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Toadstools Yield Anticancer Compounds

By Sean Henahan, Access Excellence

magic mushroomsLa Jolla, CA (10/30/00)- A interesting collection of toxic chemicals isolated from poisonous toadstools appear to have potent tumor killing abilities, even against those resistant to standard chemotherapy.

left: Omphalatus illudens, The jack-o'-lantern mushroom

The anti-cancer compounds are called acylfulvenes. One of the compounds in this class, irofulven has been shown in early clinical trials to shrink tumors in patients with pancreatic and ovarian cancer. Researchers reported promising clinical results earlier this year at the annual meeting of the American Society of Clinical Oncology. The results of Phase II clinical trials, designed to evaluate the safety and efficacy of new drugs, indicated some benefit patients with advanced pancreatic cancer who have failed chemotherapy with the drug gemcitabine therapy. In that study a handful of patients survived longer than would have been expected, and two patients saw tumors shrink by 84% and 100% respectively.

"The results observed in this study are encouraging in terms of survival and tumor response," said S. Gail Eckhardt, M.D., associate professor of medicine and director of Developmental Therapeutics, University of Colorado. "In addition, the fact that these patients had failed standard therapy is particularly important. If these results achieve statistical significance, irofulven will be the first drug to show a significant benefit for patients with previously-treated advanced pancreatic cancer."

Researchers were also encouraged by results of treatment of patients with advanced ovarian cancer who had shown no initial response to such drugs as platinum or paclitaxel. The drug also may have potential for treatment of hormone-refractory prostate cancer, say researchers.

As with many cancer therapies, the new drug produced some unpleasant side effects, including nausea, vomiting, fatigue, and bone marrow suppression.

The arrival of this drug in the clinic follows a long road of research and development. The journey began in the 1960s at the New York Botanical Garden, when Trevor McMorris, now a professor of chemistry and biochemistry at UCSD began studying the chemical properties of the orange-and-yellow colored jack-o'-lantern mushroom. This led to the isolation of illudin-S, the parent toxic compound of acylfulvenes. Moving to UCSD, McMorris continued his studies with colleague Michael Kelner, professor of pathology in the UCSD. The two scientists studied the metabolism of acylfulvenes. Eventually, they tested compounds in mice, rats and dogs and confirmed the potential cancer-fighting abilities of acylfulvenes. The two investigators continue even now to study the compounds and develop acylfulvene-based cancer drug analogs.

"It's exciting now to see our work leading to a new family of anti-tumor drug candidates," says McMorris. "Progress from the Stages I and II of clinical trials by the National Cancer Institute and MGI PHARMA appears excellent, especially relating to cancer of the pancreas, ovaries, and in some cases, the prostate - which are among three of the most difficult cancers to treat," adds Kelner.

Irofulven's unique mechanism of action in anti-tumor activity is still not fully understood. However, biomedical research and clinical trials have shown this: Irofulven is absorbed rapidly by tumor cells. Once inside the cell, the compound binds to DNA and protein targets. This binding interferes with DNA replication and cell division of tumor cells, leading to tumor-specific apoptoic cell death, or "cell suicide" -- a process in which cells automatically shut themselves down when they sense they are damaged.

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