Prostaglandins of the E-series (PGE) have been recognized as playing an important role in the regulation of normal myelopoeisis. The overall objective is to determine, at the biochemical level, the mechanism(s) which may be responsible for the loss of prostaglandin-mediated control over growth and differentiation of myeloid leukemic cells. The hypotheses presented are based, in part, on the recent detection of significant prostaglandin catabolizing activity in human HL-60 leukemia cells. Through the assimilation and integration of pertinent literature, three aspects of prostaglandin biochemistry have been identified as potential aberrant sites in various myeloid leukemias. These include elements of prostaglandin biosynthesis, catabolism and receptors. The studies will be conducted on both established myeloid leukemia cell lines and on cells obtained from patients with various types of myeloid leukemias. Where possible, comparisons will be made to normal stem and mature myeloid cells. The prostaglandin biosynthetic and catabolic pathways will be investigated both qualitatively and quantitatively, using established procedures for isolating and identifying prostanoid metabolites. The binding of PGE to membrane receptors will also be examined as well as the factors that regulate receptor expression. Attempts will be made to correlate biochemical data with the effects of PGE on growth and differentiation of leukemic cells. Evidence will be sought for a common defect within sub-classes of myeloid leukemias. The ultimate goal is to identify those defects related to prostaglandin biochemistry that may be amenable to pharmacological manipulation through the use of specific inhibitors, antagonists or agonists. It is hoped that this project will not only further our understanding of the pathophysiology of this disease, but provide insight for developing new therapeutic strategies.
