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Contamination of PC-SPES Remains a Mystery

Tom Reynolds

For thousands of prostate cancer patients who did not respond to standard treatments, the herbal preparation PC-SPES seemed to offer the last, best hope for a remission of their disease. And for researchers, PC-SPES appeared poised to become the first cancer treatment to emerge from the realm of alternative medicine, pass rigorous clinical testing, and add a powerful natural weapon to the oncologist’s arsenal.

Now, patients and researchers are left wondering what went wrong. In February, PC-SPES—labeled as a mixture of seven Chinese herbs plus saw palmetto—was taken off the market by its manufacturer, BotanicLab of Brea, Calif., after tests by the California Department of Health Services showed it contained the prescription drug warfarin, a blood thinner. The U.S. Food and Drug Administration advised men to stop taking it.

Independently, other scientists found that PC-SPES also contained diethylstilbestrol (DES), a synthetic estrogen once used to treat prostate cancer. Another herbal product made by BotanicLab was found to contain the anti-anxiety drug alprazolam (Xanax). In June, the company shut down its operations. A class action lawsuit has been filed that charges BotanicLab with selling mislabeled dietary supplements.

In this issue of the Journal (p. 1275), a team of investigators from San Diego, Long Beach, Calif., and the Czech Republic present detailed findings from a chemical analysis of eight lots of PC-SPES manufactured at different times between 1996 and 2001. (The team presented an abbreviated report in April at the annual meeting of the American Association for Cancer Research; see News, May 1, p. 649.) They sought to define the ingredients in the mixture and to determine which ones were responsible for its anticancer properties. In particular, they wanted to discover the source of the potent estrogen-like activity that apparently both suppressed tumor growth and produced characteristic side effects, including potentially dangerous blood clot formation.

One of the authors, Robert A. Nagourney, M.D., medical and laboratory director of Rational Therapeutics, Long Beach, Calif., was an early proponent of PC-SPES. He began treating his hormone-refractory prostate cancer patients with the compound after meeting its co-inventor, chemist Sophie Chen, Ph.D., who is a research associate professor at New York Medical College. Businessman John Chen, Sophie Chen’s brother and president of BotanicLab, founded the company to sell herbal remedies several years before PC-SPES was introduced.



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Dr. Robert A. Nagourney

 
Sophie Chen developed PC-SPES with Allan Wang, M.D., director of traditional Chinese medicine at Shanghai Medical University. They modified the ingredients from an existing formulation—one that is used in China to treat urologic problems—on the basis of in vitro assays on cells taken from a prostate cancer patient, she said in an interview. The first patient to use it was her brother-in-law, a physician in Taiwan who had advanced prostate cancer but is alive and well 10 years later. News of the apparent success of the formulation spread by word of mouth, first in Taiwan, then internationally, leading Chen to license the patent to BotanicLab for commercialization.

In 1996, the company gave Nagourney free samples to conduct a pilot study. He was "astonished and very favorably impressed" to see a 50% response rate (measured by reductions in pain and prostate-specific antigen levels, improvements in performance status, and other measures) in patients who had failed conventional hormone therapy and thus had few remaining treatment options. The fact that the active agent was apparently a natural product added to its allure.

"I was intrigued that they looked like estrogen-treated patients," showing breast enlargement and tenderness, he added. Nagourney and others who saw estrogen-like effects hypothesized that a plant-derived estrogenic compound was responsible, probably licochalcone A, a flavonoid from the licorice plant Glycyrrhiza glabra. However, neither licorice nor any of the other herbal ingredients showed in vitro antitumor activity when tested individually by Milos Sovak, M.D., director of the Biophysica Foundation in La Jolla, Calif., and professor of radiology at the University of California, San Diego, and his Czech colleagues.

"We couldn’t explain why the natural ingredients couldn’t reproduce the activity we saw in the commercial product," Nagourney said. "It raised questions about what might be in the commercial product that was not in the native herbs."

In the new study, Sovak and Allen Seligson, Ph.D., senior scientist at Biophysica, La Jolla, Calif., used high-pressure liquid chromatography, magnetic resonance imaging, and mass spectroscopy to identify and quantify the components of PC-SPES—a daunting technical challenge because each herb contains dozens of compounds. In addition to these natural chemicals, the researchers found DES, warfarin, and indomethacin, an anti-inflammatory drug used against arthritis. They also found that concentrations of both the drugs and the herbal components varied widely over time.

Nagourney said the results confirm rumors and suspicions—from both researchers and within the cancer patient grapevine—that PC-SPES might contain DES. DES showed activity against prostate cancer in trials in the 1970s. But it was abandoned in favor of other hormonal therapies—androgen blockers and luteinizing hormone-releasing hormone agonists—because of thromboembolic and cardiovascular side effects. In an early PC-SPES trial, published in the Sept. 17, 1998 New England Journal of Medicine, researchers at the Cancer Institute of New Jersey, New Brunswick, looked for DES in PC-SPES but could not find it or other known estrogens.

Chen questioned the function of DES in PC-SPES, saying that none of the contaminant drugs were present in therapeutic doses and that "the lots without DES worked equally well" when compared with those with traces of DES.

Results of clinical trials suggest that PC-SPES did show promise. In a trial led by Eric Small, M.D., associate professor of medicine and urology at the University of California at San Francisco, PC-SPES showed activity in both androgen-dependent and androgen-independent prostate cancer patients. Most patients experienced dramatic declines in PSA, and several had shrinkage of bone metastases—responses typically associated with symptom improvement and longer survival.

A phase II randomized trial was begun to directly compare PC-SPES to DES in patients with androgen-independent tumors. Preliminary results, reported at the American Society of Clinical Oncology’s annual meeting in 2002, showed that PC-SPES produced a 47% response rate, compared to 28% for DES, said William Oh, M.D., assistant professor of medicine at the Dana-Farber Cancer Institute in Boston, who led the trial along with UCSF’s Small.



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Dr. William Oh

 
"The response duration was also significantly greater in the PC-SPES group, and the side effects were about the same—we didn’t see undue toxicity," Oh said. But "in summer 2001, we began to hear rumors that a private laboratory had found DES present in PC-SPES." The researchers tested their four lots of PC-SPES, and all had variable amounts of DES. They halted the study in January 2002 because the contamination of PC-SPES would have confounded the interpretation of the findings.

Nevertheless, Oh believes PC-SPES has activity even without DES. The amounts of DES found in the lots of PC-SPES were minute, ranging from 0.01% to 3.1% of the 3 mg per day that men in the DES arm were receiving, he said, "which makes one believe that there had to have been something else causing the responses."

In the new study, however, Sovak and co-authors suggest that men taking PC-SPES may have received therapeutic doses of DES. They cite evidence from earlier trials that DES at 1 mg/day or even 0.1 mg/day "was both efficacious and tolerable." By comparison, their analysis shows that nine capsules of PC-SPES—the recommended dose—would deliver 0.5 mg/day of DES.

Chen expressed anger and bafflement over the adulteration of PC-SPES. She suggested three possibilities to explain how it may have occurred. First, the raw material may have been contaminated. Second, the manufacturing equipment used to extract the natural products may have been contaminated. The third explanation, which Chen favors, is that a chemical reaction between herbs, induced by the methods employed in some of the factories’ extraction processes, may have produced the drugs spontaneously.

Asked about the plausibility of this scenario, Nagourney said that "while anything could happen, it seems hard to imagine that these substances of known biological activity would be spontaneously synthesized in the formulation process."

Chen also said she would not rule out the possibility that someone, for whatever reason, may have added the drugs deliberately during the preparation process of PC-SPES in China.

In the United States, the 1994 Dietary Supplement and Health Education Act (DSHEA) set guidelines for the production, distribution, and marketing of supplements. According to the FDA, DSHEA establishes a new framework for assuring safety, requires ingredient and nutrition labeling, and grants FDA the authority to establish Good Manufacturing Practice regulations. The agency states that "FDA intends to work with the supplement industry and other interested persons to develop GMPs."

Nagourney emphasized that the new findings "should not be viewed as a cry to restrict people from selling or taking natural products. But if you sell something, you should stand behind what you say is in it and not put other things into it." DSHEA regulations are supposed to assure this, he said, but "in this case, they were breached."

Another effect of the findings, he said, is that "maybe in a strange way, this gets us to revisit diethylstilbestrol, which is a highly effective therapy for hormone-refractory prostate cancer," and to evaluate the potential of other estrogenic drugs that are more readily available. He said he is treating some patients with estrogen after they fail other hormone therapies.

Nagourney also believes it is possible that licochalcone A, baicalin, or another herbal component of PC-SPES may have anticancer activity in concert with DES.

"It remains an interesting possibility that you could take this formulation, recognizing that DES is present, and do a dose-seeking trial," he said.

Dana-Farber’s Oh said that "the worst part [of the PC-SPES saga] is that PC-SPES was a very effective treatment with minimal toxicity for advanced cancer patients. These men don’t have many choices for therapy," except for chemotherapy with more substantial toxicity.

The National Center for Complementary and Alternative Medicine has put on hold four PC-SPES studies pending a reassessment. In mid-August, the center brought together its PC-SPES grantees and other experts and interested parties, including Sophie Chen, to decide how to proceed. NCCAM was expected to update the public on the future of its PC-SPES research at the end of August after this issue of the Journal went to press.

Chen said she hopes to revive production of PC-SPES with better quality control.

"I’m going to work with NIH to see how I can help," she said. "I feel the patients who had used PC-SPES are the victims of the whole thing. I hope the problem can be resolved in the near future."



             
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