ABROGATION OF IL-3 REQUIREMENTS AND STIMULATION OF HEMATOPOIETIC-CELLPROLIFERATION IN-VITRO AND IN-VIVO BY CARBOXYLIC-ACIDS

Short-chain fatty acids, such as butyrate and propionate, induce fetal globin gene expression and are under clinical investigation in the be ta-hemoglobinopathies. Limitations of the short-chain fatty acids as t herapeutics include their rapid metabolism and a tendency to induce ce ll growth arrest if administered for prolonged periods, In studies des cribed here, the cellular effects of other inducers of fetal globin, p henoxyacetic acid and derivatives of short-chain fatty acids and cinna mic acids, were investigated in the human erythroid cell line K562, th e IL-3 dependent multi-lineage cell line (32D), and in mice and primat es, Several test compounds supported 32D cell proliferation despite a 50-fold depletion of IL-3, which resulted in growth arrest and apoptot ic death in control cells. The degree of proliferation induced by cert ain test compounds was similar to the degree of proliferation induced by Erythropoietin and G-CSF in the cells, Eight of ten compounds induc ed gamma globin mRNA in K562 cells, A 2.5 to 6-fold increase in reticu locytosis was observed in vivo in mice treated with two prototype comp ounds, Pharmacokinetic studies of three prototype compounds demonstrat ed millimolar plasma concentrations after single oral doses for many h ours in primates, These findings identify orally bioavailable compound s which induce gamma globin gene expression and hematopoietic cell pro liferation through an activity which partially abrogates requirements for IL-3, Such compounds provide potential for oral therapeutics which stimulate proliferation of hematopoietic cells of multiple lineages, as well as inducing fetal globin.