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NEW COMPOUND SEEN TO HOLD PROMISE AS AN ANTI-TUMOR AGENT IN OVARIAN AND PANCREATIC CANCER

  
A novel family of anti-cancer compounds called acylfulvenes, discovered by two scientists at the University of California, San Diego more than 10 years ago from toxins of the poisonous jack-o'-lantern mushroom, is showing promise as a highly effective chemotherapy agent, according to clinical trial results reported on recently at a meeting of the American Society of Clinical Oncology (ASCO).

The encouraging results specifically deal with irofulven, a drug candidate derived from the acylfulvene compound family, and which is currently being developed by MGI PHARMA, Inc., an emerging pharmaceutical company based in Minneapolis, MN.

Irofulven is particularly effective in shrinking tumors associated with pancreatic and ovarian cancer, especially among those patients who are no longer responding appropriately to such conventional cancer drugs as gemcitabine, platinum, and paclitaxel, according to interim clinical Phase II results released late this spring at the annual meeting of ASCO in New Orleans.

The notable anti-tumor activity of acylfulvenes was first demonstrated at UCSD in the early 1990s in chemical and biomedical studies conducted by Trevor McMorris, professor of chemistry and biochemistry, and Michael Kelner, professor of pathology in the UCSD School of Medicine. Both are also members of the UCSD Cancer Center.

Building upon the research that McMorris had already begun in the 1960s at the New York Botanical Garden on the chemical properties of the orange-and-yellow colored jack-o'-lantern mushroom, the two scientists began testing and comparing the metabolism of acylfulvenes with that of illudin-S (the parent toxic compound of acylfulvenes which is found naturally in the jack-o'-lantern mushroom). Subsequent studies with mice, rats and dogs demonstrated the potential of acylfulvenes as a viable anti-tumor agent, and further study provided more insight into its clinical application possibilities. McMorris and Kelner are continuing to explore and test other 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.

In 1993, MGI-PHARMA acquired the rights from the University of California to all illudin-S analogs devised by McMorris and Kelner, including hydroxymethylacylfulvene (now called irofulven), which was synthesized by McMorris.

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.

Reporting on the compound at the ASCO meeting, Steven Weitman, M.D., Ph.D., director of translation research at the Institute for Drug Development, University of Texas, and other researchers said irofulven's novel mechanism of action gives it the ability to be active against the most common forms of drug-resistant tumors and the potential to combine effectively with other anti-tumor therapies.

(The drug's most prevalent side effects are nausea, vomiting, fatigue, and bone marrow suppression, which are typical of other chemotherapy drugs.)

Interim results of Phase II clinical trials show that irofulven clearly has anti-tumor activity in patients with advanced pancreatic cancer who have failed gemcitabine therapy, proceedings of the ASCO meetings indicate.

On the average, such patients would have less than three months to live, researchers know. In the irofulven study, seven of 44 patients evaluable for this endpoint have survived at least six months. Equally important was the tumor shrinkage in such patients. Two pancreatic cancer patients had objective tumor responses; one had 100 percent reduction, and another experienced an 84 percent decrease in tumor mass.

"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, commenting on the irofulven results reported at the ASCO meeting. "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."

Equally encouraging results were reported in Phase II clinical trials involving patients with advanced ovarian cancer who had shown no initial response to such drugs as platinum or paclitaxel. And, irofulven's use in hormone-refractory prostate cancer is also showing promise in early Phase II trials, warranting further testing alone and in combination with other compounds and/or radiation.