BUTYRATE-STABLE MONOSACCHARIDE DERIVATIVES INDUCE MATURATION AND APOPTOSIS IN HUMAN ACUTE MYELOID-LEUKEMIA CELLS

The rapid degradation and subsequent lack of efficacy of n-butyric aci d in vivo has been improved by the synthesis of monosaccharide stable pro-drugs of butyric acid. We studied the effects of D1 (O-n-butanoyl- 2, 3-O-isopropylidene-alpha-D-mannofuranoside), G1(1-O-n-butanoyl-D,L- xylitol), and F1 (1-O-n-butanoyl 2,3-O-isopropylidene-D,L-xylitol) on the maturation and proliferation of AML cell lines HL 60 and FLG 29.1 and of purified blast cells from 10 cases of de novo acute myeloid leu kaemia (AML). AML cell maturation was measured by surface antigen expr ession, morphology and cytochemistry. Toxicology in mice was also eval uated (DL50 1000 mg/kg), In HL 60 cells G1 and D1 increased the expres sion of CD15 and CDlla (presenting 62% of promyelo-metamyelocytes), an d in 7/10 cases of primary AMLs that of CDlla, CDllb, CD15, and myelop eroxidase. D1, G1 and F1 induced a dose-dependent inhibition of tritia ted thymidine uptake. Apoptosis (evaluated by flow cytometry and agaro se gel electrophoresis) was induced in AML blasts by D1 and Fl (79% an d 94% respectively for HL 60 cells) and, with less effect, by G1 (27%) . The persistence of maturative and apoptotic activity in these new pr o-drugs of butyric acid, hydrolysed only inside the tumour cell, sugge sts a possible use in differentiation therapy of myelodysplastic syndr omes and AMLs.