Selenium (Se) supplementation in the form of selenized-yeast has been shown to decrease the risk of cancer of the prostate and other organ sites. The ongoing SELECT study in some 32,000 men was designed to validate the preventive efficacy of selenomethionine (SeMet) alone or in combination with vitamin E against prostate cancer. The selection of SeMet was controversial and remains a subject of continuing debate. Studies with rodent carcinogenesis models have implicated methylselenol as an active anti-cancer Se metabolite. The present study was designed a) to establish and compare the in vivo human prostate cancer inhibitory effects of two methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) with SeMet and the inorganic selenite in a DU145 human androgen-independent prostate cancer xenograft model in athymic nude mice and b) to profile selected biomarkers of efficacy including cancer cell proliferation, apoptosis and angiogenesis. Each Se compound was given by a daily single oral dose regimen simulating human studies starting the day after subcutaneous inoculation of tumor cells. Both MSeA and MSeC exerted a dose-dependent inhibition of xenograft growth and were more potent than SeMet and selenite. The anti-cancer efficacy of methyl Se was achieved in spite of much less Se retention in the prostate cancer tissue and liver than in the SeMet-treated mice. Selenite, but not the other three Se compounds, increased DNA single strand breaks in the peripheral lymphocytes, indicating systemic genotoxicity. In spite of comparable efficacy, we observe interesting differences in the biomarker profiles in the MSeA- vs. MSeC-treated tumors: MSeA treatment affected cancer cell proliferation (Ki67) and angiogenesis (microvessel density) more than did MSeC, whereas MSeC increased apoptosis (TUNEL and caspase-3) more than did MSeA. In summary, our data support methyl Se as superior second-generation chemopreventive Se agent for prostate cancer than SeMet. Our data also provide first of its kind evidence of in vivo genotoxicity of selenite in peripheral lymphocytes, demeriting its usefulness for chemoprevention use. Grant supports: CA92231 and CA95642 from National Cancer Institute and DAMD17-02-1-0007 from Department of Defense Prostate Cancer Program.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA