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Molecular Carcinogenesis and Chemoprevention Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210
2To whom correspondence should be addressed. E-mail: Clinton-1{at}medctr.osu.edu.
KEY WORDS: • lycopene • tomatoes • prostate cancer • rodents • humans
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This topic also highlights the often contentious debate between the purveyors of nutritional or food-based approaches to cancer prevention versus the reductionist chemopreventive approach strongly rooted in pharmacology (6). The initial observations that tomato products are associated with a lower risk of prostate cancer immediately stimulated many investigators, educated in the modern era with a pharmacologic and molecular-targeting philosophy, to consider which component in tomato products might be the "active ingredient." Lycopene, the predominant carotenoid in tomato products, responsible for the familiar red color, immediately became the primary suspect (4,7). At this time, the vast majority of research activity has focused on lycopene, whereas very little effort has targeted other carotenoids or phytochemicals found in tomatoes (8). Lycopene is a potent antioxidant in chemical reactions and thus readily interfaced with other preconceived hypotheses regarding a role for oxidative stress (another poorly understood hypothesis) in prostate carcinogenesis (4,7). Lycopene and a variety of its isomers are found in human prostate at concentrations thought to have the potential for biological activity (9). Epidemiologic studies have employed databases of food composition to provide estimates of lycopene intake, although debate continues regarding how best to estimate intake when lycopene content of specific food items varies substantially. Lycopene intake or blood concentrations have been examined with regard to prostate cancer risk, with several positive and null reports (10,11). Interestingly, blood lycopene is only weakly correlated with estimated intake from food questionnaires; thus blood concentrations are not very precise surrogate markers for overall tomato product consumption and exposure to the many other bioactive phytochemicals that may be contained in these products. The vast majority of dietary lycopene is not absorbed by humans, and ongoing studies suggest that the proportion absorbed and distributed to tissue is influenced by age, food source, food processing, cooking, mastication, other dietary components in the meal, hormonal status, and perhaps pharmaceuticals as well (12,13). Thus, given a modest relative risk reduction for tomato products to reduce prostate cancer risk, as suggested by epidemiologic studies, it is reasonable to predict that the relation between blood lycopene and prostate cancer risk can only be detected in carefully executed epidemiologic studies with substantial statistical power. Thus, lycopene remains a critical component of tomato products that warrants evaluation in carcinogenesis studies, although other substances found in tomato products must also be considered. In parallel, it is essential that we continue with efforts to examine tomato-based foods, representing a large array of phytochemicals that may have benefits beyond any single component.
An expanding assortment of rat and mouse models of prostate cancer tumorigenesis and carcinogenesis mimicking many features of human disease is now available (14). Unfortunately, very few have been employed to provide insight into the tomato, lycopene, and prostate cancer hypothesis. For these studies to be informative, it is critical that carefully designed dietary interventions are employed with detailed reporting of the dosage and composition of the components utilized. In addition, investigators must design studies with awareness that absorption of specific phytochemicals, such as lycopene, by rats and mice is substantially less than by humans and higher concentrations may be required in the diet to provide blood and tissue concentrations similar to that of humans (15). Several studies have been published supporting an inhibition of prostate tumorigenesis by lycopene in transplantable model systems (16). Remarkably, few carcinogenesis studies have been reported. One publication showed little benefit of lycopene, but dietary concentrations were such that in vivo concentrations were probably suboptimal to address an anticancer effect (17). A second study, which evaluated a combination of vitamin E, selenium, and lycopene in the Lady transgenic model, reported a substantial inhibition of cancer risk for the combination (18). Unfortunately, the individual effects of each component cannot be ascertained from this report. Our recent study (19) using the NMU (N-methyl-N-nitrosourea) and androgen-induced model of prostate carcinogenesis, examined prostate carcinogenesis in rats fed an AIN93G-based control diet, lycopene beadlets (Hoffmann-La Roche) providing total lycopene at 161 mg/kg of diet, or a freeze-dried whole tomato powder (Armour Foods) at 10% of the diet providing lycopene at 13 mg/kg of diet. We observed no anticancer effect of lycopene compared to the control group. However, risk of death with prostate cancer was lower for rats fed the tomato powder diet than for rats fed the control diet (hazard ratio of 0.74, P < 0.009). Interestingly, the lycopene-fed rats demonstrated higher blood lycopene content but did not show a reduced risk of prostate cancer. Thus, our rat carcinogenesis study supports the concept that tomato products may contain multiple other components that contribute to anticancer activity. It is imperative that lycopene and tomato products be evaluated, preferably with a range of dosages, in multiple models that mimic characteristics of human prostate carcinogenesis. These studies will provide additional insight into efficacy, safety, and biomarkers relevant to the design of future intervention studies in humans. Of critical relevance to humans with prostate cancer, animal models provide an efficient mechanism to examine tomato products or lycopene in combination with other chemopreventive agents or to consider interactions with therapeutic modalities such as androgen deprivation, radiation therapy, and commonly employed chemotherapeutic agents including taxanes, anthracyclines, platinum, and newer molecularly targeted agents.
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FOOTNOTES |
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LITERATURE CITED |
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1. Giovannucci, E., Ascherio, A., Rimm, E. B., Stampfer, M. J., Colditz, G. A. & Willett, W. C. (1995) Intake of carotenoids and retinol in relation to risk of prostate cancer. J. Natl. Cancer Inst. 87:1767-1776.
2. Giovannucci, E. (1999) Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J. Natl. Cancer Inst. 91:317-331.
3. Giovannucci, E., Rimm, E. B., Liu, Y., Stampfer, M. J. & Willett, W. C. (2002) A prospective study of tomato products, lycopene, and prostate cancer risk. J. Natl. Cancer Inst. 94:391-398.
4. Hadley, C. W., Miller, E. C., Schwartz, S. J. & Clinton, S. K. (2002) Tomatoes, lycopene, and prostate cancer: progress and promise. Exp. Biol. Med. (Maywood) 227:869-880.
5. Kristal, A. R. & Cohen, J. H. (2000) Invited commentary: Tomatoes, lycopene, and prostate cancer. How strong is the evidence?. Am. J. Epidemiol. 151:124-127.
6. Gann, P. H. & Khachik, F. (2003) Tomatoes or lycopene versus prostate cancer: is evolution anti-reductionist?. J. Natl. Cancer Inst. 95:1563-1565.
7. Clinton, S. K. (1998) Lycopene: chemistry, biology, and implications for human health and disease. Nutr. Rev. 56(Pt 1):35-51.[Medline]
8. Wang, S., DeGroff, V. L. & Clinton, S. K. (2003) 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. 133:2367-2376.
9. Clinton, S. K., Emenhiser, C., Schwartz, S. J., Bostwick, D. G., Williams, A. W., Moore, B. J. & Erdman, J. W., Jr (1996) Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol. Biomarkers Prev. 5:823-833.[Abstract]
10. Hsing, A. W., Comstock, G. W., Abbey, H. & Polk, B. F. (1990) Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J. Natl. Cancer Inst. 82:941-946.
11. Wu, K., Erdman, J. W., Jr, Schwartz, S. J., Platz, E. A., Leitzmann, M., Clinton, S. K., DeGroff, V., Willett, W. C. & Giovannucci, E. (2004) Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol. Biomarkers Prev. 13:260-269.
12. Boileau, T. W., Boileau, A. C. & Erdman, J. W., Jr (2002) Bioavailability of all-trans and cis-isomers of lycopene. Exp. Biol. Med. (Maywood) 227:914-919.
13. Allen, C. M., Schwartz, S. J., Craft, N. E., Giovannucci, E. L., De Groff, V. L. & Clinton, S. K. (2003) Changes in plasma and oral mucosal lycopene isomer concentrations in healthy adults consuming standard servings of processed tomato products. Nutr. Cancer 47:48-56.[Medline]
14. Shappell, S. B., Thomas, G. V., Roberts, R. L., Herbert, R., Ittmann, M. M., Rubin, M. A., Humphrey, P. A., Sundberg, J. P., Rozengurt, N., Barrios, R., Ward, J. M. & Cardiff, R. D. (2004) Prostate pathology of genetically engineered mice: Definitions and classification. The consensus report from the Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 64:2270-2305.
15. Boileau, T. W., Clinton, S. K. & Erdman, J. W., Jr (2000) Tissue lycopene concentrations and isomer patterns are affected by androgen status and dietary lycopene concentration in male F344 rats. J. Nutr. 130:1613-1618.
16. Tang, L., Jin, T., Zeng, X. & Wang, J. S. (2005) Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J. Nutr. 135:287-290.
17. Imaida, K., Tamano, S., Kato, K., Ikeda, Y., Asamoto, M., Takahashi, S., Nir, Z., Murakoshi, M., Nishino, H. & Shirai, T. (2001) Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis. Carcinogenesis 22:467-472.
18. Venkateswaran, V., Fleshner, N. E., Sugar, L. M. & Klotz, L. H. (2004) Antioxidants block prostate cancer in lady transgenic mice. Cancer Res. 64:5891-5896.
19. Boileau, T. W., Liao, Z., Kim, S., Lemeshow, S., Erdman, J. W., Jr & Clinton, S. K. (2003) Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J. Natl. Cancer Inst. 95:1578-1586.
20. Chen, L., Stacewicz-Sapuntzakis, M., Duncan, C., Sharifi, R., Ghosh, L., van Breemen, R. B., Ashton, D. & Bowen, P. E. (2001) Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J. Natl. Cancer Inst. 93:1872-1879.
21. Kucuk, O., Sarkar, F. H., Sakr, W., Djuric, Z., Pollak, M. N., Khachik, F., Li, Y. W., Banerjee, M., Grignon, D., Bertram, J. S., Crissman, J. D., Pontes, E. J. & Wood, D. P., Jr (2001) Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol. Biomarkers Prev. 10:861-868.
22. Hadley, C. W., Clinton, S. K. & Schwartz, S. J. (2003) The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage. J. Nutr. 133:727-732.
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