Lymphocytes and monocytes are critical cells in the pathogenesis of immunodeficiency, autoimmune, and certain malignant diseases. It is therefore important to understand the metabolic pathways that regulate lymphocyte and monocyte development and activation under normal and pathologic conditions. This is the long term goal of this research grant application. Previous experiments supported by this research grant have aimed to elucidate the biochemical basis for the association of adenosine deaminase (ADA) deficiency with combined immunodeficiency disease. The results have documented the uniqueness of adenine deoxynucleotide metabolism in lymphocytes and monocytes, and have engendered the development of 2-chlorodeoxyadenosine (CdA). This ADA-resistant analog of deoxyadenosine induces complete remissions in more than 70% of patients with hairy cell leukemia, and has excellent activity in chronic lymphocytic leukemia, and lymphoma. CdA has two biochemical properties that distinguish it from all other nucleoside antimetabolites. First, it is exquisitely toxic to quiescent T and B lymphocytes, that have no replicative DNA synthesis. Second, CdA inhibits the function and survival of monocytes at nanomolar concentrations, that do not affect other phagocytic cells. These biochemical properties suggest that CdA and related compounds should be effective in common autoimmune diseases that are sustained by long-lived memory lymphocytes and activated monocytes. Initial studies in patients with rheumatoid arthritis support this contention. Moreover, CdA and related agents could be useful for the therapy of indolent malignancies that are resistant to cell cycle specific antimetabolites. One main problem that has hindered the widespread testing of CdA in chronic diseases is the need to administer the nucleoside parenterally. In pilot experiments. this problem has been overcome with the synthesis and evaluation of an orally active CdA analog designated CAFdA. Based upon our long-term objective and previous observations, we now aim specifically: (1) To determine how the enzymes that control in vitro sensitivity of quiescent lymphocytes to adenine deoxynucleosides influence the in vivo responsiveness of chronic lymphocytic leukemia cells to CdA therapy. These enzymes include deoxycytidine kinase, cytoplasmic 5'-nucleotidase, and a Ca++/Mg++-dependent endonuclease that mediates apoptosis. (2) To define more clearly the physiologic roles of these three enzymes for the metabolism and function of normal non-dividing lymphocytes and monocytes. (3) To increase the sensitivity of lymphocytes, monocytes, and solid tumors to the inhibitory effects of CdA and CAFdA by interfering with nucleotide dephosphorylation by 5'-nucleotidase, and with cell cycle progression. (4) To prove the in vivo relevance of the results using severe combined immune deficient (SCID) mice reconstituted either with normal human lymphocytes and monocytes, or with cells from patients with rheumatoid arthritis and malignant diseases. (5) Eventually, to initiate new therapies for patients with lymphoproliferative, autoimmune, and malignant diseases.
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