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Grant Abstract

Grant Number: 5-R01-CA-101008-02
Project Title: Silibinin in Prostate Cancer Chemoprevention & Treatment

Abstract: DESCRIPTION (provided by applicant): Prostate cancer is a major public health problem. Evidence suggests that IGF-I favors prostate cancer development and proliferation and that IGF binding protein-3 has the opposite effects. Our laboratories have recently published in vitro data concerning antineoplastic and chemopreventative actions of silibinin, a polyphenolic flavonoid antioxidant molecule present in milk thistle plants, together with evidence that the mechanism of action of silibinin may involve at least in part an influence on IGF physiology. The overall objective is to further characterize the chemopreventive and antineoplastic properties of silibinin as a micronutrient with relevance to prostate cancer. The specific aims are: (1) to evaluate the effect of silibinin in preventing or delaying prostate cancer in three well-characterized in vivo prostate carcinogenesis models: the rat hormonal/N-methyI-N-nitrosourea (MNU)-induced model, the TRAMP and the BK5.lGF-1 transgenic mice; (2) to describe the effects of silibinin on apoptosis, proliferation, and genes that regulate these processes in normal rat prostates in vivo and in human untransformed prostate epithelial cells in vitro; (3) to conduct a pilot biomarker study in humans to examine the actions of silibinin administration on the prostate gland; and (4) to evaluate the effect of silibinin treatment on the growth of human prostate cancer xenografts that provide models of androgen-independent prostate cancer growth and progression of prostate cancer to androgen-independent. We will use well-described hormonal carcinogenesis and transgenic carcinogenesis systems and cell culture systems in the proposed work. The proposal also includes a pilot clinical biomarker study in men treated with silibinin or placebo. The proposed work builds on the emerging data that indicates silibinin has antineoplastic and chemopreventive activity in prostate cancer. The work is justified by the favorable toxicity profile of silibinin, together with prior positive laboratory studies reported by our group and other investigators.

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