RT Journal Article
SR Electronic
T1 Metabolism of Antitumor Hydroxymethylacylfulvene by Rat Liver Cytosol
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 983
OP 985
VO 27
IS 9
A1 Trevor C. McMorris
A1 Anissa N. Elayadi
A1 Jian Yu
A1 Yi Hu
A1 Michael J. Kelner
YR 1999
UL http://dmd.aspetjournals.org/content/27/9/983.abstract
AB Acylfulvenes are a potent class of antitumor agents derived from illudin S, a fungal sesquiterpene. Illudin S possesses antitumor activity but has a poor therapeutic index. Acylfulvene is 100-fold less toxic against human lung adenocarcinoma cells than illudin S, but inhibits tumor growth in human xenografts, opposite to illudin S. An analog of acylfulvene, MGI 114 (hydroxymethylacylfulvene), shows much greater efficacy, producing complete tumor regression in xenograft models. MGI 114 is currently in phase II clinical trials. Cytotoxicity of MGI 114, like that of illudin S, is believed to involve both chemical reaction and enzymatic reduction. Enzymatic reduction by a cytosolic NADPH-dependent enzyme (from rat liver) produced an aromatic metabolite similar to that formed from illudin S. However, the reaction occurred more slowly. In addition, four new metabolites were isolated, two hydroxylated derivatives and two in which the primary allylic hydroxyl was replaced by hydride. All retained the reactive centers of the parent MGI 114. The American Society for Pharmacology and Experimental Therapeutics