Effects of Lycopene on High-Risk Prostatic Tissue

DESCRIPTION: (provided by applicant) Lycopene is a promisingchemopreventiveagent for prostatecancer (CaP). However, the actual effects ofthis dietary antioxidant on prostatic tissue are poorly understood. Thepreclinical phase of CaP is characterized by a gradual progression from normalepithelium through high-grade prostatic intraepithelial neoplasia (HGPIN),which is very likely the precursor lesion for CaP. We propose to conduct aplacebo-controlled randomized trial to investigate the effects, after 6 months,of lycopene supplements (30 mg/day) on molecular and cell morphology markers incore needle biopsy samples from men with documented HGPIN. Participants will berecruited from the Urology services at Northwestern Memorial Hospital and theLakeside Veterans Administration Hospital. We propose to investigate thefollowing specific aims:Specific Aim 1:Molecular markers in tissue. We will use conventionalimmunohistochemistry and computer-based image analysis to test the hypothesisthat the lycopene supplements alter the expression of proteins marking thestatus of proliferation, differentiation, cell regulation and apoptosis inhigh-risk tissue. We have chosen and prioritized a panel of markers that aredifferentially expressed during precancerous progression.Specific Aim 2: Nuclear morphometry. We will use a computerized image analysissystem designed for the chemoprevention setting to test the hypothesis that theantioxidants cause a favorable change in a nuclear morphometry index based onnuclear size, shape and chromatin texture.Specific Aim 3:Serum androgen levels. We hypothesize, based on post hoc resultsof a phase Ill antioxidant trial, that the intervention will reduce levels oftestosterone (total and non-SHBG bound) and cx-androstanediol glucuronide.Specific Aim 4: Growth factors in prostatic fluid (EPF). In previous work, wedeveloped assays for EGF, TGF-a and TGF-Beta 1 in EPF, and reported that lowEGF and high TGF-f3 1 were associated with CaP. We hypothesize that treatmentincreases EGF and decreases TGF-Beta 1 in these-prostatic secretions.Specific Aim 5: DNA oxidation markers in blood. We hypothesize that treatmentdecreases the oxidized bases HMdU and 8-OHdG in lymphocytes, and increases HMdUauto-antibodies in serum detected by a novel ELISA method. Results of theproposed research will be useful for clarifying the mechanisms of action oflycopene in the prostate, for designing phase III trials, and, more generally,for determining the chemopreventive potential of this relatively non-toxicdietary compound.