Abstract
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.
Footnotes
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Send reprint requests to: Trevor C. McMorris, Ph.D., Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093-0506. E-mail: tmcmorris{at}ucsd.edu
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This investigation was supported by funds provided by the Cigarette and Tobacco Tax Fund of the State of California through the Tobacco-related Disease Research Program of the University of California (Award 7RT-0002) and by funds provided by MGI PHARMA, Inc., Minneapolis, Minnesota.
- Abbreviations used are::
- MGI 114
- hydroxymethylacylfulvene
- TLC
- thin-layer chromatography
- DMSO
- dimethyl sulfoxide
- MS
- mass spectrometry
- Received December 17, 1998.
- Accepted May 20, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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