ERYTHROID PROGENITOR PROLIFERATION IS STIMULATED BY PHENOXYACETIC ANDPHENYLALKYL ACIDS

Short-chain fatty acids, such as butyrate and propionate, are under in vestigation as therapeutic stimulants of fetal hemoglobin production i n the beta-hemoglobin disorders, Significant, limitations to these fat ty acids and derivatives as optimal therapeutics are their rapid metab olism in vivo and their induction of cell growth arrest in the G(1) ph ase of the cell cycle, This antiproliferative activity is related to t heir inhibition of metabolic transport pumps which are essential for c ell proliferation. Other small carbon compounds, the phenylalkyl acids , phenoxyacetic acids, and phenylacetic acids, which are structurally resistant to oxidative metabolism, are shown here to induce fetal glob in production in human erythroid cultures at concentrations of 0.2 mM, lower than those required for most other fatty acids, Certain of thes e compounds were found not to inhibit cellular neutral amino acid tran sport function in erythroid cells, nor to inhibit erythroid colony (Bf u-e) growth, Certain of these compounds even stimulated human Bfu-e pr oliferation in vitro beyond that induced by optimal concentrations of hematopoietic growth factors. The combination of increased fetal globi n chain production by these compounds and their stimulatory effects on erythropoiesis result in an increase in Kb F-expressing erythroid cel ls in culture several-fold greater than that achieved by tile butyrate s, These new compounds thus have the potential to provide superior the rapy for the beta-hemoglobinopathies and other anemias.