EDITORIALSPC-SPES–A Lesson for Future DietarySupplement Research

Jeffrey White

In the past few years, the herbal mixture PC-SPES had be-come one of the best prospects for an alternative medicine can-cer treatment that would be able to stand up to the intensescrutiny of biomedical research. Previously, the failure to per-form adequately in well-designed clinical trials negated furtherresearch on alternative medicine products such as laetrile andhydrazine sulfate. Now, with the report by Sovak et al. in thisissue of the Journal (1), the fatal flaw with PC-SPES is in themore fundamental issue of product integrity.

Although legally sold in the United States as a dietary supple-ment for “prostate health,” PC-SPES was in fact an alternativemedicine treatment for prostate cancer (the PC in the namestands for prostate cancer and spes is Latin for hope). After itsrelease in 1996, the product rapidly became known throughoutthe prostate cancer patient community. Figures are lacking forthe exact rate of use of PC-SPES by patients with prostate can-cer, but the results of a University of Virginia survey reported in1999 showed that 13% of the respondents used an herbal medi-cine (1a). A similar survey in a radiation oncology clinic inPhiladelphia found that 22% of survey respondents used anherbal therapy (2). The University of Virginia study also askedradiation oncologists and urologists to estimate the use of abroad range of complementary and alternative medical therapiesby their patients. They guessed 4.4%, whereas the actual figurewas 37%. This discrepancy is not surprising given the data in-dicating that approximately 70% of U.S. patients who usecomplementary and alternative medical interventions do not re-veal the use to their conventional health care practitioner (3).

Allegations that PC-SPES contained the synthetic estrogendiethylstilbestrol (DES) began appearing on e-mail listservs ofprostate cancer patients and in on-line newsletters by the sum-mer of 2001. One patient who was taking PC-SPES and his wifeapparently were concerned enough about this possibility to com-mission their own analysis of samples from two separate lots inJune 2001 (4). Simultaneously, evidence was emerging that theherbal mixture was causing abnormalities in clotting times insome patients and severe bleeding episodes in others (5–7).

In this setting, the California Department of Health Servicesdecided to test lots of PC-SPES and found contamination withboth DES and warfarin (8). This finding has now been indepen-dently verified and extended to include indomethacin by Sovaket al. Uncovering the adulteration of PC-SPES with these syn-thetic drugs initiated a cascade of effects. On February 8, 2002,the California Department of Health Services released a warningon the contamination of PC-SPES (8). Simultaneously, the Cali-fornia-based manufacturer, BotanicLab, voluntarily recalledPC-SPES nationwide. The Food and Drug Administration(FDA) published a medical product safety alert (9). Canada andIreland also announced recalls of the product. A multicenterclinical trial comparing PC-SPES and DES was stopped (10). On

June 5, 2002, the California Department of Health Services an-nounced that several other herbal products sold by the samecompany were contaminated with indomethacin, DES, or alpra-zolam, either individually or in combination. BotanicLabs wentout of business on June 1, 2002, and PC-SPES is no longeravailable (11). Lastly, the National Center for Complementaryand Alternative Medicine of the National Institutes of Healthplaced all its funded grants using PC-SPES on hold pendingfurther review (12). Likely because of the successful market-ing of PC-SPES, products with similar names (i.e., PC-Calm,PC-Plus, and PC-Care) and herbal compositions are starting tofill the void. None of these products, however, appears to haveany report of research in a search of MEDLINE (July 30, 2002).

Unlike most herbal medications, the potential anticancer ac-tivities of PC-SPES have been extensively researched, resultingin more than 45 MEDLINE-indexed research articles since theproduct was released in 1996. PC-SPES was reportedly stan-dardized via high-performance liquid chromatography profiling.Each batch was evaluated for the presence of six specific peaks(13). The main peak is baicalin, a flavone found in high con-centration in Scutellaria baicalensis, one of the eight herbs re-ported in the mixture (14,15). Baicalin is orally bioavailable inrats (16) and is metabolized in the body to baicalein, a flavonoidsimilar to genistein. (17). Baicalein inhibits 12-lipoxygenase and5�–reductase (17) and also has aromatase inhibitor activity (18).

Aqueous and ethanol PC-SPES extracts have been shown toinduce apoptosis and to prolong the G1 phase of the cell cycle ina variety of cancer cell lines (13,19–22). When added to the dietof rats that had been subcutaneously inoculated with a rat pros-tate cancer cell line, PC-SPES decreased the incidence andgrowth rate of established tumors (22,23). Four uncontrolled,clinical trial, or case series reports on PC-SPES have been pub-lished, each indicating an impressive activity in both androgen-dependent and androgen-independent prostate cancer (24–27).Prostate-specific antigen levels dropped by more than 50% inmost patients reported in these studies. One study that used theFACT–P (Functional Assessment of Cancer Therapy–Prostate)questionnaire reported an improved quality of life (25). Objec-tive improvements of bone scans and measurable disease onradiographic imaging studies were noted in some patients(25,27). The estrogen-like side effects of breast tenderness, de-creased libido and potency, and thromboembolic events werealso frequently observed.

Herbal research is complicated enough without having to dealwith the added problem of potential product adulteration. Inher-ent problems in studying herbal extracts arise from the variationin the concentration of active ingredients in herbs caused by

Correspondence to: Jeffrey White, M.D., National Cancer Institute, NationalInstitutes of Health, Executive Plaza North, Rm. 102, 6130 Executive Blvd.,Bethesda, MD 20892 (e-mail: jeffreyw@mail.nih.gov).

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1) known and unknown genetic and environmental factors (28–30); 2) inconsistent and inaccurate identification of plant species(31,32); and 3) contamination by molds, mycotoxins (33), orpesticides (34). Problems may also occur when there is insuffi-cient regulatory oversight of the production facility. Althoughthe source of contamination of BotanicLabs herbal products hasnot been determined, some have speculated that it originated atthe manufacturing plant in China (35). Other instances of herbalproducts from China being adulterated with synthetic drugs havebeen reported (36,37).

Preclinical and clinical trial research of promising herbal in-terventions should continue. The fundamental questions raisedby herbal medicine, such as the synergistic therapeutic activityof various components, need to be answered for the field toprogress. We need to know if there are sufficient reasons (sci-entific, economic, or other) to continue to pursue research of aproduct as an incompletely characterized and variable mixturerather than follow the more mainstream drug developmentmodel of isolating and purifying an active ingredient.

Regulatory challenges also exist. Clinical and, perhaps, pre-clinical investigators should preferentially study products that atleast meet the FDA’s newly developed botanic guidelines (38).However, this requirement may not be enough to identify erraticchanges in production quality. Consequently, investigatorsshould consider regular quality control evaluations by indepen-dent laboratories throughout the course of their research.

Much remains to be learned about the mechanism of action ofPC-SPES as a cancer therapy in humans. Despite some lotshaving sufficient concentrations of DES to cause one to wonderif it is responsible for some of the activity, there are intriguinghints that there may be other, possibly novel drug activitiespresent. For example, in the study by Small et al. (27), more thanone endocrine manipulation had failed for many of the patientsincluded in the study, and yet some of these patients apparentlyresponded to PC-SPES. The trial comparing DES and PC-SPES(10) was designed so that patients would cross over to the op-posite arm after progression. It will be interesting to learn wheth-er analysis of these data shows responses in any patients after thecrossover.

Perhaps the story of the demise of PC-SPES will serve as alesson to help future researchers uncover such confounding el-ements earlier in their research. The story also tells how patientinterests and concerns can help push research investigations inpositive directions. The lesson must be well learned, because theloss of a product that symbolized hope to some should not occurwithout leading to an ultimate gain for all cancer patients.

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