leukotriene-c4 and Leukemia--Myeloid--Acute

A systematic evaluation of structure-activity information led to the construction of genetically engineered interleukin 3 (IL-3) receptor agonists (synthokines) with enhanced hematopoietic potency. SC-55494, the most extensively characterized member of this series, exhibits 10- to 20-fold greater biological activity than recombinant human IL-3 (rhIL-3) in human hematopoietic cell proliferation and marrow colony-forming-unit assays. In contrast, SC-55494 is only twice as active as rhIL-3 in priming the synthesis of inflammatory mediators such as leukotriene C4 and triggering the release of histamine from peripheral blood leukocytes. The enhanced hematopoietic activity of SC-55494 correlates with a 60-fold increase in IL-3 alpha-subunit binding affinity and a 20-fold greater affinity for binding to alpha/beta receptor complexes on intact cells relative to rhIL-3. SC-55494 demonstrates a 5- to 10-fold enhanced hematopoietic response relative to its ability to activate the priming and release of inflammatory mediators. Therefore, SC-55494 may ameliorate the myeloablation of cancer therapeutic regimens while minimizing dose-limiting inflammatory side effects.

Topics: Amino Acid Sequence; Base Sequence; Cell Division; Cell Line; Cells, Cultured; Colony-Forming Units Assay; DNA Primers; Dose-Response Relationship, Drug; Hematopoiesis; Hematopoietic Stem Cells; Histamine Release; Humans; Interleukin-3; Kinetics; Leukemia, Myeloid, Acute; Leukotriene C4; Molecular Sequence Data; Mutagenesis, Site-Directed; Peptide Fragments; Peptides; Polymerase Chain Reaction; Receptors, Interleukin-3; Recombinant Proteins; Transfection; Tumor Cells, Cultured