Differentiation induction is a distinct concept in the treatment of malignant diseases, considering that malignant cells share many features with immature progenitor cells that are capable of terminal differentiation. Treatment of
tumor cells with
short-chain fatty acid treatment of erythroid progenitors in vitro and in vivo induces cellular differentiation resulting in
gamma-globin, i.e.,
fetal hemoglobin synthesis.
Valproic acid (VPA) is a branched-chain
fatty acid that is able to inhibit growth of human and rodent
tumor cells and to induce a mature phenotype. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for
epilepsy. Hypothesizing that anticonvulsive VPA levels may be used for antitumoral differentiation induction
therapy of pediatric malignant
tumors, the authors studied
fetal hemoglobin-inducing capacity of VPA in children treated with VPA for
epilepsy.
Fetal hemoglobin was significantly increased in 30 children with
epilepsy treated with VPA monotherapy for at least 3 months when compared to untreated control patients. Furthermore,
fetal hemoglobin levels correlated with VPA serum levels. The study confirms the dose-dependent stimulating effect of VPA on
fetal hemoglobin synthesis at anticonvulsive doses. The results suggest that nontoxic VPA levels reached in pediatric
epilepsy patients should be capable of inducing cellular differentiation of pediatric malignant
tumors for therapeutic purposes. Broad clinical experience with VPA and its low toxicity further encourage the evaluation of VPA in pediatric oncology for differentiation induction
therapy.