Abstract. Orders of susceptibility of Ehrlich ascites tumor to ¿-ascorbic acid (Asc), its 6-stearoyl (6S), 6-palmitoyl (6P) and 2,6-dipalmitoyl (DP) derivatives were assessed in vitro and in vivo: 6P (a 50% growth inhibitory concentration (IC50) for cultured cells. 12 pM; an increased life-span of treated mice, 283%) > 6S (61 pM; 240%) » Asc (430 pM; 122%) ^ DP (> 200 pA/; 89%), indicating that the enhanced susceptibility was due to acyl moiety substituted at C6-hydroxyl group of Asc, but was retracted by further substitution at C2-hydroxyl group. Equimolar mixture of Asc and palmitic acid, stearic acid or their methyl esters was much less cytotoxic than 6P or 6S. Thus the enhanced susceptibility was not primarily due to an additive cytotoxic effect of ascorbyl and acyl moieties, but to a balanced hydrophobicity introduced into the molecule by a poorly cytotoxic acyl moiety.
Combined antitumour effects of mono- or diacyl ascorbates and heat treatment were studied in comparison with the parent compound, L-ascorbic acid (AsA). At 37 degrees C, 75 microM 6-O-palmitoyl (6P) and 6-O-stearoyl (6S) ascorbates appreciably inhibited DNA synthesis in Ehrlich ascites tumour cells. Hyperthermia at 42 degrees C for 1 h increased the inhibition. In contrast, AsA or 2,6-O-dipalmitoyl ascorbate (DP), even at concentrations as high as 100 microM, caused no inhibition at 37 degrees C or 42 degrees C. The results suggest that the inhibitory action is not caused by the fatty acid moiety itself; it is more likely to be caused by the balance in the hydrophobicity and hydrophilicity of the monoacylated AsA, a property not found in diacylated or intact AsA. Inhibition of DNA synthesis caused by exposure to 6P during hyperthermia of tumour cells was greater than before or after hyperthermia. 6P or 6S, but not AsA or DP, released phospholipids such as phosphatidylcholine and phosphatidylethanolamine from cells labelled with [14C]oleic acid, as shown by radiocurves taken from thin-layer chromatograms. Damage of the cell membrane seemed to be involved in the inhibition of DNA synthesis caused by monoacylated AsA, which is surface-active.
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