ANTIPROLIFERATIVE AND CYTOTOXIC PROFILES OF ANTIPSORIATIC FUMARIC-ACID DERIVATIVES IN KERATINOCYTE CULTURES

Oral administration with complex mixtures of fumaric acid derivatives is known to have antipsoriatic efficacy. The present studies aimed to clarify the mode of action and toxicity of the individual compounds. H yperproliferative HaCaT keratinocytes in monolayer cultures were expos ed to fumaric acid, dimethylfumarate, zinc monoethylfumarate, calcium monoethylfumarate and magnesium monoethylfumarate at concentrations be tween 0.4 mu M and 960 mu M for 48 h. Cell proliferation was studied b y [H-3]thymidine incorporation. In addition C-14-labelled amino acid u ptake and total protein content were measured. Direct cytotoxicity was determined by the release of cytoplasmic lactate dehydrogenase (LDH) into the culture medium. The corresponding 50% inhibition concentratio ns (IC50) were calculated for DNA/ protein synthesis: 2.3/2.5 mu M (di methylfumarate), 133/145 mu M (zinc monoethylfumarate), 215/230 mu M ( calcium monoethylfumarate), 275/270 mu M (magnesium monoethylfumarate) , > 960/ > 960 mu M (fumaric acid). The total protein content was less sensitive. Antiproliferative activity was found for dimethylfumarate and to a lesser degree for calcium monoethylfumarate already at the su btoxic concentrations of 1.3 and 4 mu M, respectively. In the case of magnesium monoethylfumarate, zinc monoethylfumarate and fumaric acid t here was no such dissociation between their cytotoxic and antiprolifer ative potential. These data indicate that most of the antipsoriatic po tential of fumaric therapies is due to the dimethylfumarate compound.