CYTOTOXICITY OF CIS-PARINARIC ACID IN CULTURED MALIGNANT GLIOMAS

THE CYTOTOXIC EFFECTS of cis-parinaric acid, a plant-derived 18-carbon polyunsaturated fatty acid, were assessed in vitro on normal and neop lastic glia. After being incubated for 24 hours in the presence of 12 mu mol/L cis-parinaric acid, 36B10 glioma cultures demonstrated nearly 90% toxicity (unpaired Student's t test, P < 0.001). Similar results were obtained after the exposure of C6 rat glioma cultures, A172 human glioma cultures, and U-937 human monocytic leukemia cultures to cis-p arinaric acid. In contrast, fetal rat astrocytes incubated with 12 mu mol/L cis-parinaric acid demonstrated no significant toxicity (3% redu ction, P = 0.12); fetal rat astrocytes showed only 20% toxicity after exposure to 40 mu mol/L cis-parinaric acid (P = 0.001). The cytotoxic effects of cis-parinaric acid were antagonized with the addition of eq uimolar concentrations of alpha-tocopherol. Enzyme immunoassay of trea ted 36B10 glioma supernatant fluid for 8-isoprostane (a known oxidativ e metabolite) demonstrated a 10-fold increase of 8-isoprostane over 24 hours (123.0 +/- 10.3 versus 10.0 +/- 0.7 pg/ml for control, P < 0.00 1). These studies indicate that cis-parinaric acid may be significantl y cytotoxic to malignant glioma cells in concentrations that spare nor mal astrocytes and that the mechanism of cytotoxicity is related to an oxidative process. The selective cytotoxic effect of cis-parinaric ac id we describe represents the first step in the development of new che motherapeutic agents for gliomas; these new agents act by preferential ly enhancing lipid peroxidation in neoplastic cells.