CYCLOSPORIN A, POSSIBLE PROMOTOR OF LYMPHOMA INDUCTION

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进展。的确有 越来越多的证据表明，癌症在许多器官系统的发展是一种 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)是非遗传毒性的，因此不太可能是 但它们可能会作为肿瘤促进剂发挥作用。在这 提案，我们将首先确定CyA和硫唑嘌呤是否作为 实验动物淋巴网状肿瘤的诱导启动子 以亚致癌剂量的甲基亚硝脲开始。在 初步研究，我们已经证明了饮食给药 环磷酰胺诱导大鼠淋巴组织中非典型B细胞增殖。 通过我们对肝脏促癌机制的研究， 我们推测，促进肝脏肿瘤可能涉及两个组成部分， 对启动细胞生长的选择性刺激和抑制 周围未启动的细胞。差异化的创造 成长环境会导致对成长的放大启动 细胞数量。我们将通过演示来检验这一概念 作为肿瘤促进剂的免疫抑制剂抑制肿瘤的生长 淋巴细胞亚群并选择性刺激其增殖 导致淋巴网状细胞发育的起始细胞群 肿瘤。免疫抑制剂是否具有促进作用 与它们对宿主的免疫抑制作用相关的将是 分析过了。我们将进一步确定CyA和硫唑嘌呤是否 在淋巴组织中引起类似的病理损害，以及 CyA诱导的非典型淋巴组织增生可逆或进展为 肿瘤。我国肿瘤发展阶段的划分 由免疫抑制剂诱导的淋巴瘤在概念上是 重要的是，因为启动子的影响是可逆的，至少在 早期阶段，这一过程可能通过选择性的调节 治疗方案。

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.