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Drug Insight: lycopene in the prevention and treatment of prostate cancer Emma S Guns* and Simon P Cowell
INTRODUCTION
S U M M A RY For almost a decade researchers in the field of urology have investigated lycopene and the chemopreventive potential of the tomato. A potent antioxidant found in abundance in the tomato, lycopene has repeatedly been correlated with reduced risk of prostate cancer in numerous epidemiological and population-based studies. Researchers and clinicians continue to investigate beyond the potent antioxidant properties of lycopene for other mechanisms of action and chemotherapeutic potential. This review examines the preclinical and preliminary clinical evidence surrounding the tomato and the health claims based on lycopene. We have explored recent mechanistic insights and conclude that more clinical research is warranted. The scope and extent of scientific evidence accrued on lycopene and tomato extracts, reported molecular mechanisms of action, and its potential impact on the incidence and severity of prostate cancer are discussed. KEYWORDS disease prevention, lycopene, prostate cancer, treatment
REVIEW CRITERIA The majority of publications cited in this review were retrieved from PubMed and Natural Medicines Comprehensive Database (www.naturaldatabase.com) using the search term “Lycopene” or are cited in the bibliographies herein. Papers selected demonstrated or discussed mechanistic aspects of lycopene action or represented clinical evidence for therapeutic effects. Only papers published in English have been cited in this review.
Lycopene (psi, psi-carotene) is abundant in the tomato and gives the fruit its red colour. Lycopene is an unsaturated straight-chain hydrocarbon with a total of 13 double bonds, 11 of which are conjugated. The anticancer properties of the tomato are often attributed to lycopene, because the unsaturated chemical structure apportions the compound potency as an antioxidant, outperforming vitamin E by 10-fold, and proving to be twice as potent as beta-carotene in terms of its singlet oxygen quenching ability.1 The validity of attributing the anticancer potential of the tomato to lycopene alone has yet to be confirmed, and there is a strong case for further, more rigorous clinical investigation of the use of lycopene and tomato extracts in prostate cancer patients, particularly in those for whom treatment options are limited. LYCOPENE IN CHEMOPREVENTION OF PROSTATE CANCER
Numerous epidemiologic, experimental and tissue culture studies have been published that describe the association of lycopene and/or a tomato-rich diet with the prevention of prostate cancer.2–4 Clinical studies in humans
ES Guns is an Assistant Professor in the Department of Surgery, University of British Columbia. She is also Head of Analytical Pharmacology and Natural Products Research Program, where SP Cowell is a Postdoctoral Fellow based in The Prostate Cancer Centre, Vancouver, Canada. Correspondence *The Prostate Cancer Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver BC, Canada.
[email protected] Received 29 September 2004 Accepted 9 December 2004 www.nature.com/clinicalpractice doi:10.1038/ncpuro0073
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A case-control study, conducted in 1982, examined the relationship between serum levels of antioxidants, including lycopene, on the risk of developing prostate cancer and the incidence of aggressive prostate cancers.5 Odds ratios calculated for prostate cancer incidence using logistic regression models after 13 years of follow up show that lycopene was the only antioxidant for which plasma levels were strongly correlated to a reduced prostate cancer risk. In a study published in 1995, an inverse relationship was observed between the consumption of tomatoes and tomato products and the risk of prostate cancer.6 Bowen et al. also report a significant reduction in damage to DNA and prostate tissue in men following a diet supplemented
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Table 1 Summary of the sources of lycopene used in independent reports. Authors
Model
(2003)24
Material
Source
Animal (dogs)
5% lycopene (with starch)
Roche/NCI/McKesson
Ferreira (2000)22
Animal (ferret and rat)
Lycopene oleoresin
Lycored NP
Liu (2003)40
Animal (ferret)
Lycovit (10% synthetic WD)
BASF
Animal (ferret)
Pure lycopene and Lycored 5%
Lycored NP
Korytko
Boileau
(1999)17
Venkateswaran (2004)11
Animal (mouse)
Pure lycopene in chow
Purina Mills
Guttenplan (2001)9
Animal (mouse)
3.7% suspension
Cognis Corp
Herzog (2004)33
Animal (rat)
Redivivo 5% TG
DSM Nutritional Products
Zhao (1998)23
Animal (rat)
Betatene
Animal (rat)
Lycopene 6% oleoresin
Jain
(1999)26 (2001)8
Lycored NP
Animal (rat)
Pure lycopene (>97%)
Lycored NP
Boileau (2003)10
Animal (rat)
Pure lycopene
Hoffman-La Roche
Boileau (2003)10
Animal (rat)
Dried tomato
Armour/Del Monte
(2001)25
Animal (rat)
250 ppm in chow from 10% lycopene
Hoffman-La Roche
Imaida
Boileau
Levy (1995)30
Cell
Synthetic lycopene
Hoffman-La Roche
Amir (1999)32
Cell (HL-60)
Pure lycopene (>97%)
Lycored NP
Richards (2003)28
Cell (LNCaP)
(2002)27
Cell (LNCaP)
0.258% lycopene emulsion
Lycored NP
Karas (2000)29
Cell (MCF-7)
Pure lycopene (>97%)
Lycored NP
Livny (2002)31
Cell (Oral KB-1)
“Natural tomato lycopene”
Makhteshim (Beer Sheva)
Gann (1999)5
Human epidemiological
Normal diet
Human case study
“Lycopene”
Not stated Not Stated
Kim
Matlaga
(2001)47
(2004)49
Human clinical
Lycopene softules
Rao (1999)15
Human clinical
Normal diet
Rao (1998)14
Human clinical
Spaghetti sauce, juice, 6% Lycomato
Hunt Wesson, Heinz, Lycored
Kucuk (2001)46
Human clinical
Lycopene oleoresin
Lycored NP
(2002)7
Human clinical
Spaghetti sauce
Hunt-Wesson
Ansari (2003)48
Human clinical
“Lycopene”
Not stated
Agarwal (1998)20
Human clinical
Spaghetti sauce, juice, and 6% lycomato
Hunt Wesson, Heinz, Lycored
Mucci (2001)38
Ansari
Bowen
Human epidemiological
Normal diet
(2002)2
Human epidemiological
Normal diet
Giovannucci (1995)6
Human epidemiological
Normal diet
Human epidemiological
Normal diet
Giovannucci
Clinton
(1996)19
with tomato sauce.7 Both studies suggested that the beneficial properties of tomato products might be attributable to lycopene. On the whole, during the past decade, lycopene has surreptitiously been used as a serum marker for
the consumption of tomato extracts; however the tendency for researchers to support lycopene as the lead therapeutic compound in tomato extracts and to disregard other components of the fruit, while persuasive, is not yet conclusive.
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Animal studies
Chemoprevention studies into the effects of lycopene conducted in animals have largely been inconsistent in both their test material and scientific findings (Table 1). Treatment with a product comprised of 97% lycopene (Lycored™, Lycored Natural Products, Beer-Sheva, Israel) indicated no effects of lycopene on carcinogenesis in 3,2'-dimethyl-4-aminobiphenyl (DMAB) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)-induced rat ventral prostate cancer models.8 Similar results were observed in a benzo(a)pyrene-induced prostate carcinogenesis model using LacZ mice and a 3.7% lycopene-rich tomato oleoresin.9 Conversely, two studies conducted more recently have quite different outcomes. Prostate cancer was induced using N-methyl-N-nitrosourea and testosterone, in rats fed diets containing either powder made from whole tomatoes (13 mg lycopene/kg rat diet), lycopene beadlets (161 mg lycopene/kg rat diet), or control beadlets.10 Only the powdered tomato was associated with a significant reduction in cancer incidence. A study conducted in mice using the transgenic Lady TRAMP model for prostate carcinogenesis reported a significant reduction in the incidence of prostate cancer in mice fed a combined diet containing vitamin E, selenium, and lycopene.11 The role of whole tomato extract has subsequently been under scrutiny, and debate continues regarding the validity of attributing all of the numerous health benefits of tomatoes to lycopene.10–13 LYCOPENE BIOAVAILABILITY Studies in humans
A number of articles that have investigated lycopene source and bioavailability in humans have been published.14–16 They report lycopene bioavailability in studies comparing serum lycopene levels following consumption of processed sources of tomato, such as tomato juice, paste, sauce and dietary supplements.16 Heating tomatoes in oil has been shown to significantly enhance the absorption properties of lycopene in the gut, and an abundance of the cis-isomeric forms of lycopene has been identified in these products and attributed to the enhancement in bioavailability.17,18 Other groups have also carried out extensive pharmacokinetic research concluding that the most abundantly absorbed isomers of lycopene in humans are of the cis configuration.17,19 Serum lycopene levels were shown to increase significantly after the consumption
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of tomato products and supplements, with a concomitant decrease in the biomarkers of oxidation, including the oxidation of serum lipids, lowdensity lipoprotein cholesterol, serum proteins, and DNA,20,21 providing evidence that the antioxidant activities of lycopene/tomato extracts are significant in humans. Animal studies
Tissue distribution studies carried out in rats show that in rats fed a tomato oleoresin diet, lycopene is distributed to the liver, testes, stomach, intestine and prostate gland.22 Physiological levels of lycopene were also detected in the prostate gland, lungs, mammary glands and serum of rats fed a diet containing a carotenoid mixture extracted from tomatoes.23 A study examining the pharmacokinetics of lycopene in dogs showed a mean plasma half-life of 36 h and significant steady-state plasma concentrations reaching up to 1 μm following repeat dosing (30 mg/kg per day for 28 days), suggesting that lycopene is not rapidly cleared from the blood.24 Organs were harvested and homogenized 1 and 5 days after the cessation of lycopene treatment. Lycopene levels were assessed using high performance liquid chromatography, and were highest in the liver, adrenal glands, lymph nodes and intestinal tissues and at low levels in the prostate.24 The distribution of lycopene isomers recovered from serum and organs was approximately 70% cis and 30% trans following administration, compared with the lycopene administered, which had a 70% trans content. Additional studies suggest that the cis-lycopene is also the predominant isomer found in the liver and that androgens modulate the metabolism of lycopene in the liver.25 BIOLOGICAL ACTIVITY OF LYCOPENE Antioxidant properties
Oxidative stress refers to the generation of reactive oxygen species which trigger a host of procarcinogenic processes, including DNA damage. The potent antioxidant properties of lycopene are often used to rationalize the reduction in prostate cancer risk associated with consumption of tomatoes,15,26 although other evidence suggests whole tomato products may contain other active substances that might offer additional value in preventing prostate cancer.10 Many biological activities of lycopene and tomato extracts have been evaluated in vitro using cultured cancer cells to probe and determine specific mechanisms of action.
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Antiproliferative effects
There is evidence indicating that lycopene and tomato products have antiproliferative effects in prostate cancer cells (PC-, DU-, lncap)27,28 and similar effects have also been demonstrated in other cancer cell lines. In mammary cancer cell lines, reduced expression of cell cycle regulatory proteins, such as cyclins d and e and the CYCLIN-dependent kinases (cdks) 2 and 4, as well as suppression of insulin-like growth factor- (IGF-) action, have been reported in association with the effects of lycopene on proliferation.29,30 Studies using KB-1 oral mucosa cells show that other cell signaling proteins are also significantly impacted by lycopene treatment, procuring an enhancement in gap junction communication.31 Furthermore, while not directly studied in a prostate cancer cell line, 1,25-dihydroxy-vitamin D3, an active product of vitamin D3 metabolism with known antiproliferative potency against prostate cancer, has been shown to synergistically sensitize the inhibition of cell proliferation and differentiation of promyelocytic leukemia cells upon co-exposure with lycopene.32 This and other studies, including one report of a dramatic chemopreventive effect of selenium, vitamin E and lycopene dosed in combination in the murine Lady TRAMP prostate carcinogenesis model,11 suggest that lycopene not only acts in an antiproliferative sense on its own, but works in concert when combined with other dietary factors. Endocrine properties
It is well established that prostate cancer is, at the onset, an androgen-dependent disease and evidence suggesting that prostate cancer and lycopene metabolism share a dependency on this regulatory influence is growing.25 Recent evidence suggests that pure lycopene limits conversion of testosterone to dihydrotestosterone in the MattLyLu Dunning rat model by inhibiting 5-alpha-reductase type 1 activity.33 IGF-1 cell signaling is androgen-regulated and elevated serum IGF-1 is positively correlated with prostate cancer incidence.34–39 A suppression of IGF-1-mediated cell signaling reported in mammary carcinoma cells supports this association.29,30 Lycopene has also been shown to upregulate IGF-binding protein 3 (IGF-BP3) in smoke-exposed ferrets, an event considered protective against smoke-induced carcinogenesis.40 In a report using endpoints of
reduced cellular proliferation, the lycopene-rich tomato product Lycopen™ (Lycored™, Lycored Natural Products, Beer-Sheva, Israel) slowed cell growth by impairing transition from G1 into S-phase in LNCaP prostate cancer cells (Cowell SP et al., unpublished data). Phosphorylation of Rb was shown to be inhibited by Lycopen™ allowing the release of bound E2F protein, which regulates the transcription of several key proteins required for DNA replication to proceed.41 Lycopen™ was also shown to modulate levels of IGF-1 receptor and IGF-BP2 in LNCaP cells along with cdk4 and cyclins D1 and E in this system (Cowell SP et al., unpublished data). If confirmed in clinical studies, inhibition of IGF-1 signaling by lycopene-enriched tomato extracts could provide a basis for the observed protective properties against prostate cancer.42 Interleukin-6 (IL-6) is a pro-inflammatory cytokine and growth factor found in the prostate, which has been shown to transactivate the androgen receptor independently of hormonal activation.43,44 Recent studies have shown that chronic inflammation and proliferative inflammatory atrophy (PIA) are direct precursors to prostatic intraepithelial neoplasia (PIN), suggesting that the proinflammatory role of IL-6 may be significant in both the onset and progression of prostate cancer.45 In studies using the MatLyLu Dunning rat model, pure lycopene was shown to lower the local expression of IL-6 in prostate tumours.33 CLINICAL EVIDENCE FOR PREVENTION OF PROSTATE CANCER PROGRESSION
Recent clinical studies report significant therapeutic benefit of lycopene for both androgendependent and independent prostate cancer.46–49 Preoperative lycopene administration to men 2 weeks prior to radical prostatectomy was shown to decrease the number and size of cancerous foci in the prostate as well as associated high-grade PIN in lycopene-treated men, as compared with control-treated men.46 The prostate tissue that was sectioned and used for immunohistochemical staining from the treated group displayed a significant increase in connexin 43, a cellular gap junction protein, and bax, a pro-apoptotic protein, compared with control tissues. While the results of this study are positive the treatment modality used cannot be definitively assigned to lycopene, as there was significant carotenoid and retinoid content in the supplement administered.46
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GLOSSARY PC-3 CELL LINE Initiated from a bone metastasis of a grade IV prostatic adenocarcinoma, these cells lack endogenous androgen receptor and are androgen insensitive DU-145 CELL LINE Established from tumor tissue removed from a metastatic central nervous system prostate cancer lesion, these cells are independent of androgen regulation LNCaP CELL LINE Originating from a prostate cancer lymph node metastasis, these cells are well-differentiated, androgen-sensitive, and express a functional but mutated androgen receptor CYCLINS D1 AND E Proteins that govern transition through late G1 into S-phase of the cell cycle by regulating the activity of the cyclindependent kinases CYCLIN-DEPENDENT KINASES (cdks) Protein kinases involved in regulation of the cell cycle through the formation of a complex with a specific cyclin INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) A hormone similar in sequence and function to insulin, which has been implicated as a risk factor in both prostate and breast cancer PROLIFERATIVE INFLAMMATORY ATROPHY (PIA) A histologic lesion characterized by atrophic but proliferating prostatic epithelial cells, often located near activated inflammatory cells PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) Cellular proliferations with cytological changes mimicking cancer, including nuclear and nucleolar enlargement without basement membrane disruption
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A second clinical study describes a singlecase response of hormone-refractory prostate cancer to lycopene.47 Extensive nodal disease was reported in a man whose serum PSA was 365 ng/ml. After 2 years of daily lycopene (10 mg per day) and saw palmetto treatment (300 mg orally 3 times per day), the man was reported to be asymptomatic. Obvious limitations exist regarding the interpretation of a single case study, and other potentially influential parameters such as saw palmetto coadministration and the lack of defined product quality. More compelling clinical evidence for the therapeutic efficacy of lycopene and tomato extracts has come from two studies examining the effects of lycopene in patients with metastatic hormone-refractory prostate cancer.48,49 Compared with control treatment, lycopene supplementation (4 mg per day, source not stated) alongside orchidectomy in 54 patients with histologically confirmed metastatic prostate cancer caused an overall reduction in size of primary tumors, a consistent decrease in serum PSA and diminution of secondary tumours with enhanced symptomatic relief.48 Treatment of 20 consecutive cases of metastatic hormonerefractory prostate cancer with 10 mg lycopene daily for a 3 month duration was also reported to have a significant benefit in >30% of cases. One complete response, defined as “normalization of PSA (50% decrease in PSA level for at least 8 weeks associated with improvement (or no worsening) in ECOG PS [Eastern Cooperative Oncology Group performance status] and relief of bone pain if present” were observed with no evidence of toxicity.50 CONCLUSIONS
As more evidence emerges regarding the anticancer and therapeutic benefits of lycopene, and as we begin to unravel more mechanistic detail of its activities, the question remains as to whether lycopene-enriched nutritional supplements should replace dietary tomato products as a prostate cancer prevention regimen. On this question the jury is still out, but consumers should be aware of the significant discrepancies in nutritional supplement label claims.50 Stricter enforcement of label claims for natural health products should rectify this in the short term.51,52 Large-scale placebo-controlled clinical
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trials would help substantiate and clarify the health benefits of tomato extracts and lycopene. Nevertheless, the preclinical and clinical evidence suggesting that tomato extracts play an important role in our defense against prostate cancer is compelling, and the inclusion of tomato extracts in prostate cancer treatment and prevention programs should be seriously considered by clinical researchers and those positioned in health advisory roles. References 1 Di Mascio P et al. (1989) Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 274: 532–538 2 Giovannucci E et al. (2002) A prospective study of tomato products, lycopene and prostate. J Natl Cancer Inst 94: 391–398 3 Rao AV (1999) Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr Res 19: 305–323 4 Wertz K et al. (2004) Lycopene: modes of action to promote prostate health. Arch Biochem Biophys 430: 127–134 5 Gann PH et al. (1999) Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 59: 1225–1230 6 Giovannucci E et al. (1995) Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87: 1767–1776 7 Bowen P et al. (2002) Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood) 227: 886–893 8 Imaida K et al. (2001) Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis. Carcinogenesis 22: 467–472 9 Guttenplan JB et al. (2001) Effects of a lycopene-rich diet on spontaneous and benzo[a]pyrene-induced mutagenesis in prostate, colon and lungs of the lacZ mouse. Cancer Lett 164: 1–6 10 Boileau TW et al. (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 11 Venkateswaran V et al. (2004) Antioxidants block prostate cancer in lady transgenic mice. Cancer Res 64: 5891–5896 12 Gann PH and Khachik F (2003) Tomatoes or lycopene versus prostate cancer: is evolution anti-reductionist? J Natl Cancer Inst 95: 1563–1565 13 Limpens J et al. (2004) Re: Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst 96: 554; author reply 554–555 14 Rao AV (1998) Bioavailability and in vivo antioxidant properties of lycopene from tomato products and their possible role in the prevention of cancer. Nutr Cancer 31: 199–203 15 Rao AV and Agarwal S (1999) Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study. Nutr Cancer 33: 159–164 16 Rao AV and Agarwal S (1998) Lycopene content of tomatoes and tomato products and their contribution to dietary lycopene. Food Res Intern 31: 737–741 17 Boileau AC et al. (1999) Cis-lycopene is more bioavailable than trans-lycopene in vitro and in vivo in lymph-cannulated ferrets. J Nutr 129: 1176–1181
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18 Stahl W et al. (1992) cis-trans isomers of lycopene and beta-carotene in human serum and tissues. Arch Biochem Biophys 294: 173–177 19 Clinton SK et al. (1996) cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev 5: 823–833 20 Agarwal S and Rao AV (1998) Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 33: 981–984 21 Agarwal A et al. (2001) Lycopene content of tomato products: its stability, bioavailability and in vivo antioxidant properties. J Med Food 4: 9–15 22 Ferreira AL et al. (2000) Tissue distribution of lycopene in ferrets and rats after lycopene supplementation. J Nutr 130: 1256–1260 23 Zhao Z et al. (1998) Lycopene uptake and tissue disposition in male and female rats. Proc Soc Exp Biol Med 218: 109–114 24 Korytko PJ et al. (2003) Pharmacokinetics and tissue distribution of orally administered lycopene in male dogs. J Nutr 133: 2788–2792 25 Boileau TW et al. (2001) Testosterone and food restriction modulate hepatic lycopene isomer concentrations in male F344 rats. J Nutr 131: 1746–1752 26 Jain CK and Rao AV (1999) The effect of dietary lycopene on bioavailability, tissue distribution, in vivo antioxidant properties and colonic preneoplasia in rats. Nutr Res 19: 1383–1391 27 Kim L and Rao LG (2002) Effect of lycopene on prostate LNCaP cancer cells in culture. J Med Food 5: 181–187 28 Richards LR et al. (2003) The synergistic effect of conventional and sustained delivery of antioxidants on LNCaP prostate cancer cell line. Biomed Sci Instrum 39: 402–407 29 Karas M et al. (2000) Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer 36: 101–111 30 Levy J et al. (1995) Lycopene is a more potent inhibitor of human cancer cell proliferation than either alphacarotene or beta-carotene. Nutr Cancer 24: 257–266 31 Livny O et al. (2002) Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells. J Nutr 132: 3754–3759 32 Amir H et al. (1999) Lycopene and 1,25dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer 33: 105–112 33 Herzog A et al. (2004) Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J Nov 15 [Epub ahead of print] 34 Chan JM et al. (1998) Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563–536 35 Cohen P et al. (1993) Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients. J Clin Endocrinol Metab 76: 1031–1035
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Competing interests The authors declared they have no competing interests.
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