ORIGINAL ARTICLE Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study NJ Barber 1 , X Zhang 2,3 , G Zhu 3 , R Pramanik 2 , JA Barber 4 , FL Martin 5 , JDH Morris 2 and GH Muir 3 1 Department of Urology, Frimley Park Hospital, Surrey, UK; 2 The Rayne Institute, King’s College London, London, UK; 3 Department of Urology, King’s College Hospital, London, UK; 4 Department of Medical Statistics, University College Hospital, London, UK and 5 Department of Biological Sciences, IENS, Lancaster University, Lancaster, UK Interest in lycopene has focused primarily on its use in the chemoprevention of prostate cancer (CaP); there are few clinical trials involving men with established disease. In addition, most data examining its mechanism of action have been obtained from experiments using immortal cell lines. We report the inhibitory effect(s) of lycopene in primary prostate epithelial cell (PEC) cultures, and the results of a pilot phase II clinical study investigating whole-tomato lycopene supplementation on the behavior of established CaP, demonstrating a significant and maintained effect on prostate- specific antigen velocity over 1 year. These data reinforce the justification for a large, randomized, placebo-controlled study. Prostate Cancer and Prostatic Diseases (2006) 9, 407–413. doi:10.1038/sj.pcan.4500895; published online 19 September 2006 Keywords: prostate cancer; lycopene; diet Introduction Issues relating to male health, including prostate disease, continue to become more prominent in the public eye. Prostate cancer (CaP) is being diagnosed more frequently following the advent of plasma prostate-specific antigen (PSA) testing. Nevertheless, adenocarcinoma of the prostate remains the second biggest cancer killer of men. 1 Owing to greater public access to information, the male population is becoming more aware of the risk of developing this disease. In recent years, there has been increasing interest in the possible role of dietary factors in the development and progression of cancers, including CaP, based on mounting circumstantial epidemiological and scientific data. As a consequence, it is claimed that a number of dietary supplements prevent CaP or reduce its rate of progression. Among these dietary supplements are included selenium, vitamin E, genestein and lyco- pene. Indeed, significant numbers of men diagnosed with CaP admit to having tried or taken health food supplements with a view to treating their cancer. 2 Lycopene, a member of a group of natural pigments known as the carotenoids, is a powerful dietary antioxidant. It can be synthesized by plants or micro- organisms and is widely found in the environment, giving red or yellow color to a number of plant species. For humans, lycopene is found in a relatively narrow range of foods and the principal dietary source for most people is tomatoes. Dietary lycopene has been shown to accumulate in a number of specific organs in the human body, including the liver, prostate and adrenal glands. A number of epidemiological studies have suggested an inverse relationship between dietary lycopene intake and the risk of developing CaP. This has been supported by in vitro experiments using PC3, LnCaP and DU145 immortalized CaP cell lines, which demonstrate that lycopene at physiological concentrations inhibits cell proliferation. 3 Although clinical CaP has a fairly typical behavior, most commercially available CaP cell lines (the exception being LnCaP cells that do secrete PSA) do not show a recognizable ‘prostatic’ phenotype. Such cell lines exhibit many abnormal growth characteristics that make them flawed surrogates to predict the behavior of prostate epithelial cells (PECs) in vivo and the use of these continuous cell lines of transformed phenotype should be treated with caution. In order to improve the reliability and relevance of cell culture experiments, we employed in this study primary PECs isolated from tissues (n ¼ 6) obtained at the time of prostatic surgery and examined the effect of lycopene on DNA synthesis as measured by the incorporation of 5-bromo-2-deoxyuridine (BrdU). As a result of these preliminary investigations, we proceeded to a small-scale study on patients (n ¼ 41) previously diagnosed with CaP to investigate if supplementary dietary lycopene would retard the rate of progression of the disease as judged by changes in serum PSA levels. Published clinical trials of this type are rare. Received 11 January 2006; revised 25 April 2006; accepted 5 May 2006; published online 19 September 2006 Correspondence: Dr NJ Barber, Department of Urology, Frimley Park Hospital, Portsmouth Road, Camberley, Surrey GU16 5UJ, UK. E-mail. Neil.barber@fph-tr.nhs.uk Prostate Cancer and Prostatic Diseases (2006) 9, 407–413 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00 www.nature.com/pcan