Prooxidant Activity and Cytotoxic Effects of Indole-3-acetic Acid Derivative Radicals

摘要

Previously,it was shown that indole-3-acetic acid(IAA)is a nontoxic prodrug that forms aradical,toxic to tumor cells when activated by peroxidase.Because of this,IAA and peroxidaseconjugated to an antibody specific to an extracelluar tumor antigen are currently in phase IIclinical trials.In the following,the prooxidant activities of the radicals formed were comparedwhen IAA or its derivatives were metabolically oxidized by peroxidase/H_20_2.In general,itwas found that the effectiveness of IAA analogues for catalyzing the cooxidation of ascorbate,NADH,or GSH increased as the IAA derivatives were more readily oxidized by HRP/H2O2.The order of effectiveness of IAA derivatives at cooxidizing NADH,ascorbate,GSH,andhepatocyte GSH was 5MeO-2Me-IAA > 2Me-IAA > 5MeO-IAA > IAA.The rates of NADHand ascorbate cooxidation were faster at pH 7.4 than at pH 6.0,whereas GSH cooxidationwas faster at pH 6.0 than at pH 7.4.Furthermore,NADH,ascorbate,and GSH prevented the/ oxidation of IAA derivatives,which suggested that the indolyl cation radical was responsible