Originally published as JCO Early Release 10.1200/JCO.2004.10.195 on August 2 2004

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oh, W. K. Articles by Small, E. J. Search for Related Content PubMed PubMed Citation Articles by Oh, W. K. Articles by Small, E. J. Related Articles Related Editorial Social Bookmarking                            What's this?

Prospective, Multicenter, Randomized Phase II Trial of the Herbal Supplement, PC-SPES, and Diethylstilbestrol in Patients With Androgen-Independent Prostate Cancer

From the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute; Department of Chemistry, Northeastern University; Massachusetts General Hospital Cancer Center; Beth Israel Deaconess Medical Center, Boston, MA; Department of Food Science and Center for Advanced Food Technology, Rutgers University; University of Medicine and Dentistry of New Jersey, Piscataway, NJ; and University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA

Address reprint requests to Eric J. Small, MD, UCSF Comprehensive Cancer Center, 1600 Divisadero St, A718, San Francisco, CA 94115; e-mail: smalle{at}medicine.ucsf.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC).

PATIENTS AND METHODS: A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES.

RESULTS: Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots.

CONCLUSION: PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Treatment options are limited in androgen-independent prostate cancer (AIPC).^1,2 Secondary hormonal therapy and chemotherapy demonstrate activity in 20% to 70% of patients, but response duration is typically 6 to 12 months.^1,2 Clinical trials demonstrate significant activity of diethylstilbestrol (DES) in AIPC. A phase II study of 1 mg oral DES in 21 patients with AIPC demonstrated a 50% decline in prostate-specific antigen (PSA) in 43% of patients.³ Other studies confirm that DES (1 to 4 mg daily) has substantial activity in AIPC, with PSA declines 50% in 29% to 66% of patients.⁴

Herbal therapies are used with increasing frequency by prostate cancer patients.⁵ A popular herbal combination called PC-SPES was commercially available from 1996 to 2002.⁶ PC-SPES was a combination of eight herbal compounds: Ganoderma lucidum, Scutellaria baicalensis, Rabdosia rubescens, Isatis indigotica, Dendranthema morifolium, Seronoa repens (saw palmetto), Panax pseudoginseng, and Glycyrrhiza uralensis (licorice root). PC-SPES inhibited growth of androgen-sensitive and androgen-independent prostate cancer cells, both in vitro and in animal models.^7-10 Antitumor effects were dose- and time-dependent,^7,8 and toxicity in rodents was limited.¹⁰ Growth inhibitory effects were seen in different cell types, ranging from the androgen-sensitive (LNCaP)^9,10 to the androgen-independent (DU145)⁹ to the aggressive Mat-Ly-Lu rat prostate cancer.⁸

Several investigators studied PC-SPES in AIPC.^11,12 One analysis of 23 patients reported significant efficacy.¹¹ Eighteen patients had received prior secondary hormonal treatment, while 10 had received prior chemotherapy, signifying a heavily pretreated group of patients. Fifty-two percent of patients had a PSA decline 50%. Median time from the start of therapy to PSA progression was 6 months. Small et al¹² reported 19 (54%) of 35 AIPC patients with a PSA decline 50%. Median time to PSA progression was 4 months. PC-SPES was well tolerated, with leg cramps, gynecomastia, and breast tenderness more common, and thromboembolism infrequent.

While PC-SPES had anticancer effects, its estrogenic properties raised the question of whether the observed effects exceeded those anticipated with estrogens alone. In this context, if PC-SPES had antitumor activity independent of an estrogenic effect, it would represent an additional therapeutic option for AIPC patients.¹³ The current trial was designed to evaluate the efficacy of PC-SPES following DES therapy and conversely, DES following PC-SPES therapy in patients with AIPC.

Though PC-SPES had potent estrogenic activity by an estrogen receptor assay, high-performance liquid chromatography (HPLC) and gas chromatography (GC) of extracts failed to identify DES, estrone, and estradiol.⁶ However, in the midst of this clinical trial, reports indicated that two laboratories detected DES in some lots of PC-SPES.¹³ We therefore performed chemical analyses of the four lots used in this clinical trial. Because the results demonstrated contamination with DES, the clinical trial was halted prematurely. This report summarizes our findings at study closure and the results of chemical analyses of PC-SPES.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
This clinical trial was approved by the institutional review boards of Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, Massachusetts General Hospital (Boston, MA), and University of California San Francisco Medical Center/San Francisco Veterans Affairs Medical Center (San Francisco, CA). All patients provided written informed consent before participation.

Eligibility
Patients had documented histologic evidence of prostate cancer. Progressive androgen-independent disease was defined according to the PSA Working Group criteria.¹⁴ Baseline serum PSA was 5 ng/mL. No history of thromboembolic disease was allowed within the prior year, including deep venous thrombosis, pulmonary embolism, stroke, or myocardial infarction. No prior therapy with estrogens, PC-SPES, or chemotherapy was allowed. Patients previously treated for progressive disease with ketoconazole, aminoglutethimide, megestrol acetate, or other megestrol agents or corticosteroids were not eligible. Patients could not be receiving concurrent saw palmetto, megestrol acetate, or steroid hormones, and at least 1 month must have passed since discontinuation of any of these agents. Eastern Cooperative Oncology Group performance status was required to be between 0 and 2. Patients who had not undergone prior orchiectomy and were receiving luteinizing hormone-releasing hormone analogs remained on this medication. Laboratory criteria included WBC count > 3,000/mm³, hemoglobin > 8.0 g/dL, platelets > 80,000/mm³, creatinine < 2.0 mg/dL or 1.5x upper limit of normal, total bilirubin less than 1.5 mg/dL or 1.5x upper limit of normal, AST less than 1.5x upper limit of normal, and serum testosterone less than 50 ng/mL. No surgery or radiation therapy was allowed within 4 weeks and no radiopharmaceuticals within 8 weeks.

Treatment Plan
According to the manufacturer, each PC-SPES capsule contained 320 mg of the herbal combination.¹⁵ Eligible patients were randomly assigned to either initial PC-SPES at a dose of three capsules (960 mg) by mouth three times a day or DES at 3 mg per day. The PC-SPES dose selected was the dose reported in an earlier prospective phase II trial.¹² Patients received warfarin 2 mg per day continuously because of the known risk of thromboembolism with PC-SPES and DES. On disease progression, patients were eligible to receive cross-over therapy with the agent that they had not already received (Fig 1). Imaging studies were repeated at the time of cross-over, if it had not been obtained within the prior 28 days. To assess possible differential effects of these agents on testicular and adrenal androgen production, baseline levels of testosterone, dihydrotestosterone, estradiol, estrone, sex hormone-binding globulin, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S) and androstenedione were obtained at baseline and every 12 weeks.⁴

View larger version (17K): [in this window] [in a new window]   Fig 1. Treatment schema. DES, diethylstilbestrol.

Statistical Considerations
The primary goal of the study was to determine the response to PC-SPES after DES therapy, and vice versa. If disease progression occurred following an initial response, or if patients did not respond to the initial treatment, patients were treated with the second agent. Patients were stratified by the presence of metastases and randomized with equal probability to either intial PC-SPES or DES (Fig 1). The primary outcome measure was frequency of response to the second regimen in the randomized sequence as a function of initial response. Secondary outcome measures were the likelihood of and the duration of response to the first regimen and frequency of toxicities. All patients receiving at least one dose of treatment were included in the analysis of toxicity. Only patients on study for at least 2 months of therapy were evaluated for response using the PSA Working Group definition. Descriptive statistics were used to characterize patient, disease, and outcome measures. Comparability of the two study arms was assessed using a ² statistic for categoric variables, a t statistic for continuous variables, and the nonparametric Mann-Whitney test to compare distributions. The duration of response and time to disease progression were estimated using the Kaplan-Meier product limit method.

From previous experience, 50% of the patients were expected to respond to initial PC-SPES or DES.^3,4,11,12 We sought to determine a 20% response frequency to the second treatment assuming a null hypothesis of 5%, which required 27 patients. Thus, approximately 54 patients were needed for each treatment arm, so that the secondary therapy could be evaluated in patients who had responded to the first therapy, as well as in patients who had failed to respond to the first therapy. This assumed a level of significance for a one-sided, one sample test of 0.04 and power of 0.82 for each of the four subsets (responders and nonresponders to initial PC-SPES or DES). Therefore, total accrual of 108 patients was anticipated. These two sequential treatments were not designed to compare any outcome measures between treatment arms.

Two underlying assumptions of this trial were that (1) there was no DES present in PC-SPES and (2) there was minimal lot-to-lot variability of PC-SPES content. However, because chemical analyses demonstrated variable amounts of DES in each lot, it was decided that the primary outcome measure (cross-over response rate) was uninterpretable and the study was halted. At first, patients responding to treatment were allowed to remain on treatment. However, by February 2002, the manufacturer voluntarily recalled PC-SPES, at which point all patients were removed from treatment.^13,16

Detection of DES in PC-SPES
PC-SPES was extracted from each of the four lots used in the clinical trial. A known amount (typically 13 to 16.5 grams) of PC-SPES was removed from the capsules and combined with 170 mL of absolute ethanol. The sample was sonicated at 50° to 60°C for 2 hours, filtered, and concentrated under vacuum. The sample residue was partitioned between dichloromethane (400 mL) and deionized water (200 mL). The resulting emulsion was broken down by lowering pH less than 1 with 6M HCl. After layer separation, the dichloromethane layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The sample was then analyzed by HPLC and GC/mass spectroscopy (MS). GC was performed using a DB-1 column (30 M), while HPLC was performed using a C-18 column (15 cm).

Analytic samples were prepared from the residue of the isolation by sonicating with acetonitrile (1.0 mL/100 mg residue) at 20°C for 5 minutes and filtered through a 0.4 micron polytetrafluoroethylene membrane. Quantitation was based on HPLC area counts against known standard concentrations. Standards were run at 0.05 mg/mL through 1.0 mg/mL concentrations. Calculated DES amounts were the average of three determinations. The identity of DES was confirmed by GC/MS.

Detection of Ethinyl Estradiol (EE) in PC-SPES
Three lots were tested, including one lot used in the trial. To further enhance the ability to detect estrogens, fractionation of PC-SPES extracts was guided by a functional estrogen receptor (ER) assay. The growth-based assay used Saccharomyces cerevisiae strain PL3, which carries a URA3 gene under the control of either the human ER alpha and beta.⁶ After fractionation using hexane, ethyl acetate, and butane, the fraction with the strongest activation of alpha and beta ER in the yeast system was subjected to RP-C18 column eluted with methanol-water solvent system to give eight additional fractions. The subsequent fraction with the greatest ER activity contained a pure compound. Normal phase column chromatography was used to further concentrate the compound of interest. Fifty grams of silica gel (100 to 200 A°) was used and five columns were packed. The elution for each column was performed first with 500 mL chloroform followed by 50:1 chloroform/acetone. In order to get an accurate value of its concentration, the internal standard method was employed, in which ß-estradiol was used as an internal standard. Each sample went through silylation by reacting with bissilyltrifluoroacetamide. ¹H (600 Hz) Nuclear magnetic resonance (NMR) spectra were run on a Varian AM-600 NMR spectrometer (Varian Inc, Palo Alto, CA). MS was performed on a Fisons/VG Platform II mass spectrometer (Thermo Electron Inc, San Jose, CA). Thin-layer chromatography was performed on Sigma-Aldrich TLC plates (Sigma-Aldrich Corp, St Louis, MO; 250 µm thickness, 2 to 25 µm particle size), with compounds visualized by spraying with 5% (v/v) H₂SO₄ in ethanol solution. The compound was determined to be EE and confirmed by NMR.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
A total of 90 patients were registered onto this trial. Five patients, three initially assigned to PC-SPES and two to DES, received only 1 month of treatment at the time the study closed and were nonassessable for response but evaluated for toxicity. Thus, 85 patients are considered assessable for response, 43 patients in the initial PC-SPES arm and 42 patients in the initial DES arm. The two groups were well balanced in terms of baseline characteristics (Table 1). In general, patients had an excellent performance status. All patients had progression of disease despite androgen deprivation therapy. Most patients had bone metastases, but approximately one-fifth of the patients had progressive disease evidenced by a rising PSA only. No differences in baseline testosterone, dihydrotestosterone, estradiol, estrone, sex hormone-binding globulin, DHEA, DHEA-S, or androstenedione levels were seen between groups (data not shown).

View larger version (13K): [in this window] [in a new window]   Fig 2. Proportion of patients free of progression. DES, diethylstilbestrol.

Two of eight patients treated with DES at cross-over demonstrated a decrease in PSA, though neither achieved a 50% PSA response. One of two patients who responded to PC-SPES had a decrease with DES, while one of six nonresponders to PC-SPES had a subsequent decrease with DES. Patients received between 2 to 5 months of cross-over therapy until the study closed. Time to progression was not different between the two groups (data not shown). The only grade 3/4 toxicity reported with cross-over therapy was grade 3 fatigue with DES. At the time of study closure, 20 (47%) of 43 of initial PC-SPES-treated patients and 11 (26%) of 42 initial DES-treated patients were still receiving their initial therapy. Twelve and 11 patients were receiving cross-over therapy with DES and PC-SPES, respectively.

Detection of DES in PC-SPES
All four lots of PC-SPES used in this trial contained measurable quantities of DES, although the amounts varied considerably. Table 4 lists the amount of DES detected in PC-SPES capsules. The total dose of DES administered to patients taking PC-SPES was estimated to be between 0.3 and 94.2 µg per day, corresponding to 0.01% to 3.1% of the DES used in the actual DES arm. Using HPLC and GC/MS, investigators at two additional laboratories confirmed the presence of DES in at least three of four lots.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Given the few effective therapeutic options and short, often symptomatic median survival of hormone refractory prostate cancer patients, it is not surprising that PC-SPES was such a popular therapeutic option for patients and their physicians. An oral therapy with a modest toxicity profile, PC-SPES appeared to have antitumor activity as measured by PSA declines that were comparable to the best secondary hormonal and chemotherapies available. In addition, as a natural therapy, it had tremendous appeal to patients. On the other hand, it was extremely expensive, seldom covered by insurance plans, and was not regulated by the US Food and Drug Administration or any other governmental organization that was able to assure consistent production and proper labeling. Indeed the appeal of combination herbal therapy as cancer treatment was in fact the very problem with PC-SPES—it remained unclear how it worked and which particular component(s) accounted for its clinical benefits.

To study this question, we undertook a randomized trial of PC-SPES and DES with a cross-over design to determine whether the active ingredient in PC-SPES mimicked the mechanism of action of DES itself. Based on prior studies and assurances from the manufacturer, we made several assumptions, which later were found to be untrue. First, we assumed a production process that created a consistent product across lots. In fact, initial publications describing PC-SPES, as well as the company's own literature, cited a process of "HPLC-standardization" which, it was claimed, led to consistent lots of PC-SPES. Second, we assumed that no synthetic agents were present in PC-SPES, in particular DES itself. The subsequent observation of the presence of DES and EE in PC-SPES makes it extremely difficult to interpret the results observed.

Although this trial was discontinued early, results at study closure suggest that PC-SPES has moderate activity in the treatment of AIPC and that this activity was similar to 3 mg DES. However, this study was not designed to directly compare these treatments. Conclusive cross-over analysis was not possible, though these data suggested that patients might respond to sequential therapies.

There are several possible explanations for these results. The first is that PC-SPES indeed represents combination therapy, and that although small amounts of DES and EE are present in the mixture, these are additive or synergistic with plant estrogens present in the mixture and together produce an effect better than synthetic estrogen alone. Another possibility is that a single active agent in PC-SPES (eg, DES, EE, or as-yet-unidentified compound) is responsible for the anticancer effects noted. No dose-finding studies have been undertaken with DES in prostate cancer, with the lowest reported doses being 1,000 µg. Thus it is difficult to know if 0.3 to 94.2 µg of DES could have anticancer activity, though this is unlikely.

Recent reports confirm our findings.^17,18 Sovak et al¹⁷ reported the presence of DES in PC-SPES lots manufactured from 1996 to 1999 at doses of 107 to 159 µg/g. In lots manufactured from 1999 to 2001, DES was noted in declining concentrations (0 to 46 µg/g). In addition, warfarin and indomethacin was detected. The California Department of Health Services (CDHS) detected warfarin, indomethacin, DES, and EE in various lots of PC-SPES.¹⁹ While in the present study, warfarin levels were not measured, these results are interesting in light of the fact that 15% of patients receiving PC-SPES required cessation of warfarin therapy because of an INR > 2, compared with 5% of DES patients. Furthermore, CDHS found significant lot-to-lot and within-lot variation in the concentration of the contaminants.

Recent laboratory studies have further explored PC-SPES activity. In one study, cDNA microarray analysis was performed on LNCaP cells exposed to PC-SPES and DES.²⁰ PC-SPES altered the expression of 156 genes, including marked downregulation of transcripts encoding alpha- and beta-tubulins, cell-cycle regulatory proteins, and androgen receptor. By comparison, DES altered expression of only 62 genes, only six (10%) of which were concordant with changes seen with PC-SPES. In another microarray study, the profile signatures of PC-SPES, DES, and another herbal combination (PC-CARE) were compared.²¹ Gene expression profiles induced by PC-SPES and DES were again different in LNCaP cells. However, PC-CARE and DES had similar profiles, though PC-CARE has the same component herbs as PC-SPES. These studies confirm the complex and uncertain nature of unregulated herbal combinations.

Our experience demonstrates the difficulty of applying standard clinical trial design to the study of complex herbal combinations, especially when uniform production standards and quality control are not used.²² It remains to be seen whether the efficacy of such herbal combinations can be validated unless the purity of these treatments is assured.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by a grant from the C. Brendan Noonan Jr. Charitable Foundation (to W.K.O.) and CaPCURE (to E.J.S.).

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Gilligan T, Kantoff PW: Chemotherapy for prostate cancer. Urology 60:94–100, 2002 (3 suppl 1)[CrossRef][Medline]

2. Oh WK: Secondary hormonal therapies in the treatment of prostate cancer. Urology 60:87–93, 2002 (3 suppl 1)[CrossRef][Medline]

3. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer. Urology 52:257–260, 1998[CrossRef][Medline]

4. Oh WK: The evolving role of estrogens in prostate cancer. Clinical Prostate Cancer 1:81–89, 2002[Medline]

5. Nam RK, Fleshner N, Rakovitch E, et al: Prevalence and patterns of the use of complementary therapies among prostate cancer patients: An epidemiological analysis. J Urol 161:1521–1524, 1999[CrossRef][Medline]

6. DiPaola RS, Zhang H, Lambert GH, et al: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339:785–791, 1998[Abstract/Free Full Text]

7. Halicka HD, Ardelt B, Juan G, et al: Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC-SPES. Int J Oncol 11:437–448, 1997

8. Tiwari RK, Geliebter J, Garikapaty VP, et al: Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 14:713–719, 1999[Medline]

9. de la Taille A, Buttyan R, Hayek O, et al: Herbal therapy PC-SPES: In vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164:1229–1234, 2000[CrossRef][Medline]

10. Kubota T, Hisatake J, Hisatake Y, et al: PC-SPES: A unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo. Prostate 42:163–171, 2000[CrossRef][Medline]

11. Oh WK, George DJ, Hackmann K, et al: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57:122–126, 2001[Medline]

12. Small E, Frohlich M, Bok R, et al: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18:3595–3603, 2000[Abstract/Free Full Text]

13. Oh WK, Small EJ: Complementary and alternative therapies in prostate cancer. Semin Oncol 29:575–584, 2002[Medline]

14. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461–3467, 1999[Abstract/Free Full Text]

15. PC-SPES, Package insert. Botaniclab, Brea, CA

16. Press release: State health director warns consumers about prescription drugs in herbal products, February 7, 2002, No. 02-03. http://www.dhs.ca.gov.

17. Sovak M, Seligson AL, Konas M, et al: Herbal composition PC-SPES for management of prostate cancer: Identification of active principles. J Natl Cancer Inst 94:1275–1281, 2002[Abstract/Free Full Text]

18. Guns ES, Goldenberg SL, Brown PN: Mass spectral analysis of PC-SPES confirms the presence of diethylstilbestrol. Can J Urol 9:1684–1688, 2002[Medline]

19. Ko R, Wilson RD, Loscutoff S: Letter to the editor: PC-SPES. Urology 61:1292, 2003[Medline]

20. Bonham M, Arnold H, Montgomery B, et al: Molecular effects of the herbal compound PC-SPES: Identification of activity pathways in prostate carcinoma. Cancer Res 62:3920–3924, 2002[Abstract/Free Full Text]

21. Bigler D, Guilding KM, Dann R, et al: Gene profiling and promoter reporter assays: Novel tools for comparing the biological effects of botanical extracts on human prostate cancer cells and understanding their mechanisms of action. Oncogene 22:1261–1272, 2003[CrossRef][Medline]

22. White J: PC-SPES—a lesson for future dietary supplement research. J Natl Cancer Inst 94:1261–1263, 2002[Free Full Text]

Submitted October 31, 2003; accepted April 17, 2004.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• PC-SPES: Hope or Hype?
  Michael P. Kosty
  JCO 2004 22: 3657-3659 [Full Text]

This article has been cited by other articles:

				R. S. Bhatt and G. J. Bubley The Challenge of Herbal Therapies for Prostate Cancer Clin. Cancer Res., December 1, 2008; 14(23): 7581 - 7582. [Abstract] [Full Text] [PDF]

				R. S. DiPaola and M. A. Gallo Hearsay Medicine Is Not Evidence-Based Medicine Clin. Cancer Res., January 15, 2008; 14(2): 337 - 338. [Full Text] [PDF]

				S. Goodin, F. Shen, W. J. Shih, N. Dave, M. P. Kane, P. Medina, G. H. Lambert, J. Aisner, M. Gallo, and R. S. DiPaola Clinical and Biological Activity of Soy Protein Powder Supplementation in Healthy Male Volunteers Cancer Epidemiol. Biomarkers Prev., April 1, 2007; 16(4): 829 - 833. [Abstract] [Full Text] [PDF]

				L. Rice, R. Handayani, Y. Cui, T. Medrano, V. Samedi, H. Baker, N. J. Szabo, C. J. Rosser, S. Goodison, and K. T. Shiverick Soy Isoflavones Exert Differential Effects on Androgen Responsive Genes in LNCaP Human Prostate Cancer Cells J. Nutr., April 1, 2007; 137(4): 964 - 972. [Abstract] [Full Text] [PDF]

				D. R. Yance Jr and S. M. Sagar Targeting Angiogenesis With Integrative Cancer Therapies Integr Cancer Ther, March 1, 2006; 5(1): 9 - 29. [Abstract] [PDF]

				R. S. DiPaola and R. A. Morton Proven and Unproven Therapy for Benign Prostatic Hyperplasia N. Engl. J. Med., February 9, 2006; 354(6): 632 - 634. [Full Text] [PDF]

				D. R. Berthold, C. N. Sternberg, and I. F. Tannock Management of Advanced Prostate Cancer After First-Line Chemotherapy J. Clin. Oncol., November 10, 2005; 23(32): 8247 - 8252. [Abstract] [Full Text] [PDF]

				M. Bonham, J. Posakony, I. Coleman, B. Montgomery, J. Simon, and P. S. Nelson Characterization of Chemical Constituents in Scutellaria baicalensis with Antiandrogenic and Growth-Inhibitory Activities toward Prostate Carcinoma Clin. Cancer Res., May 15, 2005; 11(10): 3905 - 3914. [Abstract] [Full Text] [PDF]

				B. R. Cassileth and A. J. Vickers High Prevalence of Complementary and Alternative Medicine Use Among Cancer Patients: Implications for Research and Clinical Care J. Clin. Oncol., April 20, 2005; 23(12): 2590 - 2592. [Full Text] [PDF]

				D. S. Rosenthal and E. Dean-Clower Integrative Medicine in Hematology/Oncology: Benefits, Ethical Considerations, and Controversies Hematology, January 1, 2005; 2005(1): 491 - 497. [Abstract] [Full Text] [PDF]

				M. P. Kosty PC-SPES: Hope or Hype? J. Clin. Oncol., September 15, 2004; 22(18): 3657 - 3659. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oh, W. K. Articles by Small, E. J. Search for Related Content PubMed PubMed Citation Articles by Oh, W. K. Articles by Small, E. J. Related Articles Related Editorial Social Bookmarking                            What's this?