Picking a poison for cancer
During World War II, the development of penicillin was credited with saving thousands of Allied lives. Afterward, battalions of scientists swarmed over swamps, marshes, jungles and forest underbrush looking for other fungi that could combat infection. Researchers screened thousands of compounds, leading to the discovery of streptomycin and other early antibiotics.
But others didn’t pan out. Among them was a toxin from the jack-o’-lantern mushroom. Although it showed promise as an antibiotic, it was too poisonous to be used on humans. Half a century later, however, this mushroom may soon be added to our cancer-fighting arsenal.
A chemical derived from this toxin, irofulven, is being tested as a possible therapy for difficult-to-treat cancers, such as advanced ovarian, prostate, breast, liver, gastrointestinal and brain cancers. Early studies also suggest irofulven may be even more potent when used in combination with such standard chemotherapies as cisplatin and taxotere.
The original studies of the jack-o’-lantern mushroom’s poisonous compounds, known as illudins, were abandoned because the substances were extremely toxic. Consequently, the orange and yellow mushroom, which glows in the dark and causes vomiting and gastric distress if eaten, became a forgotten laboratory curiosity until the 1960s.
It was rescued from obscurity by Trevor McMorris, a chemist at UC San Diego in La Jolla, who began studying the mushroom’s chemical constituents when he was a researcher at the New York Botanical Garden in the 1960s. McMorris submitted the compounds for an analysis by the National Cancer Institute. That analysis found illudins to be powerful anti-tumor agents.
Once McMorris deciphered illudins’ chemical structure, the next step was to figure out a way to change the structure of the compound so that it still killed tumor cells but wasn’t poisonous. His aim was to “reduce the toxicity but retain the anti-cancer activity.”
The work went slowly; it wasn’t until the late 1980s that his lab devised a compound, irofulven, that was effective. He sent the substance to his collaborator, Dr. Michael Kelner, a UC San Diego pathologist, who tested it on mice with leukemia and lung cancer.
Kelner found that the compound killed tumors known as adenocarcinomas, deadly malignancies of the lung, breast and colon that have few effective treatments. “Since it had an affinity for these type of cancer cells, our thought was to exploit it as a drug,” said Kelner. “We still haven’t quite figured out the exact mechanism of how this works, but it is very lethal.”
Scientists do know irofulven is rapidly absorbed by cancer cells, making it a more precisely targeted drug than current treatments, which often kill healthy tissue as well as malignancies. Once inside, the compound latches on to the cell’s DNA and proteins, preventing it from reproducing. This prompts tumor cells to die off, instead of replicating wildly out of control, which is the hallmark of cancer.
Irofulven traveled a long road, however, from the laboratory bench to a patient’s bedside. It was tested extensively on animals before the first tests on humans, in people with advanced pancreatic cancer, began in 1995, more than 30 years after McMorris had begun his research.
The drug has side effects like those of traditional chemotherapy, including nausea, vomiting, fatigue and bone marrow suppression; a test on patients with advanced pancreatic cancer was halted because irofulven was no more potent than standard treatments.
“It’s unclear what it’s role in pancreatic cancer may be,” says Dr. J. Randolph Hecht, an oncologist at UCLA’s Jonsson Cancer Center who tested irofulven on pancreatic cancer patients. “But it’s an interesting drug, and clearly there are people who’ve had responses in other cancers.”
Preliminary results of recent research in a wide variety of other cancers have been encouraging. In a 2000 trial of 15 women with recurrent ovarian cancer, five patients experienced at least a 50% reduction in tumor size, while two others’ disease was stabilized. And in an ongoing test of 14 patients with inoperable liver cancer, one patient experienced a 74% reduction in tumor size, and three other patients’ tumors didn’t grow any larger.
“If it proves as effective as we hope,” Kelner said, “it will open up a whole new front in the fight against cancer.”
Testing the power of mushrooms
Other mushrooms may also prove powerful in the fight against cancer. Pure extracts of exotic mushrooms such as shiitake, enoki, maitake and oyster have shown promise in research conducted in China, Japan and South Korea.
Studies have indicated they may be able to shrink tumors, stimulate the immune system to fight disease and reduce side effects from radiation and chemotherapy.
Experts caution, however, that some of these studies may not have used rigorous scientific standards. In the U.S., scientists at Memorial Sloan-Kettering Cancer Center in New York are studying the maitake mushroom, and are gearing up for tests of the mushroom’s extract on breast-cancer patients.
