GROWTH SUPPRESSION OF MALIGNANT LEUKEMIA-CELL LINE IN-VITRO BY ASCORBIC-ACID (VITAMIN-C) AND ITS DERIVATIVES

In recent years there has been a growing interest in the therapeutic a pplication of L-ascorbic acid (AA) and its derivatives as anticancer a gents. AA is a gamma-crotonolactone derivative with reactive hydroxyl groups al the 2- and 3-positions and an ethylene glycol substitution a t the 4-position. Despite the various reports on AA toxicity, no work has been reported underlying the critical chemical structural features for its activity. The present study addresses this question. We teste d in vivo, using malignant leukemia cell line P388D1, (i) L-AA and its isomers, (ii) substitution at the 2-position: -PO4, -SO4, O-Me, O-oct adecyl, (iii) substitution at the B-position: -PO4, -SO4, -palmitate, -stearate, (iv) substitution at the 2,6-position: dipalmitate, (v) 6-d eoxy derivative: -Cl, -Br, -NH2 and (vi) dihydroxy gamma-crotonolacton e with substitutions at the 4-position: -H, -CH3, -CH2-CH3 and -CH=CH2 . L-AA and its isomers were very cylotoxic even at very low concentrat ion. All 6-substituted and 6-deoxy derivatives were as toxic as AA. Ho wever, 2-substituted and 2,6-disubstituted AA derivatives were non-tox ic. Interestingly, dihydroxy gamma-crotonolactone with or without subs titution at the 5-position also exhibited toxicity. These results sugg est that the underlying criterion for AA toxicity resides in dihyroxy gamma-crotonolactone moiety. Either substitution in the hydroxy groups or saturating the double bond render the molecule inactive. (C) 1998 Elsevier Science Ireland Ltd.