GLUCOCORTICOID-RESISTANT LEUKEMIC LYMPHOCYTES

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These studies have two general goals, both related to the use of glucocorticoids in treatment of leukemias and lymphomas. One goal is to apply and extend our knowledge of glucocorticoid receptors and mechanisms of action to normal and malignant lymphocytes and related cells. For these studies we are applying our recently developed minicolumn procedure to the analysis of nonactivated, activated, and meroreceptor complexes in cytosols from the cells mentioned under various conditions. Of particular current interest to us is the role in stabilizing receptors of calpastatin, a naturally occurring protein inhibitor of a family of calcium-activated proteases called calpains. We have found that the relative stability of receptors in cytosols from cells of patients with chronic lymphocytic leukemia (CLL) compared to those from patients with acute nonlymphocytic leukemia (ANLL) is at least partly due to the presence in the former cells of a stabilizer that closely resembles calpastatin. The other goal is to extend our observations on glucocorticoid effects on lymphocytes and other cells that are mediated by inhibition of, or synergism with, lymphokines such as interleukin 2 (IL-2) and immune or gamma interferon. We have shown that gamma interferon is the major lymphokine that increased Fc-Receptors for IgG on human monocytes, and that glucocorticoids added together with gamma interferon augment this effect as well as antibody-dependent and\-independent tumor cell lysis and expression of class I and class II HLA antigens. We are now investigating the mechanisms of these effects. In relation to IL-2, an autocrine mechanism of neoplastic growth involving IL-2 production and response has been established in MLA 144, an IL-2 producing leukemia cell line derived from a Gibbon ape. (D)