Increase of Fetal Hemoglobin Synthesis Indicating Differentiation Induction in Children Receiving Valproic Acid

Abstract

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.

Molecular and Therapeutic Potential and Toxicity of Valproic Acid

“…Just as it has been reported for hepatotoxicity, it appears that aplastic anemia has a higher prevalence during polytherapy. However, given that aplastic anemia is a malfunction of hematopoietic stem cells, inducing a break in the production of erythrocytes, the results reported in this study contradict those which suggest VPA as a potent activator of erythropoiesis in epileptic patients [152]. This study of 30 young patients treated for more than 3 months with VPA anticonvulsive doses shows an increase of the expression of fetal hemoglobin, with dose-dependent stimulation.…”

The Effects of Antiepileptic Drugs on Complete Blood Cell Counts in Children with Epilepsy

“…Lenfosit ve monosit oranı ise artmıştı (sırasıyla, p=0.016 ve p=0.000). artıran nedenler olarak yüksek serum VPA düzeyi (4), tedavi öncesi düşük trombosit sayısı ve kadın cinsiyet bildirilmiştir(13). Valproata bağlı trombositopenisi olan hastaların %82'sinde trombosit ile ilişkili immünglobulin düzeyinde artış bulunmuştur(9).…”