by Wyn Snow, Managing Editor, SupplementQuality.com
Some months ago, SupplementQuality.com reported on a promising herbal remedy for prostate cancer. PC SPES was achieving highly positive results in clinical studies (see story: Herbs That Fight Prostate Cancer). Now, however, cancer researchers report finding three synthetic compounds in the mix.
Robert Nagourney, MD, Director of Rational Therapeutics in Long Beach CA, told cancer scientists at the 93rd annual meeting of the American Association for Cancer Research in San Francisco that he and his colleagues found three prescription drugs in samples of PC SPES that they analyzed:
- diethylstilbestrol, a hormone-like compound more familiarly known as DES
- warfarin, a blood thinner, also known as Coumadin®
- indomethacin, a pain killer
Product success launches detective story of research
According to Nagourney, he and his colleagues initially "were delighted that an herbal product was effective against cancer and became intrigued with finding out chemically what was inducing these changes. We wanted to know what made this stuff so effective."
Knowing how PC SPES worked would be useful not only for prostate cancer but might supply knowledge for fighting other kinds of cancer as well, so Nagourney and Dr. Milos Sovak of the Biophysica Foundation in La Jolla CA, in collaboration with associates at the Palacky University in Olomouc, Czech Republic, decided to investigate.
PC SPES exhibits estrogenic effects, so Nagourney and Sovak began looking for an estrogenic compound among the herbal ingredients, "and that's where we ran into trouble," says Nagourney. "We weren't managing to explain the types of results we were seeing."
The formula for PC SPES combines saw palmetto with seven herbs used in traditional Chinese medicine, including: licorice, reishi, Baikal skullcap, rabdosia, Dyers woad, mum, and Panax ginseng. Marian Hajduc of Palacky University took extracts of these herbs and tested them for bioactivity by mixing them in test tubes with three different strains of prostate cancer cells, both singly and in combinations. None of Hajduc's extracts or mixtures slowed growth of the cancer cells — but PC SPES does.
Sophie Chen, PhD, of BotanicLab, Inc. (the manufacturer of PC SPES, located in Brea CA), has gone on record explaining that PC SPES consists of highly concentrated fractions derived from the plants noted above. Thus, the failure of Hajduc's mixtures to inhibit cancer cell growth is not evidence that PC SPES contains other active components. A different extraction process or more highly concentrated mixture might slow the cancer cell growth.
Research takes a new direction
However, Nagourney and Sovak wanted to know "What's different between our mixture of these herbs and the manufacturer's mixture of herbs?" To find out, they decided to analyze the various herbs and the PC SPES mixture itself in order to identify exactly what was in each of them.
The researchers purchased samples of PC SPES from the manufacturer and took them to the Biophysica Foundation where Dr. Allen Seligson subjected them to analysis using HPLC (high performance liquid chromatography) methodology.
"HPLC tracings look like a forest," Seligson told SupplementQuality.com. "We compared the tracings of PC SPES with tracings of the individual herbs and mixtures of herbs. Among the several hundred peaks, we found three discrepancies between the tracings of PC SPES and the herbs." The researchers identified these three discrepancies as consisting of DES, warfarin, and indomethacin.
Synthetic drugs or natural analogues?
In 2001, the New England Journal of Medicine published a letter from Weinrobe and Montgomery that said they found warfarin (also known as Coumadin®) in the blood of a patient who was using PC SPES (NEJM, vol 345, pages 1213-1214). BotanicLab replied that the product might contain a natural coumarin. Indeed, coumarin compounds do appear in many plants — including strawberries, apricots, cherries, cinnamon, lavender, woodruff, and clover, so this could be a plausible explanation.
However, Nagourney states there are chemical differences between synthetic and natural coumarins. What they found was "consistent with synthetic warfarin rather than plant-based." Warfarin is a prescription blood-thinner.
Similarly, the researchers found 150 micrograms of DES per gram in their samples of PC SPES. DES is also a synthetic compound. According to Nagourney, "DES interacts with estrogenic receptors in a similar way to natural estrogens, and was used as a treatment for prostate cancer decades ago. We moved to other drugs because DES tends to cause blood clotting."
BotanicLab did not return phone calls from SupplementQuality.com. However, their website states unequivocally: "DES was never an ingredient formulated in the composition of PC SPES."
BotanicLab also states on its website: "Studies performed by Peter Nelson and Michael Bonham compared the effects of PC SPES and DES on several genes involved in the growth of prostate carcinoma, and found that the compounds exhibited distinctly different activities." The website quotes Dr. Nelson as saying, "The cellular effects of PC SPES and DES are quite distinct, and I believe, based on our findings, that PC SPES kills cancer cells through very different mechanisms than those utilized by DES."
On February 8, BotanicLab issued a voluntary recall of PC SPES, after the California Department of Health announced it had found warfarin in the product. BotanicLab said its independent lab results found that the material "may instead be a phytocoumarin (a compound naturally synthesized in various green plants) that may mimic warfarin in laboratory testing."
Does processing cause chemical changes to herbs?
It can. According to Staci Eisner, Technical Director at ExtractsPlus in Vista CA, the process of transforming a plant into an extract or concentrate can create new chemical compounds and cause others to degrade. It might break a molecule in two, or alter a molecule in other specific and generally predictable ways.
So processing can change an HPLC tracing, but Eisner says, "These changes should make sense. Generally speaking, the process of extracting and concentrating herbal compounds from a plant usually would not generate a chemical compound that is the same as a patented pharmaceutical drug."
Pharmaceutical drugs are deliberately made of unique molecules that do not occur in nature or through commonly used processing methods. To be eligible for a patent, a substance has to be either man-made (synthetic) or a new use of a natural substance. Also, manufacturers want to make it difficult for competitors to reproduce their results. All three of the drugs in question began their lives as patented pharmaceuticals, although the patents have now run out and the drugs can be manufactured and sold by others.
Roy Upton, a leading herbalist and Executive Director of the American Herbal Pharmacopoeia, is not surprised by Nagourney's report. He states, "Herbalists have suspected adulteration of PC SPES for some time. It was working too well and causing side effects that are not typical of the herbs in the formula." However, Upton cautions that "the jury is still slightly out" on whether PC SPES does actually contain these substances — and if it does, why they are there.
Upton says PC SPES is not based on any formulation of traditional Chinese medicine (TCM), which he practices. Instead, "it looks like a modern mixture of herbs shown to have anticancer properties, some of which happen to be Chinese herbs."
If warfarin were added to the mix, the purpose from a Western point of view would be to reduce the risk of blood clots from DES. From the perspective of Chinese medicine, however, warfarin might be added to enhance the herbs. Upton says, "In Chinese medicine, one primary means of dissolving tumors is to use substances that dispel blood coagulation and break up blood stasis. Tumors are viewed as masses of tissue that are enervated with blood, so adding warfarin to the mix could be seen as a legitimate method [from the TCM point of view] for potentiating the blood-breaking effects of these herbs."
Upton also says, "Conceptually, there's nothing wrong with combining drugs and herbs, but in the US, supplement ingredients must be disclosed on the label. If a product contains drugs, it cannot be sold as a dietary supplement."
The cloud and the silver lining
The evidence from Nagourney and Sovak's research has not yet received the intense scrutiny that follows publication of scientific work, but soon will. Further investigation is also highly likely.
Mark Blumenthal, Executive Director of the American Botanical Council (ABC) in Austin TX and Editor/Publisher of HerbalGram, cautions that testing of botanical substances is fraught with technical difficulties. His experience in testing more than 500 ginseng products for ABC taught him how challenging it can be to develop reliable and rigorous test methods so that two independent laboratories get the same results from the same samples.
However, if PC SPES does contain these pharmaceutical drugs, its future is cloudy. If PC SPES contains drugs, it cannot be sold as an herbal supplement. Because of the recall, PC SPES is currently not available to prostate cancer patients. Ironically, however, this cloud may have a silver lining.
If PC SPES gets its results from DES plus warfarin, then any physician can prescribe these two pharmaceutical medications, as Dr. Nagourney has been doing for some of his prostate cancer patients for approximately two years now. Also, warfarin is a powerful drug. Taking too much can cause uncontrolled bleeding, a very serious and life-threatening condition. Therefore, people who use warfarin, which is often prescribed under the brand name of Coumadin®, need to have their dosages and blood-clotting times closely monitored.
Also, if PC SPES does contain these drugs, the current regulatory framework for supplements worked. Richard Ko, at the California Department of Health, was the first to find warfarin in PC SPES, triggering a voluntary recall at the national level by BotanicLab.
The larger picture
PC SPES raises issues of testing and globalization of commerce that all revolve around quality. Several fledgling programs have begun to test and certify dietary supplement products and to inspect and certify the manufacturing facilities that produce them. The organizations developing these programs include:
- National Nutritional Foods Association
- NSF International
- US Pharmacopeia
Once these programs have become widely adopted throughout industry and the marketplace, it will be difficult if not impossible for a manufacturer to sell a product containing pharmaceutical drugs under a dietary supplement label.
Indeed, any manufacturer who passes good-manufacturing-practice (GMP) inspections today must have a reliable process for verifying the identity of raw ingredients from anywhere in the globe. To pass these inspections, manufacturers must also establish and follow procedures that ensure ingredients do not become contaminated at any stage of the manufacturing process.
If PC SPES contains prescription pharmaceuticals, there are only two ways this could happen: accidental contamination or deliberate adulteration. If PC SPES was deliberately adulterated at one or more stages in the supply, manufacturing or distribution process, then the law was knowingly broken — which is a very different issue from whether a new supplement is both safe and effective.
An old folk injunction advises people to be careful what they wish for. Indeed, if PC SPES was adulterated, this is a case where the wished-for success attracted a level of scientific scrutiny that proved its undoing.
Mark Blumenthal; Executive Director of the American Botanical Council, Austin TX; Editor/Publisher of HerbalGram. Personal communication, 18 April 2002.
BotanicLab, Inc., Brea CA. Information from website, including press release: "BotanicLab pursues investigation of `compound' found in PC SPES." www.BotanicLab.com.
Staci Eisner; Technical Director at ExtractsPlus, Inc., Vista CA. Personal communication, 19 April 2002.
Robert A. Nagourney, MD; Medical and Laboratory Director of Rational Therapeutics Testing Lab; also affiliated with Memorial Medical Center and UCI Medical Center in Orange CA. Personal communication, 18 April 2002.
Allen Seligson, PhD; chemist and General Manager, Biophysica Foundation, La Jolla CA. Personal communication, 18 April 2002.
Roy Upton; herbalist, Executive Director of American Herbal Pharmacopoeia, Santa Cruz CA. Personal communication, 19 April 2002.