Lycopene and prostate cancer: emerging evidence

Prostate cancer has the third highest incidence of all cancers in men worldwide and is the most common neoplasm diagnosed among men beyond middle age in many developed countries. Mounting evidence surrounding the consumption of tomato products has shown promise for the prevention of prostate cancer. This protective effect has more recently been linked to lycopene, the most abundant carotenoid in tomatoes. Lycopene is a natural pigment that gives the red color to many foods. In Western countries, 85% of dietary lycopene can be attributed to the consumption of tomato-based products. This article reviews emerging evidence from epidemiologic studies for the role of lycopene in prostate cancer prevention. The majority of evidence currently comes from observational studies, but recent human clinical trials and animal studies have provided additional support. Growing evidence on the biologic mechanisms of lycopene in prostate cancer prevention also confirm the epidemiologic findings.     

Lycopene and prostate cancer: emerging evidence

Prostate cancer has the third highest incidence of all cancers in men worldwide and is the most common neoplasm diagnosed among men beyond middle age in many developed countries. Mounting evidence surrounding the consumption of tomato products has shown promise for the prevention of prostate cancer. This protective effect has more recently been linked to lycopene, the most abundant carotenoid in tomatoes. Lycopene is a natural pigment that gives the red color to many foods. In Western countries, 85% of dietary lycopene can be attributed to the consumption of tomato-based products. This article reviews emerging evidence from epidemiologic studies for the role of lycopene in prostate cancer prevention. The majority of evidence currently comes from observational studies, but recent human clinical trials and animal studies have provided additional support. Growing evidence on the biologic mechanisms of lycopene in prostate cancer prevention also confirm the epidemiologic findings.     

Can the consumption of tomatoes or lycopene reduce cancer risk?

Lycopene, a natural antioxidant found predominantly in tomato products, is attracting attention as a cancer prevention agent. Serum and dietary lycopene levels have been found to be inversely related to the incidence of several types of cancer, including prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its apparent beneficial effects, other mechanisms may also be involved. We outline the possible mechanisms of action of lycopene and review the current findings of in vitro and in vivo studies in cancer prevention and to some extent treatment. We examine the epidemiologic evidence regarding consumption of tomato and tomato products with the risk of cancer at various sites. Data suggest lycopene may account for or contribute to chemoprevention, but this hypothesis requires further study. Numerous other potentially beneficial compounds are present in tomatoes and complex interactions among multiple components may contribute to the anticancer properties of tomatoes.     

Lycopene and prostate cancer

Despite being one of the most common malignancies, the preventable measures for prostate cancer remain poorly defined. Dietary intake of tomatoes and tomato products containing lycopene have been shown in cell culture, animal, epidemiologic and case-control studies to be inversely associated with the risk of prostate cancer. Its unique structural and biologic properties enable lycopene to prevent free-radical damage to cells caused by reactive oxygen species, thus acting as a potent antioxidant. Although some studies have provided contradictory results, these should not be considered incongruous to the many larger studies which have shown reliable results in favor of prostate cancer. Further research involving large randomized case-control trials would confirm the potential anticancer effect of this molecule, which might provide new dimensions not only to the prevention but also the treatment of prostate cancer.     

Micronutrients in cancer chemoprevention

The selection of micronutrients, defined as essential and nonessential dietary components consumed in minute quantities, for testing in clinical chemoprevention trials is based on the totality of evidence arising from epidemiologic, in vitro, animal, and clinical studies. Those micronutrients that surface with chemopreventive potential, in terms of high efficacy and low toxicity, in early-phase clinical studies are then candidates for large-scale, randomized clinical chemoprevention trials with cancer endpoints. Micronutrients currently being examined in National Cancer Institute (NCI)-sponsored phase I, II, or III chemoprevention trials for prostate, breast, and colon cancers include isoflavones, lycopene, selenized yeast, selenomethionine, selenium, vitamin E, perillyl alcohol, folic acid, vitamin D, calcium, and curcumin. The response to micronutrients may vary not only in magnitude but also in direction. This variation and response likely depend on individual genetic polymorphisms and/or interactions among dietary components that influence absorption, metabolism, or site of action. Research priorities include investigation of possible molecular targets for micronutrients and whether genetic and epigenetic events dictate direction and magnitude of the response.     

Curcumin for chemoprevention of colon cancer

The most practical approach to reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through the use of chemopreventive agents. This necessitates that safer compounds, especially those derived from natural sources must be critically examined for chemoprevention. A spice common to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa. Pre-clinical studies in a variety of cancer cell lines including breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that curcumin possesses anti-cancer activity in vitro and in pre-clinical animal models. The robust activity of curcumin in colorectal cancer has led to five phase I clinical trials being completed showing the safety and tolerability of curcumin in colorectal cancer patients. To date clinical trials have not identified a maximum tolerated dose of curcumin in humans with clinical trials using doses up to 8000mg per day. The success of these trials has led to the development of phase II trials that are currently enrolling patients. Overwhelming in vitro evidence and completed clinical trials suggests that curcumin may prove to be useful for the chemoprevention of colon cancer in humans. This review will focus on describing the pre-clinical and clinical evidence of curcumin as a chemopreventive compound in colorectal cancer.     

The role of diet and nutrition in cervical carcinogenesis: a review of recent evidence

Our objective was to provide an update on recent epidemiologic evidence about the role of diet and nutrition on the risk of human papillomavirus (HPV) persistence and cervical neoplasia, taking HPV into account. We conducted a systematic review and qualitative classification of all observational studies controlling for HPV infection published between March 1995 and November 2003 and of all randomized clinical trials published between January 1991 and November 2003. Scientific evidence was classified as convincing, probable, possible or insufficient, as used in a previous study on diet and cancer. Thirty-three studies were eligible for this review (10 clinical trials, 8 observational prospective studies and 15 case-control studies). The few studies on HPV persistence showed a possible protective effect of fruits, vegetables, vitamins C and E, beta- and alpha-carotene, lycopene, luterin/zeaxanthin and cryptoxanthin. Evidence for a protective effect of cervical neoplasia was probable for folate, retinol and vitamin E and possible for vegetables, vitamins C and B12, alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin and cryptoxanthin. Evidence for an increased risk of cervical neoplasia associated with high blood homocysteine was probable. Results did not differ between studies looking at preneoplastic and invasive lesions or between retrospective and prospective studies. The available evidence for an association between diet and nutritional status and cervical carcinogenesis taking HPV infection into account is not yet convincing. Large cohort studies are needed to adequately assess the role of foods and nutrients in cervical HPV carcinogenesis.     

Multitargeted therapy of cancer by lycopene

Lycopene (psi,psi-carotene) is the most abundant carotenoid in tomatoes and is the red pigment of not only tomatoes but also rosehips, watermelon, papaya, pink grapefruit, and guava. Unlike beta-carotene, lycopene lacks a beta-ionone ring and therefore has no pro-vitamin A activity. However, the 11 conjugated and two non-conjugated double bonds in lycopene make it highly reactive towards oxygen and free radicals, and this anti-oxidant activity probably contributes to its efficacy as a chemoprevention agent. The reactivity of lycopene also explains why it isomerizes rapidly in blood and tissues from the biosynthetic all-trans form to a mixture of cis-isomers. Prospective and retrospective epidemiological studies indicating an inverse relationship between lycopene intake and prostate cancer risk have been supported by in vitro and in vivo experiments showing that oral lycopene is bioavailable, accumulates in prostate tissue and is localized to the nucleus of prostate epithelial cells. In addition to antioxidant activity, in vitro experiments indicate other mechanisms of chemoprevention by lycopene including induction of apoptosis and antiproliferation in cancer cells, anti-metastatic activity, and the upregulation of the antioxidant response element leading to the synthesis of cytoprotective enzymes. Lycopene is a substrate for carotene-9',10'-monooxygenase (CMO2) and can be converted to apo-10'-carotenal. Although Phase I and II studies have been published that establish the safety of lycopene supplementation, carefully designed and adequately powered clinical studies of lycopene are still needed to confirm its efficacy as a chemoprevention agent.     

Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial.

BACKGROUND: Reports from several studies have suggested that carotenoids, and in particular lycopene, could be prostate cancer-preventive agents. This has stimulated extensive laboratory and clinical research, as well as much commercial and public enthusiasm. However, the epidemiologic evidence remains inconclusive. MATERIALS AND METHODS: We investigated the association between prediagnostic serum carotenoids (lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin) and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to examine methods of early detection and risk factors for cancer. The study included 692 incident prostate cancer cases, diagnosed 1 to 8 years after study entry, including 270 aggressive cases, with regional or distant stage (n = 90) or Gleason score >or=7 (n = 235), and 844 randomly selected, matched controls. As study participants were selected from those who were assigned to annual standardized screening for prostate cancer, results are unlikely to be biased by differential screening, a circumstance that is difficult to attain under non-trial conditions. RESULTS: No association was observed between serum lycopene and total prostate cancer [odds ratios (OR), 1.14; 95% confidence intervals (95% CI), 0.82-1.58 for highest versus lowest quintile; P for trend, 0.28] or aggressive prostate cancer (OR, 0.99; 95% CI, 0.62-1.57 for highest versus lowest quintile; P for trend, 0.433). beta-Carotene was associated with an increased risk of aggressive prostate cancer (OR, 1.67; 95% CI, 1.03-2.72 for highest versus lowest quintile; P for trend, 0.13); in particular, regional or distant stage disease (OR, 3.16; 95% CI, 1.37-7.31 for highest versus lowest quintile; P for trend, 0.02); other carotenoids were not associated with risk. CONCLUSION: In this large prospective study, high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer. Lycopene and other carotenoids were unrelated to prostate cancer. Consistent with other recent publications, these results suggest that lycopene or tomato-based regimens will not be effective for prostate cancer prevention.     

Statin use and the risk of prostate cancer: A metaanalysis of 6 randomized clinical trials and 13 observational studies

Statins have been suggested to prevent prostate cancer. Our aim was to examine statin use in relation to both total prostate cancer and the more clinically important advanced prostate cancer, through a detailed metaanalysis of the epidemiologic studies published on the subject in peer-reviewed literature. A comprehensive search for articles published up to November 2007 was performed, reviews of each study were conducted and data were abstracted. Prior to metaanalysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup and sensitivity analyses were also performed. Nineteen studies [6 randomized clinical trials (RCTs), 6 cohort and 7 case-control studies] contributed to the analysis. There was no evidence of an association between statin use and total prostate cancer among either RCTs (RR = 1.06, 95% CI: 0.93-1.20) or the observational studies (RR = 0.89, 95% CI: 0.65-1.24). However, high heterogeneity was detected among the observational studies. Moreover, long-term statin use did not significantly affect the risk of total prostate cancer (RR = 0.93, 95% CI: 0.77-1.13). In contrast, synthesis of the available reports that had specifically examined statin use in relation to advanced prostate cancer indicated a protective association (RR = 0.77, 95% CI: 0.64-0.93). Our results do not support the hypothesis that statins reduce the risk of total prostate cancer. However, further research is required to investigate whether the particular association of statin use with lower risk of advanced prostate cancer is indeed causal.     

绿茶对前列腺癌的化学预防作用

绿茶是许多国家和地区的重要饮料之一,近年来不断有体外和动物体内实验表明绿茶可以诱导前列腺癌细胞凋亡、抑制前列腺癌浸润及转移,流行病学调查及临床试验也发现绿茶对前列腺癌具有预防作用,可减少高分级前列腺上皮内瘤发展成为前列腺癌的概率,将有可能成为良好的前列腺癌化学预防物质.     

Polycyclic aromatic hydrocarbon-DNA adduct formation in prostate carcinogenesis

The evidence for polycyclic aromatic hydrocarbons (PAH) playing a role in prostate carcinogenesis comes mainly from associations between reported PAH exposures and prostate cancer in epidemiologic studies. Associations between prostate cancer and DNA repair genotypes and phenotypes have also been reported, lending further credence to a PAH-induced carcinogenesis pathway in prostate cancer. Recent work that demonstrates the human prostate has metabolic enzyme activity necessary for PAH activation and will form DNA adducts upon exposure to PAH further supports PAH carcinogenesis. We have demonstrated the presence of PAH-DNA adducts in prostate cancer cases, but further validation of this biomarker as a carcinogenic agent in human prostate is needed.     

Clinical trials involving vitamin D analogs in prostate cancer

Vitamin D shows significant potential as a therapy for prostate cancer. However, its use in clinical trials has been hampered by its induction of hypercalcemia at serum concentrations required to suppress cancer cell proliferation. This has spurred the development of less calcemic analogs of vitamin D. In this article, we review the clinical trials and consider the future directions of the use of vitamin D and its analogs in the treatment or chemoprevention of prostate cancer. First, we summarize the epidemiological evidence leading to the hypothesis that vitamin D has anticancer activity. We then review the clinical trials using vitamin D analogs that involve patients with prostate cancer and conclude with a brief overview of our planned study with vitamin D5, [1alpha(OH)D5], which will begin shortly. Data for this review were identified by searches of PubMed, the Cochrane Library, Biosis, and references from relevant articles, using the search terms "vitamin D," "prostate cancer," "chemoprevention" and "vitamin D analog." Abstracts from recent international meetings were also reviewed but were only included when they were the only known reference to the clinical trial or the research mentioned. Only papers published in English were included.     

Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials

INTRODUCTION: Chemoprevention strategies are very attractive and have earned serious consideration as potential means of controlling the incidence of cancer. An important element of anticancer drug development using plants is the accumulation and analysis of pertinent experimental data and purported ethnomedical (folkloric) uses for plants. The aim of this review is to provide an updated overview of experimental in vitro and in vivo investigations focused on the anticancer activity of saffron (Crocus sativus L.) and its principal ingredients. Potential use of these natural agents in cancer therapy and chemopreventive trials are also discussed. METHODS: A computerized search of published articles was performed using the MEDLINE database from 1990 to 2004. Search terms utilized including saffron, carotenoids, chemoprevention, and cancer. All articles were obtained as reprints from their original authors. Additional sources were identified through cross-referencing. RESULTS: Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor and cancer preventive activities of saffron and its main ingredients, possible mechanisms for these activities are discussed. More direct evidence of anticancer effectiveness of saffron as chemopreventive agent may come from trials that use actual reduction of cancer incidence as the primary endpoint CONCLUSIONS: This work suggests that future research be warranted that will define the possible use of saffron as effective anticancer and chemopreventive agent in clinical trials.     

Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.     

Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: an ASTRO outcomes initiative

PURPOSE: To perform a systematic review of the evidence to determine the efficacy and effectiveness of three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer; provide a clear presentation of the key clinical outcome questions related to the use of 3D-CRT in the treatment of localized prostate cancer that may be answered by a formal literature review; and provide concise information on whether 3D-CRT improves the clinical outcomes in the treatment of localized prostate cancer compared with conventional RT. METHODS AND MATERIALS: We performed a systematic review of the literature through a structured process developed by the American Society for Therapeutic Radiology and Oncology's Outcomes Committee that involved the creation of a multidisciplinary task force, development of clinical outcome questions, a formal literature review and data abstraction, data review, and outside peer review. RESULTS: Seven key clinical questions were identified. The results and task force conclusions of the literature review for each question are reported. CONCLUSION: The technological goals of reducing morbidity with 3D-CRT have been achieved. Randomized trials and follow-up of completed trials remain necessary to address these clinical outcomes specifically with regard to patient subsets and the use of hormonal therapy.     

Understanding the biology of bone metastases: key to the effective treatment of prostate cancer.

Advanced prostate cancer is dominated by bone-forming osseous metastases. Understanding the biology behind this striking clinical manifestation is the key to its effective treatment. A clinical trial using a bone-targeting radiopharmaceutical agent, strontium 89, combined with chemotherapy showed increased survival time among patients with progression of prostate cancer in bone, suggesting that therapeutic strategies focused on treating the tumor in bone are effective. We and others thus hypothesize that interactions between prostate cancer cells and the bone microenvironment play a role in the progression of prostate cancer in bone. Clinical trials and basic science investigations aiming to understand such interactions have been carried out in parallel. In the laboratory studies, human bone marrow specimens have been collected for identification of proteins involved in the bidirectional interactions between prostate cancer cells and bone. In addition, specimens from bone biopsies of the cancer lesions have been used to generate xenografts in animals to establish animal models for testing therapeutic strategies. Clinical trials using agents to inhibit the stromal-prostate cancer interactions (e.g., docetaxel/imatinib or thalidomide) have been done. Analyses of the specimens from these trials provided support of our hypothesis and future development of diagnosis and therapy strategies.     

Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer.

PURPOSE: There is epidemiologic evidence that high garlic consumption decreases the incidence of prostate cancer, and compounds isolated from garlic have been shown to have cancer-preventive and tumor-suppressive effects. Recent in vitro studies in our laboratory have shown that garlic-derived organosulfur compound S-allylmercaptocysteine suppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin. S-allylmercaptocysteine is therefore a potential antimetastatic drug with broad clinical applications that we tested in vivo for the first time in this study. EXPERIMENTAL DESIGN: We used a newly established fluorescent orthotopic androgen-independent prostate cancer mouse model to assess the ability of S-allylmercaptocysteine to inhibit tumor growth and dissemination. RESULTS: We showed that oral S-allylmercaptocysteine not only inhibited the growth of primary tumors by up to 71% (P < 0.001) but also reduced the number of lung and adrenal metastases by as much as 85.5% (P = 0.001) without causing notable toxicity. This metastatic suppression was accompanied by a 91% reduction of viable circulating tumor cells (P = 0.041), suggesting that S-allylmercaptocysteine prevents dissemination by decreasing tumor cell intravasation. CONCLUSIONS: Our results provide in vivo evidence supporting the potential use of S-allylmercaptocysteine as an E-cadherin up-regulating antimetastatic agent for the treatment of androgen-independent prostate cancer. This is the first report of the in vivo antimetastatic properties of garlic, which may also apply to other cancer types.