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.
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