Retinoic acid and its analogs (retinoids) stimulate normal human myelopoiesis and erythropoiesis, and inhibit leukemic blast cell clonal proliferation and induce differentiation of leukemic blast cells in vitro. The phenotypic abnormality of human acute myelogenous leukemia is the inability of the leukemic cells to differentiate to functional, non-dividing cells. Preleukemia is a hematopoietic syndrome that preceeds leukemia; the leukemic clone is often established and abnormalities of differentiation are predominant in this disease. The only standard therapy for these patients is supportive. One approach to the therapy of preleukemia (and leukemia) is the induction of differentiation of the neoplastic cells. We are conducting a double blind, randomized trial of administering 13-cis retinoic versus placebo to 80 preleukemia patients in order to determine if the therapy improves their hematopoiesis decreases the size of their neoplastic clone (as determined by karyotypic examinations), and possibly alters the course of their disease. A number of new retinoids have recently been synthesized; these compounds are 10-1000 fold more potent than all trans retinoic acid in several non-hematopoietic assays of inhibition of transformation. We will test the potency of these compounds on clonal growth and induction of differentiation of normal and neoplastic human myeloid progenitor cells in vitro. Treatment of cancer patients with chemotherapy has clearly taught us that a combination of agents is frequently more efficiacious than treatment with a single drug. We shall identify and study compounds that interact synergistically with retinoids to decrease proliferation of leukemia cells and/or to enhance differentiation of leukemia cells. Agents that appear to be effective in vitro frequently are ineffective in vivo. We shall try to develop a murine model to study the effect of retinoids on proliferation of leukemia cells in vivo. Retinoids alter expression of several oncogenes in HL-60 myeloid leukemic cells; we shall examine alterations of chromatin and nuclear matrix in the vicinity of these oncogenes in HL-60 cells exposed to retinoids. An understanding of the process of myeloid differentiation may provide the framework to understand the defect in differentiation of blast cells in leukemia.
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