Investigational New Drugs

, Volume 25, Issue 2, pp 139–146 | Cite as

A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients

  • Thomas W. Flaig
  • Daniel L. Gustafson
  • Lih-Jen Su
  • Joseph A. Zirrolli
  • Frances Crighton
  • Gail S. Harrison
  • A. Scott Pierson
  • Rajesh Agarwal
  • L. Michael Glodé
Phase I Studies


Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer. Silybin-phytosome is a commercially available formulation containing silibinin. This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose. Silybin-phytosome was administered orally to prostate cancer patients, giving 2.5–20 g daily, in three divided doses. Each course was 4 weeks in duration. Thirteen patients received a total of 91 courses of silybin-phytosome. Baseline patient characteristics included: median age of 70 years, median baseline prostate specific antigen (PSA) of 4.3 ng/ml, and a median ECOG performance status of 0. The most prominent adverse event was hyperbilirubinemia, with grade 1–2 bilirubin elevations in 9 of the 13 patients. The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was noted. No objective PSA responses were observed. We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose. Asymptomatic liver toxicity is the most commonly seen adverse event.


Silibinin Phase I Prostate cancer 



The authors wish to acknowledge the invaluable research support of Spencer Green and Cynthia Snedden. This work was supported in part by a grant from the National Center for Complementary and Alternative Medicine (NCCAM), P30 CA046934 supplement.


  1. 1.
    Pares A, Planas R, Torres M, Caballeria J, Viver JM, Acero D, Panes J, Rigau J, Santos J, Rodes J (1998) Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28:615–621PubMedCrossRefGoogle Scholar
  2. 2.
    Flora K, Hahn M, Rosen H, Benner K (1998) Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 93:139–143PubMedCrossRefGoogle Scholar
  3. 3.
    Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B (1989) Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 9:105–113PubMedCrossRefGoogle Scholar
  4. 4.
    Singh RP, Dhanalakshmi S, Tyagi AK, Chan DC, Agarwal C, Agarwal R (2002) Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res 62:3063–3069PubMedGoogle Scholar
  5. 5.
    Kohno H, Suzuki R, Sugie S, Tsuda H, Tanaka T (2005) Dietary supplementation with silymarin inhibits 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in male F344 rats. Clin Cancer Res 11:4962–4967PubMedCrossRefGoogle Scholar
  6. 6.
    Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie S, Tsuda H, Mori H (2002) Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 101:461–468PubMedCrossRefGoogle Scholar
  7. 7.
    Vinh PQ, Sugie S, Tanaka T, Hara A, Yamada Y, Katayama M, Deguchi T, Mori H (2002) Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res 93:42–49PubMedGoogle Scholar
  8. 8.
    Singh RP, Mallikarjuna GU, Sharma G, Dhanalakshmi S, Tyagi AK, Chan DC, Agarwal C, Agarwal R (2004) Oral silibinin inhibits lung tumor growth in athymic nude mice and forms a novel chemocombination with doxorubicin targeting nuclear factor kappaB-mediated inducible chemoresistance. Clin Cancer Res 10:8641–8647PubMedCrossRefGoogle Scholar
  9. 9.
    Lahiri-Chatterjee M, Katiyar SK, Mohan RR, Agarwal R (1999) A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 59:622–632PubMedGoogle Scholar
  10. 10.
    Zi X, Agarwal R (1999) Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96:7490–7495PubMedCrossRefGoogle Scholar
  11. 11.
    Zi X, Grasso AW, Kung HJ, Agarwal R (1998) A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res 58:1920–1929PubMedGoogle Scholar
  12. 12.
    Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M (1998) Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279:563–566PubMedCrossRefGoogle Scholar
  13. 13.
    Singh RP, Sharma G, Dhanalakshmi S, Agarwal C, Agarwal R (2003) Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. Cancer Epidemiol Biomarkers Prev 12:933–939PubMedGoogle Scholar
  14. 14.
    Barzaghi N, Crema F, Gatti G, Pifferi G, Perucca E (1990) Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 15:333–338PubMedCrossRefGoogle Scholar
  15. 15.
    Schandalik R, Perucca E (1994) Pharmacokinetics of silybin following oral administration of silipide in patients with extrahepatic biliary obstruction. Drugs Exp Clin Res 20:37–42PubMedGoogle Scholar
  16. 16.
    Hoh C, Boocock D, Marczylo T, Singh R, Berry DP, Dennison AR, Hemingway D, Miller A, West K, Euden S, Garcea G, Farmer PB, Steward WP, Gescher AJ (2006) Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences. Clin Cancer Res 12:2944–2950PubMedCrossRefGoogle Scholar
  17. 17.
    Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, Alton K, Patrick JE, Zbaida S (2004) Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos 32:314–320PubMedCrossRefGoogle Scholar
  18. 18.
    Sridar C, Goosen TC, Kent UM, Williams JA, Hollenberg PF (2004) Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 32:587–594PubMedCrossRefGoogle Scholar
  19. 19.
    Wasserman E, Myara A, Lokiec F, Goldwasser F, Trivin F, Mahjoubi M, Misset JL, Cvitkovic E (1997) Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. Ann Oncol 8:1049–1051PubMedCrossRefGoogle Scholar
  20. 20.
    van Erp NP, Baker SD, Zhao M, Rudek MA, Guchelaar HJ, Nortier JW, Sparreboom A, Gelderblom H (2005) Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 11:7800–7806PubMedCrossRefGoogle Scholar
  21. 21.
    Dhanalakshmi S, Agarwal P, Glode LM, Agarwal R (2003) Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death. Int J Cancer 106:699–705PubMedCrossRefGoogle Scholar
  22. 22.
    Chlopcikova S, Psotova J, Miketova P, Simanek V (2004) Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Phytother Res 18:107–110PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Thomas W. Flaig
    • 1
  • Daniel L. Gustafson
    • 2
  • Lih-Jen Su
    • 1
  • Joseph A. Zirrolli
    • 2
  • Frances Crighton
    • 3
  • Gail S. Harrison
    • 1
  • A. Scott Pierson
    • 1
  • Rajesh Agarwal
    • 2
  • L. Michael Glodé
    • 1
  1. 1.Department of Medicine, Division of Medical OncologyUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  2. 2.Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  3. 3.Urologic OncologyUniversity of Colorado HospitalDenverUSA

Personalised recommendations