by immunosuppressive agents would be conceptually important, since the effects of promoters are reversible at least in the early stages, and the process may be amenable to modulations by selective therapeutic regimens.

该提案旨在阐明淋巴网状肿瘤的发病机制 接受免疫抑制治疗的患者的发展。 有 越来越多的证据表明许多器官系统的癌症发展是一个 多步骤过程，大致可分为启动和推广。 目前临床使用的免疫抑制剂，如环孢素A (CyA) 是非基因毒性的，因此不太可能是 癌发生，但更确切地说，它们可能充当肿瘤促进剂。 在这个 提案中，我们首先确定 CyA 和硫唑嘌呤是否作为 实验动物淋巴网状肿瘤诱导的启动子 以亚致癌剂量的甲基亚硝基脲开始。 在 初步研究表明，饮食管理 CyA 诱导大鼠淋巴组织中的非典型 B 细胞增殖。 通过我们对肝脏肿瘤促进机制的研究， 我们假设肝脏肿瘤的促进可能涉及两个组成部分， 选择性刺激起始细胞的生长并抑制 周围的非起始细胞。 差异化的创造 成长环境会导致成长的放大 细胞群。 我们将通过证明来测试这个概念 免疫抑制剂作为肿瘤促进剂抑制肿瘤的生长 淋巴细胞亚群并选择性地刺激增殖 启动细胞群导致淋巴网状细胞的发育 肿瘤。 免疫抑制剂是否有促进作用 与其对宿主的免疫抑制作用相关 分析了。 我们将进一步确定CyA和硫唑嘌呤是否 在淋巴组织中诱发类似的病理病变，以及是否 CyA 诱导的非典型淋巴样增生是可逆的或进展为 瘤形成。 肿瘤发展阶段的区别 免疫抑制剂诱导淋巴瘤在概念上是 重要的是，因为启动子的作用至少在 早期阶段，并且该过程可能会受到选择性调节的影响 治疗方案。