Metabolism of antitumor hydroxymethylacylfulvene by rat liver cytosol

Acylfulvenes are a potent class of antitumor agents derived from illudin S, a fungal sesquiterpene. Illudin S possesses antitumor activity but has a p oor therapeutic index. Acylfulvene is 100-fold less toxic against human lun g adenocarcinoma cells than illudin S, but inhibits tumor growth in human x enografts, opposite to illudin S. An analog of acylfulvene, MGI 114 (hydrox ymethylacylfulvene), shows much greater efficacy. producing complete tumor regression in xenograft models, MGI 114 is currently in phase II clinical t rials. Cytotoxicity of MGI 114, like that of illudin S, is believed to invo lve both chemical reaction and enzymatic reduction. Enzymatic reduction by a cytosolic NADPH-dependent enzyme (from rat liver) produced an aromatic me tabolite similar to that formed from illudin S. However, the reaction occur red more slowly. In addition, four new metabolites were isolated, two hydro xylated derivatives and two in which the primary allylic hydroxyl was repla ced by hydride. All retained the reactive centers of the parent MGI 114.