© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Prostate Carcinogenesis in N-methyl-N-nitrosourea (NMU)–Testosterone-Treated Rats Fed Tomato Powder, Lycopene, or Energy-Restricted Diets
Affiliations of authors: Division of Hematology and Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital (SKC); Department of Human Nutrition, The Ohio State University, Columbus, OH (TWMB); Division of Nutritional Sciences, The University of Illinois, Champaign-Urbana (JWE).
Correspondence to: Steven K. Clinton, MD, PhD, Arthur G. James Cancer Hospital, A431 Starling Loving Hall, 320 West 10th Ave., The Ohio State University, Columbus, OH 43210 (e-mail: clinton-1{at}medctr.osu.edu)
The correspondence by Limpens et al. and the editorial by Drs. Gann and Khachik (1) that accompanied our article reinforce the complexities surrounding the relationships among tomato products, lycopene, and prostate carcinogenesis. Both highlight uncertainties regarding dose–response relationships for carotenoids and biologic effects. Indeed, chemists have long understood that carotenoids can be antioxidants under certain conditions and pro-oxidants under other conditions (2,3). Limpens et al. further state that our paper "does not prove inefficacy of pure lycopene." The funding for our study allowed only one dose of lycopene or tomato products to be tested, and we can only speculate regarding outcomes over a range of exposures. We encourage funding agencies to recognize the importance of clearly defining dose–response relationships for carotenoids tested at concentrations relevant to diet and nutrition but also at pharmacologic dose ranges that may be applicable to chemoprevention or therapy.
As Limpens et al. note, the lycopene concentrations in the tomato powder–and lycopene-supplemented diets were not equal. It was not our intention to provide lycopene at equal concentrations in the two intervention diets. The concentration of pure lycopene selected was based on our prior studies in rats showing that this dietary exposure would achieve blood and tissue concentrations similar to those found in humans without evidence of toxicity (4,5). The 10% concentration of tomato powder in an otherwise nutritionally complete formulation was chosen to mimic a diverse human diet, of which tomatoes are only one component. This formulation ensured an adequate intake of nutrients and minimized risk of confounding by nutritional deficiencies or imbalances that could occur if a larger portion of the diet was replaced by tomato powder. However, lycopene concentrations in blood were fairly similar in the two groups, supporting the hypothesis that components other than lycopene are active in the inhibition of prostate carcinogenesis.
Which components of tomato powder may be active in prostate cancer prevenion? Several other carotenoids found in tomatoes, including 
-carotene, 
-carotene, 
-carotene, phytofluene, and phytoene are detected in the human prostate (5). However, little is known about their biologic effects on prostate biology, either individually or in combination. Recent improvements in HPLC technology, detection systems, and mass spectrometry have allowed investigators to gain greater insight into carotenoid metabolism (1–3). Lycopene is found in food primarily as the all-trans isomer, whereas the majority of lycopene in blood and tissue is in the cis configuration (4,5). It is clear that many variables, including food processing, meal composition, and hormonal environment influence lycopene absorption, metabolism, and distribution (1–3). Perhaps even more complex are lycopene metabolism and degradation (1,2,3). However, the biologic activity of lycopene isomers and metabolites remains largely unexplored. Tomatoes also contain other phytochemicals, such as polyphenols, that can inhibit proliferative and survival signaling from critical growth factors, such as insulin-like growth factor-I (6). We encourage the continued elucidation of mechanisms by which these and other components found in tomatoes influence prostate carcinogenesis.
What do we convey to the medical community and the public? The reductionist philosophy, illustrated by the popular press emphasis on lycopene, often dominates modern scientific inquiry in the field of diet and cancer and is further encouraged by entrepreneurs anticipating profit through marketing of pure supplements. Our rodent study clearly indicates that tomatoes contain a collection of compounds, in addition to lycopene, whose total contribution to cancer prevention may not be achieved by a single supplement. Our results emphasize that investigating specific foods and dietary patterns is an essential component to cancer prevention efforts. Few clinical intervention trials of tomato products or lycopene have been completed. Until more definitive data are obtained, it is prudent to recommend that tomato products should be considered in the daily selection of a diverse array of fruits and vegetables with the goal of achieving a minimum of five servings of fruits and vegetables per day. Until clinical trials assessing risk and benefit have been completed, the use of high doses of lycopene supplements for men with prostate cancer should be discouraged (7). Optimal health and therapy can best be achieved through the practice of evidence-based medicine.
REFERENCES
1 Gann PH, Khachik F. Tomatoes or lycopene versus prostate cancer: is evolution anti-reductionist? J Natl Cancer Inst 2003;95:1563–5.
2 Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 1998;56(2 Pt 1):35–51.[Web of Science][Medline]
3 Mayne, ST. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J 1996;10:690–701.[Abstract]
4 Boileau TW, Clinton SK, Zaripheh S, Monaco MH, Donovan SM, Erdman JW Jr. Testosterone and food restriction modulate hepatic lycopene isomer concentrations in male F344 rats. J Nutr 2001;131:1746–52.
5 Clinton SK, Emenhiser C, Schwartz SJ, Bostwick DG, Williams AW, Moore BJ, et al. cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev 1996;5:823–33.[Abstract]
6 Wang S, DeGroff VL, Clinton SK. Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. J Nutr 2003;133:2367–76.
7 Miller EC, Hadley CW, Schwartz SJ, Erdman JW Jr, Boileau TW, Clinton SK. Lycopene, tomato products and prostate cancer prevention: have we established causality? Pure Appl Chem 2002;74:1435–41.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||