This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hoh, C. Articles by Gescher, A. J. Search for Related Content PubMed PubMed Citation Articles by Hoh, C. Articles by Gescher, A. J. Related Collections Clinical Intervention Clinical Intervention: Early-Phase (I/II) Clinical or Translational Trials

Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Authors' Affiliations: ¹ Cancer Biomarkers and Prevention Group, Departments of Cancer Studies and Biochemistry, University of Leicester and Departments of ² Hepatobiliary Surgery, ³ Coloproctology, and ⁴ Histopathology, University Hospitals of Leicester, Leicester, United Kingdom

Requests for reprints: Andreas Gescher, Department of Cancer Studies, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, University of Leicester, Leicester LE2 7LX, United Kingdom. Phone: 44-116-223-1856; Fax: 44-116-223-1855; E-mail: ag15{at}le.ac.uk.

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M₁dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 µmol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M₁dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

This article has been cited by other articles:

				J.-W. Wu, L.-C. Lin, S.-C. Hung, C.-H. Lin, C.-W. Chi, and T.-H. Tsai Hepatobiliary Excretion of Silibinin in Normal and Liver Cirrhotic Rats Drug Metab. Dispos., March 1, 2008; 36(3): 589 - 596. [Abstract] [Full Text] [PDF]

				D. J. Kroll, H. S. Shaw, and N. H. Oberlies Milk Thistle Nomenclature: Why It Matters in Cancer Research and Pharmacokinetic Studies Integr Cancer Ther, June 1, 2007; 6(2): 110 - 119. [Abstract] [PDF]

				M. C. Comelli, U. Mengs, C. Schneider, and M. Prosdocimi Toward the Definition of the Mechanism of Action of Silymarin: Activities Related to Cellular Protection From Toxic Damage Induced by Chemotherapy Integr Cancer Ther, June 1, 2007; 6(2): 120 - 129. [Abstract] [PDF]

				C. Tamayo and S. Diamond Review of Clinical Trials Evaluating Safety and Efficacy of Milk Thistle (Silybum marianum [L.] Gaertn.) Integr Cancer Ther, June 1, 2007; 6(2): 146 - 157. [Abstract] [PDF]

				H. Greenlee, K. Abascal, E. Yarnell, and E. Ladas Clinical Applications of Silybum marianum in Oncology Integr Cancer Ther, June 1, 2007; 6(2): 158 - 165. [Abstract] [PDF]

				S. M. Sagar Future Directions for Research on Silybum marianum for Cancer Patients Integr Cancer Ther, June 1, 2007; 6(2): 166 - 173. [Abstract] [PDF]