How Do Intermediate Endpoint Biomarkers Respond to Lycopene in Men With Prostate Cancer or Benign Prostate Hyperplasia? Dr. Richard B. van Breemen, University of Illinois Dr. van Breemen first described several in vitro studies carried out with prostate cancer cell lines to investigate lycopene effects and uptake. He concluded that: 1) analytical methods development facilitated both in vitro and in vivo studies; 2) lycopene exhibited only minor inhibition of human prostate cancer cell proliferation in some cell lines (e.g., LNCaP); and 3) all prostate cancer cells took up lycopene from the cell culture media at different rates. Proteomics studies of the effect of lycopene on prostate cancer cells are in progress. Dr. van Breemen also described the design of a 21-day Phase II clinical trial conducted with 116 men to investigate lycopene effects on biomarkers in men with benign prostate hyperplasia (BPH) and cancer. The study will test the following hypotheses: 1) Lycopene prevents DNA oxidation both in vitro and in vivo (i.e., Does lycopene prevent formation of multiple DNA oxidation products, or only certain products? Is lycopene a prooxidant? Can in vitro experiments predict in vivo effects of lycopene?). 2) Oral administration of lycopene results in increased concentration in the prostate. 3) Serum lycopene reflects prostate levels. 4) Lycopene administration reduces serum PSA. Sixty men diagnosed with BPH and 60 men with prostate cancer were recruited. Subjects were randomized into two groups who either took pills containing lycopene (30 mg) or placebo for 21 days in a double-blind study. Blood samples were obtained at the beginning (baseline) and at the end of the intervention period, and prostate tissue was obtained at the end of the study from either resected tissue or biopsy. Total lycopene was measured in blood samples and prostate tissue using negative ion atmospheric pressure chemical ionization (APCI) liquid chromatography (LC)-mass spectrometry (MS)-MS with a C 18 high-performance liquid chromatography column; two DNA oxidation products (8-oxo-dG, 8-oxo-dA) were measured in peripheral blood white blood cells and prostate tissue using electrospray LC-MS-MS; lipid peroxidation in plasma was measured using APCI LC-MS-MS; and PSA levels were measured in blood before and after intervention using an enzyme-linked immunosorbent assay (ELISA). The data from this trial currently are being analyzed. Dr. van Breemen also provided a summary of the preliminary dietary intervention study (9) Men with elevated serum PSA were recruited into the tomato sauce/whole foods-based study prior to radical prostatectomy. Biopsy and blood samples were obtained for lycopene and DNA oxidation measurements. Thirty-two men with stage T1 or T2 adenocarcinoma of the prostate completed the study. Subjects consumed 200 g of tomato sauce in pasta dishes for 21 days (30 mg/d lycopene). Total lycopene was measured in serum and prostate tissue obtained at the time of radical prostatectomy, 8-oxo-dG was measured in peripheral blood white blood cells and prostate tissue, and PSA levels were measured in serum before and after intervention. The results suggest that: 1) lycopene in serum increased twofold, but lycopene levels in prostate tissue increased threefold; 2) DNA oxidation (measured as 8-oxo-dG) decreased 21 percent in leukocytes; 3) DNA oxidation decreased 28 percent in prostate tissue; and 4) total PSA in serum decreased approximately 20 %. These results are consistent with epidemiological data showing an inverse correlation between tomato consumption and risk of prostate cancer. Discussion A participant asked why Dr. van Breemen failed to observe an effect of lycopene in cell culture, when many studies in the literature show profound inhibitory effects and changes in outcomes. Dr. van Breemen replied that he has published relatively little on cell culture work because he has observed variation from one technician to the other as well as variation with the method of lycopene delivery (liposomes versus beadlets), with the use of organic solvents, and with tissue culture conditions and cell passage number. A comment was made that it may be more difficult to obtain cell culture data relevant to in vivo conditions with carotenoids than with other agents (e.g., isoflavones or polyphenols). In several cell culture studies in the literature, lycopene alone failed to inhibit cell growth significantly, but inhibition was observed in conjunction with other agents (e.g., phytoene and phytofluene). It was suggested that the biological effects of lycopene are mediated by its metabolites; thus, if the cell cannot convert lycopene to its metabolites, there may be no effect. A participant asked if Dr. van Breemen checked for the presence of lycopene metabolites in the cell culture study. Dr. van Breemen replied that he had checked for this. Because lycopene is under such unusually high oxidative stress in the cell culture system, and because many lycopene degradation products are so short lived, there are no definitive quantitative data to report. The cis and trans forms of lycopene appear to be interconverting, so Dr. van Breemen will report total lycopene in the study he is currently conducting. A participant commented that it is unclear whether other investigators are measuring physiological levels of cis and trans isomers or the equilibrium state in serum samples that cannot be stabilized. A counterpoint was offered that although lycopene is unstable in an organic solution, there are other carotenoids, lipids, etc., present in a serum sample that tends to stabilize and preserve the isomeric distribution. Another participant asked if cross-study comparisons can be made, given the methodological problems with these studies. Dr. van Breemen responded that the lycopene levels are high enough and the analytical methods reliable enough, whether based on electrochemical detection, absorbance detection, or MS, to compare lycopene levels in tissue and blood between studies. With regard to measuring other outcomes, PSA measurements were done with ELISA and should provide similar results between studies. The DNA oxidation measurements were difficult, however, and variation has been found in measuring similar systems across laboratories. DNA damage in cells is controllable and repairable, and unrepaired damage is on the order of parts per billion. Some have suggested that a better measure of oxidative stress would be levels of 8-oxo-dG and other excised and excreted nucleosides in urine, where they are stable. This would not be specific to oxidative stress in the prostate, however; it is a whole body oxidative stress measurement. 2/05 NIH Meeting Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.