2010hohcslmd.pdf (4.16 MB)
The clinical evaluation of the putative cancer chemopreventive agent silybinin in colorectal cancer and resectable hepatic metastases
thesisposted on 2010-07-29, 11:21 authored by Carmen Suet Li Hoh
Silybinin and its crude form silymarin exhibit cancer chemopreventive efficacy in rodents including models of colorectal carcinogenesis. Silymarin is used clinically as a hepato-protectant against alcohol- and drug-related damage. Silybinin is a strong antioxidant and modulates the insulin-like growth factor (IGF) system in mice in vivo by increasing circulating levels of IGF binding protein-3 (IGFBP-3). In this thesis, the hypothesis that oral consumption of silybinin affords pharmacologically active levels in blood, liver and colorectum was tested. Twelve patients with colorectal carcinoma and twelve with colorectal liver metastases received silybinin phosphatidylcholine (silipide) at varying doses for 7 days. Blood, normal and malignant colorectal or liver tissue were obtained before and after silybinin ingestion. A HPLC-UV method was developed and validated prior to quantifying levels of silybinin in plasma and tissue samples. Plasma metabolites were identified by liquid chromatography-mass spectrometry. Levels of IGFBP-3 and IGF-1 in serum and of the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) in leucocytes were determined as potential pharmacodynamic markers of silybinin efficacy. Repeated administration of silipide was safe and well tolerated. Silybinin levels recovered from plasma between 1-4 h post final silipide dose were 0.3-4.0 μM. Silybinin monoglucuronide, silybinin di-glucuronide, silybinin mono-sulphate and silybinin glucuronide sulphate were identified as metabolites in the plasma. Silybinin concentrations in liver and colorectal tissues obtained by resection 3-6 h post last silipide dose were 0.3-2.5 and 20-141 nmolesg-1, respectively. Intervention with silipide did not affect blood levels of IGF-1, IGFBP-3 or M1dG. In conclusion, silipide ingestion at safe doses can achieve detectable levels of agent in plasma and liver, and silybinin concentrations reached in the colorectal tract are of the level which has been shown to elicit pharmacological effects in cells in vitro. The results support the further development of silybinin as a potential human colorectal cancer chemopreventive agent.
Date of award2010-07-07
Awarding institutionUniversity of Leicester