Correspondence
PC-SPES in Prostate Cancer
N Engl J Med 1999; 340:566-568February 18, 1999
- Article
To the Editor:
Although DiPaola et al. (Sept. 17 issue)1 have done a superb job of evaluating the estrogenic properties of PC-SPES, a commercially available combination of eight herbs, there is an implication that this is the only “active” component of this compound. For example, the Results section includes a subsection entitled “Composition of PC-SPES,” although this subsection more accurately is a comparative analysis of only the estrogenic components of PC-SPES. Other studies of ethanolic extracts of PC-SPES have identified a large number of components, far more than the four peaks noted by DiPaola et al. on high-performance liquid chromatography.2 . . .
2 ReferencesEric J. Small, M.D.
University of California, San Francisco–, Mount Zion Cancer Center, San Francisco, CA 941151
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 1998;339:785-791
Full Text | Web of Science | Medline2
Hsieh T ,Chen SS ,Wang X ,Wu JM . Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 1997;42:535-544
Medline
To the Editor:
DiPaola et al. state, “although PC-SPES is promoted as a nonestrogenic food supplement, some of its constituents have estrogenic activity.” One of the three references they cite to support this statement refers to our work on the ability of 70 percent ethanolic extracts of PC-SPES to down-regulate the expression of androgen receptors and prostate-specific antigen.1 Our article does not even contain the word “estrogen,” let alone suggest that PC-SPES may have estrogenic activity.
We also take issue with the dose of PC-SPES given to mice in the study by DiPaola et al. According to our calculations, on a body-weight basis, the amount the mice received (assuming a final body weight of 20 g) was equivalent to a 60-kg man's consuming 750 capsules (0.24 kg) of PC-SPES. This amount is 83 times the conventional dose.
DiPaola et al. state that “serum testosterone concentrations decreased during the use of PC-SPES and increased within three weeks after PC-SPES was discontinued.” No data are given on testosterone concentrations before treatment with PC-SPES. Therefore, there is no initial testosterone concentration from which to assess whether there was a decrease. Since all patients had received androgen-ablation therapy before the study, it is possible that serum testosterone concentrations were low before treatment with PC-SPES (as a result of androgen ablation) and rose after the cessation of androgen-ablation therapy independently of treatment with PC-SPES. Although pretreatment values are given for prostate-specific antigen (in Table 3 of the article), it is unclear whether these values were obtained at diagnosis (before androgen-ablation therapy) or after androgen-ablation therapy. One would be led to believe that they were obtained before androgen-ablation therapy, since it is stated that “all eight patients had histologically proved prostate cancer, without progression during previous androgen-ablation therapy.” (One patient had a prostate-specific antigen concentration of 122 ng per milliliter, which is a high level for a patient without progression.) With respect to these measurements, two points are critical: values obtained before treatment with PC-SPES must be measured after androgen-ablation therapy is discontinued, and prostate-specific antigen concentrations must be allowed to rise to “natural concentrations” before changes are assessed.
1 ReferencesJan Geliebter, Ph.D.
Raj Tiwari, Ph.D.
Joseph M. Wu, Ph.D.
New York Medical College, Valhalla, NY 105951
Hsieh T ,Chen SS ,Wang X ,Wu JM . Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 1997;42:535-544
Medline
Author/Editor Response
The authors reply:
To the Editor: As noted by Small, Hsieh et al. demonstrated multiple peaks on high-performance liquid chromatography, with the number of peaks varying depending on the methods used.1 These results are in agreement with our combined analysis using high-performance liquid chromatography, gas chromatography, and mass spectrometry, suggesting that PC-SPES has multiple organic compounds. Although nonestrogenic molecules with biologic activity may be present, we found that the androgen ablation was of a magnitude similar to that produced by known therapies (treatment with leuprolide or pharmacologic doses of estrogen or orchiectomy), which also have similar antitumor effects. In addition, studies of pharmacologic doses of estrogen in patients with hormone-refractory disease have demonstrated antitumor activity.2 Therefore, it is likely that the clinical activity observed with PC-SPES is secondary to estrogenic activity inducing androgen ablation. Further studies are in progress to identify molecules with biologic activity and determine whether any compound is clinically active.
Hsieh et al. studied the effects of PC-SPES in vitro and did not identify its potent estrogenic activity.1 Since estrogen alone has been demonstrated to cause cellular changes including apoptosis in prostate-cancer cell lines, the estrogenic activity of PC-SPES is an important unidentified confounding variable.3
Our study in mice was designed to investigate the estrogenic activity of PC-SPES in a classic animal model rather than to determine the lowest effective dose capable of producing uterine hypertrophy. However, the results of the yeast assay suggest that the estrogenic activity in PC-SPES is potent, as compared with that of standard estrogen (a 1:200 dilution of an extract of one 320-mg capsule of PC-SPES had estrogenic activity equivalent to that of 1 nM estradiol), and the effects in patients support the conclusion that the estrogenic activity in PC-SPES is clinically potent.
Our clinical results were not confounded by the recent use of standard androgen-ablation therapy in our patients, contrary to the suggestion of Geliebter et al. Seven of the eight patients had never received standard androgen-ablation therapy; one patient had received androgen-ablation therapy, and the treatment ended 22 months before our study began.
3 ReferencesRobert S. DiPaola, M.D.
William N. Hait, M.D., Ph.D.
Michael A. Gallo, Ph.D.
University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 089011
Hsieh T ,Chen SS ,Wang X ,Wu JM . Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 1997;42:535-544
Medline2
Citrin DL ,Kies MS ,Wallemark CB , et al. A phase II study of high-dose estrogens (diethylstilbestrol diphosphate) in prostate cancer. Cancer 1985;56:457-460
CrossRef | Web of Science | Medline3
Robertson CN ,Roberson KM ,Padilla GM , et al. Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells. J Natl Cancer Inst 1996;88:908-917
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Heather A Jones, James M Metz, Pamela Devine, Stephen M Hahn, Richard Whittington. (2002) Rates of unconventional medical therapy use in patients with prostate cancer: standard history versus directed questions. Urology 59:2, 272-276
CrossRef2
Tetsuya Kubota, Junichi Hisatake, Yasuko Hisatake, Jonathan W. Said, Sophie S. Chen, Stuart Holden, Hirokuni Taguchi, H. Phillip Koeffler. (2000) PC-SPES: A unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo. The Prostate 42:3, 163-171
CrossRef
