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METABOLISM STUDIES SHED LIGHT ON ACTIVITY OF POTENT NEW CLASS OF ANTI-CANCER DRUGS
Studies at the University of California, San Diego on metabolism using rat liver enzymes offer insight into why a promising new class of anti-tumor drugs-derived from a toxin of the poisonous jack-o'-lantern mushroom-could show selectivity and effectiveness in destroying cancer cells without harming healthy ones.
The findings concerning a family of anti-cancer compounds called acylfulvenes were reported by UCSD researchers Trevor McMorris, professor of chemistry, and Michael Kelner, professor of pathology, in the January issue of the journal of Biochemical Pharmacology. Also contributing to the study were co-authors Anissa Elayadi and Jian Yu of the UCSD Department of Chemistry and Biochemistry.
"As with any new drug or class of drugs, it is important that we understand how these compounds are metabolized after they are introduced into the body," says McMorris. "Although we know that acylfulvenes have high anti-tumor activity, we still don't know exactly why; however, our studies have shed light on the mechanism of action involved."
The UCSD study compared the metabolism of acylfulvene with that of illudin-S (the parent toxic compound found in the orange and yellow jack-o'-lantern mushroom) using rat liver enzymes. The researchers found that the structures of aromatic and hydroxylated metabolites produced from acylfulvene may explain, in part, the anti-tumor activity of acylfulvene.
A better understanding of the metabolism of acylfulvenes and how it contrasts with that of illudin-S, "could provide more insight into clinical applications of acylfulvene-based cancer drugs and analogs," says Kelner.
One such analog, hydroxymethylacyfulvene, was synthesized by McMorris and later tested by Kelner in mice. (In 1993, MGI PHARMA, a pharmaceutical company based in Minneapolis, acquired the rights from the University of California to all illudin-S analogs, including hydroxymethylacyfulvene.) This analog is currently in Phase I and Phase II clinical trials conducted by MGI PHARMA and by the National Cancer Institute. Known in pharmaceutical circles as MGI 114, the analog is being tested clinically as an anti-cancer drug at more than 10 oncology research sites nationally on a wide range of hard-to-manage cancers.
McMorris and Kelner will conduct further metabolic studies on acylfulvenes while adding to the more than 100 analogs that have been created from illudin-S in an effort to find better anti-cancer agents.
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Note to photo editors: A color photograph of the poisonous jack-o'-lantern mushroom can be downloaded from the UCSD Office of University Communications website at: http://www-uris.ucsd.edu/ucomm/newsreleases/science/mushroom
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