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Induction of erythroid differentiation and fetal hemoglobin production in
human leukemic cells treated with phenylacetate
D Samid, A Yeh and P Prasanna
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD
20892.
There is considerable interest in identifying nontoxic differentiation
inducers for the treatment of various malignant and nonmalignant blood
disorders, including inborn beta-chain hemoglobinopathies. Using the human
leukemic K562 cell line as a model, we explored the efficacy of
phenylacetate, an amino acid derivative with a low toxicity index when
administered to humans. Treatment of K562 cultures with pharmacologically
attainable concentrations of phenylacetate resulted in erythroid
differentiation, evident by the reduced growth rate and increased
hemoglobin production. The effect was time- and dose- dependent, further
augmented by glutamine starvation (phenylacetate is known to deplete
circulating glutamine in vivo), and reversible upon cessation of treatment.
Molecular analysis showed that phenylacetate induced gamma globin gene
expression with subsequent accumulation of the fetal form of hemoglobin
(HbF). Interestingly, the addition of phenylacetate to antitumor agents of
clinical interest, eg, hydroxyurea and 5-azacytidine, caused superinduction
of HbF biosynthesis. The results suggest that phenylacetate, used alone or
in combination with other drugs, might offer a safe and effective new
approach to treatment of some hematopoietic neoplasms and severe
hemoglobinopathies.
Volume 80,
Issue 6,
pp. 1576-1581,
09/15/1992
Copyright © 1992 by The American Society of Hematology
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