Chemoprevention of prostate cancer: Natural compounds, antiandrogens, and antioxidants – In vivo evidence

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Nur Özten-Kandas, Maarten C Bosland
Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA

Date of Submission 08-Sep-2011
Date of Acceptance 20-Oct-2011
Date of Web Publication 30-Nov-2011

Correspondence Address:
Maarten C Bosland
Department of Pathology, University of Illinois at Chicago, Chicago, IL
USA

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1477-3163.90438

Abstract

Prostate cancer is the leading non-skin malignancy detected in US males and the second cause of death due to male cancer, in the US. Interventions with drugs or diet supplements that slow down the growth and progression of prostate cancer are potentially very effective in reducing the burden of prostate cancer, particularly if these treatments also prevent the de novo development of new prostatic malignancies. Challenges to identify efficacious agents and develop them for chemopreventive application in men at risk for prostate cancer have included uncertainty about which preclinical models have the ability to predict efficacy in men and lack of consensus about which early phase clinical trial designs are the most appropriate and cost-effective to test promising agents. Efficacy studies in animal models have identified several agents with potential chemopreventive activity against prostate cancer, but few of these findings have been translated into clinical trials. This article identifies some of the major issues associated with prostate cancer chemoprevention research and summarizes the most significant current results from animal efficacy studies and human clinical prevention trials. This summary focuses on: (1) Naturally occurring agents and compounds derived from such agents, including green tea and its constituents, silibinin and milk thistle, and genistein and soy, (2) chemoprevention drugs including agents interfering with androgen action, and (3) antioxidants such as selenium, vitamin E, and lycopene. The general lack of activity of antioxidants is discussed, followed by considerations about translation of preclinical chemoprevention efficacy data, focusing on dose, form, bioavailability, and timing of administration of the agent, as well as discussion of study design of clinical trials and the predictive ability of preclinical models.

Keywords: Animal models, antioxidants, chemoprevention, clinical trials, natural compounds, prostate cancer

How to cite this article:
Özten-Kandas N, Bosland MC. Chemoprevention of prostate cancer: Natural compounds, antiandrogens, and antioxidants – In vivo evidence. J Carcinog 2011;10:27

How to cite this URL:
Özten-Kandas N, Bosland MC. Chemoprevention of prostate cancer: Natural compounds, antiandrogens, and antioxidants – In vivo evidence. J Carcinog [serial online] 2011 [cited 2021 Oct 14];10:27. Available from: https://carcinogenesis.com/text.asp?2011/10/1/27/90438

 Introduction

Prostate cancer is the leading non-skin malignancy detected in US males and the second cause of death due to male cancer, in the US. [1] The disease typically develops and progresses slowly over a period that may include decades. There are reports indicating that about 30% of US men between the ages of 20 and 40 years have microscopic size cancers in their prostate. [2] Thus, interventions with drugs or diet supplements that slow down the growth and progression of these small tumors are potentially very effective in reducing the burden of prostate cancer, particularly if these treatments also prevent the de novo development of new prostatic malignancies. [3],[4] The challenge has been to identify efficacious agents and to develop them for chemopreventive application in men at risk for prostate cancer. One problem is the uncertainty about which preclinical models have the ability to predict efficacy of agents in men. Another difficulty has been the lack of consensus about which early phase clinical trial designs are the most appropriate and cost-effective to test promising agents, before embarking on hugely expensive, large, randomized prevention clinical trials, with cancer detection as endpoint.

Several approaches have been used to select candidate agents for efficacy testing. One approach is to select agents that have been active for other cancer sites, but with a few exceptions this has not been very successful. Efficacy studies in animal models have identified several agents with potential chemopreventive activity against prostate cancer, [5] but few of these findings have been translated into clinical trials. The purpose of this article is to identify some of the major issues associated with prostate cancer chemoprevention research and to provide a summary of the most significant current results from animal efficacy studies and human clinical prevention trials, but not to provide an exhaustive summary of all such studies. There are many studies on the effects of various compounds on the growth of prostate cancer cells in vitro or when xenografted into immunodeficient mice. Such cell models are useful for studying the molecular mechanisms of chemoprevention agents. However, they are relevant to therapy, but not prevention, as the vast majority of these models involve cells derived from metastatic prostate cancer deposits and none reflect the early stages of prostate carcinogenesis, and will not be discussed here.

Naturally Occurring Agents and Compounds Derived from Naturally Occurring Agents


Green tea and its constituents

Green tea polyphenols have been reported to inhibit tumor development in the so-called transgenic adenocarcinoma of the mouse prostate (TRAMP) model, [6] but unpublished data from other investigators suggest that this finding has been difficult to reproduce and may be restricted to prevention of early stage tumors and treatment that begins before the onset of puberty. [7],[8] Partly published studies with other in vivo prostate cancer models using rats, in our laboratory, were uniformly negative for green tea extract. [9],[10] The activity of green tea polyphenols in the TRAMP model may be related to the known inhibitory effects of the green tea catechin epigallocatechin-3-gallate (ECGC) on the activity of the enzyme 5α-reductase, which converts the male sex hormone testosterone to the active androgen 5α-dihydrotestosterone. [11] Also, the expression and activity of the androgen receptor is attenuated by green tea polyphenols and catechins. [8],[12],[13] The expression and activity of the oncogenic SV40-large and small T antigens (SV40-Tag) in the TRAMP model are targeted to the prostate by the probasin gene promoter, which is under the control of the androgen receptor. Therefore, it is probable that the green tea polyphenols interfered with the expression of the SV40-Tag at a critical moment and, thereby, prevented the oncogenic events to take place in this model. [14] Consistent with this notion, protein expression of SV40-Tag was not detectable in the prostate of TRAMP mice that did not develop tumors following ECGC treatment, but was detectable in those prostate tumors that were not prevented by this agent, [15] although others [8] did not find effects of ECGC on the protein expression of SV40-Tag in the TRAMP model. The major drawbacks of the TRAMP model are its aggressiveness and the predominantly neuroendocrine phenotype of the tumors that develop, which are not frequent in humans, who mostly develop adenocarcinomas. [16] Lesions in this model, that resemble high-grade prostate intraepithelial neoplasia (PIN) found in the human prostate, do not appear to progress to adenocarcinoma, [16] casting some doubt on the relevance of the TRAMP model.

A randomized placebo-controlled clinical trial of 12 months intervention, with a green tea catechin mixture (600 mg / day), was conducted in men with elevated prostate-specific antigen (PSA) and high-grade PIN on biopsy, but no cancer. Follow-up biopsies at 6, 12, and 24 months were carried out in the treatment arm (n = 30, 30, and 13, respectively) and the placebo arm (n = 30, 24, and 9, respectively). A statistically significant reduction in the detection of prostate cancers, from 30 to 3.3% at 12 months and 53 to 11% at 24 months, was found in the treated men compared to men on placebo. [17],[18] On account of the small number of subjects, the short duration of this trial, and the inherent sampling problems associated with prostate biopsies, these findings should be considered preliminary and await reproduction. In summary, there are mixed findings from animal studies about the preventive efficacy of green tea and its constituents, while there are human data suggestive of the protective activity of green tea catechins against prostate cancer. Further human studies are needed to firmly establish whether green tea can prevent prostate cancer.

Silibinin and milk thistle

Silibinin derived from Silybin or extract from the milk thistle plant has been show to inhibit prostate tumor formation in the TRAMP model, [19] but this effect appeared to be limited to inhibition of the growth of established prostate neoplasms late in the process of tumor progression. [20],[21] This suggests that the effects of silibinin in the TRAMP model are more of a therapeutic nature than chemopreventive. Importantly, silibinin did not appear to reduce the expression of the SV40-Tag. [19] On basis of these findings and the absence of toxic or carcinogenic effects of milk thistle, [22] a small placebo-controlled phase I / II clinical trial with a silibinin-containing milk thistle preparation was conducted in men, prior to radical prostatectomy for prostate cancer. [23] Although the dose of this preparation was high (a total of 13 g ingested daily for two weeks), most of the six treated subjects reported only mild grade 1 or 2 adverse events; one subject experienced a postsurgical grade 4 thromboembolic event, which may have been associated with the treatment. No adverse events were reported for the six control subjects. Serum concentrations of silibinin reached 20 – 23 μM, but tissue levels were extremely low, ranging from undetectable to no more than 0.5 nM. There were no effects of the treatment on serum levels of IGF-1 and IGFBP-3, nor were there effects on the labeling index for Ki-67 and caspase-3 and COX-2 positive cells in prostate tissue. These human data do not provide support for the notion that silibinin or milk thistle prevent prostate cancer.

Genistein and soy

We and others have shown that dietary exposure to soy isoflavones, the Bowman-Birk protease inhibitor occurring in soy, and whole soy protein inhibit prostate carcinogenesis induced by carcinogens plus hormones in adult rats and in the TRAMP mouse model and a similar rat model. [24],[25],[26],[27],[28],[29],[30],[31],[32] However, there are reports that in the TRAMP model the major soy isoflavone genistein at lower, nutritionally relevant, doses stimulated carcinogenesis and greatly enhanced metastatic capacity. [33],[34] Clearly, both the dose and form of the agent as well as probably the timing of administration are critical determinants for whether genistein, and by inference soy, have cancer-preventive effects or enhance prostate cancer development. The anti-cancer effects of genistein have been attributed to its known inhibitory effects on tyrosine kinase, topoisomerase II, 5α-reductase, and angiogenesis, and its activation of several growth factor receptor pathways, but most of these effects, particularly those on tyrosine kinase activity, occur only at non-physiologically high concentrations. [35],[36],[37],[38] At low, physiological concentrations genistein binds to both the estrogen receptors (ER)-α and -β, with a greater affinity for ER-β, and genistein is thought to probably exert some or most of its effects through ER-β. [39] How genistein might elicit proliferative, rather than anti-proliferative effects on prostate cancer cells at low doses is uncertain. Genistein also has an antioxidant activity (see later in the text) and may inhibit carcinogenesis via protection of cells against oxidative stress. [35],[40],[41],[42] The other major soy isoflavone, diadzein, is far less biologically active. Daidzein, but not genistein, is converted to equol by intestinal microbes in 30 – 60% of humans, a phenomenon that appears to be quite stable within a given individual. [43],[44] This daidzein metabolite has significant estrogenic and anti-androgenic activities, including prostatic effects in rats. [45],[46],[47] It is conceivable that the chemopreventive activity of soy isoflavones may differ in men who produce equol and those who do not and that is related to the hormonal properties of equol, [44] but this has not be explored to date.

There are several reports of placebo-controlled clinical trials with soy products, often enriched for isoflavones. In healthy men (i.e., men without detected prostate cancer) soy does not seem to affect the serum levels of PSA. [48],[49] Also, in men with a rising PSA after local radiation or surgical therapy, soy does not appear to significantly affect the serum PSA levels, [50],[51],[52] which we confirmed [Bosland, unpublished data]. Studies on the effects of soy on PSA without placebo control or cross-over designs and trials with complex mixtures containing soy have also been reported, [53],[54],[55],[56],[57] but are not discussed here, because their results are difficult to interpret. Most interesting are the few studies, reported to date, on changes in prostate tissue biomarkers following intervention with soy in placebo-controlled trails, but unfortunately there is no clear pattern of changes that has yet emerged. [58],[59],[60] In a placebo-controlled clinical trial with men diagnosed with high-grade PIN on biopsy, a supplement mixture of selenium and soy (exact preparation was not defined for either in the article) was provided for three years, together with alpha-tocopherol, but the cumulative incidence of prostate cancer was not affected, [57] casting doubt on the ability of soy to affect prostate cancer development.

Other naturally occurring agents

There is a large literature on the potential to prevent or treat prostate cancer with vitamin D or vitamin D analogs, [61] but there is increasing evidence to dispute this notion, [62],[63] and there is the problem of toxicity of vitamin D and analogs that limit their application in humans. A 1,25(OH) 2 D 3 analog has not been active when given mixed into the diet in a TRAMP-like mouse model, [64] but systemic administration of 1,25-D 3 inhibited the development of PIN-like lesions in mutant mice lacking both Pten and Nkx3.1 genes. [65] There are no other animal studies with appropriate models and we will not further discuss vitamin D chemoprevention here. Curcumin, derived from turmeric, has in vitro properties that are consistent with cancer inhibiting activity, but it is poorly bioavailable in vivo. [66] Nonetheless, dietary curcumin inhibited tumor development in the TRAMP model, as did phenylethylisocyanate (PEICT), which occurs naturally in cruciferous and other vegetables. [67] However, in a chemically induced rat prostate cancer model, dietary curcumin has not been active. [68] Resveratrol, which occurs in grape seeds and red wine inhibited late stage tumor development in TRAMP mice, [69] and had marginal inhibitory activity in a similarly aggressive SV-40-based model in rats. [70] Pomegranate extracts and juice have anticancer-like activity in cell models, but has not been tested in vivo. [71] None of these substances have been tested in human studies.

Chemoprevention Drugs


Agents interfering with androgen action

Agents interfering with androgen action, such as androgen receptor blockers or 5α-reductase inhibitors, have been very effective in preventing prostate cancer development in most, but not all, appropriate animal models. [5],[72],[73],[74] The 5α-reductase-type 2 inhibitor finasteride and 5α-reductase-type 1 and 2 inhibitor dutasteride have each been tested in a large clinical trial, named the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) trial, respectively. [75],[76] In both of these studies, a reduced risk of developing prostate cancer by 23 – 24%, over a four-to-seven-year intervention period, was seen in men at average risk of prostate cancer (finasteride) or high risk men (dutasteride). [77],[78] Both agents exerted the strongest preventive effect on low-grade prostate cancer, whereas, for high-grade cancer there was no protective effect in the dutasteride trial (Gleason score 7 or higher) and a small, but significant, increased risk in the finasteride trial (Gleason score 8 or higher). These findings have been hotly debated in the literature and explanations for the increased risk of high-grade cancer in the finasteride trial have been developed. [79],[80],[81] Neither agent is currently approved by the US FDA for the prevention of prostate cancer, and a long-term follow-up of finasteride study participants is still ongoing which will allow to observe their response to hormone ablation therapy, if recurrence develops. Nevertheless both studies do provide evidence in support of androgen action as an important and biologically plausible potential target for chemoprevention of prostate cancer.

Other drugs

Dehydroepiandrosterone (DHEA), which is strongly inhibitory in mammary cancer models, also inhibited prostate cancer induction in rats with a combination of chemical carcinogen treatment (methylnitrosourea) and long-term, low-dose testosterone administration, via slow release Silastic implants. [82] Fluasterone, a non-hormonally active fluorinated analog of the androgen precursor DHEA, was also inhibitory in the latter model. [83] One of the most active inhibitory compounds was the pan-retinoic acid receptor (RAR and RXR) agonist 9-cis-retinoic acid, which reduced prostate cancer incidence in the above-mentioned rat model by more than 70%. [84] Unfortunately, 9-cis-retinoic acid is too toxic to be considered for application in humans in a prevention setting and Fluasterone is currently not available for clinical studies. The retinoid-like agent N-(4-hydroxyphenyl)all-trans-retinamide (4-HPR) was not efficacious in this rat model, [85] and in two small clinical trials no evidence was found of its protective activity. [86],[87]

Antioxidants


Oxidative stress generating reactive oxygen species (ROS) has the potential to cause oxidative DNA damage and has been associated with the causation of human cancer, including prostate cancer. [88],[89],[90] One mechanism by which ROS may be produced and leads to cancer is inflammation, which has been implied in the etiology of several major human malignancies, including prostate cancer. [91],[92] Basic research and many epidemiological studies have suggested the cancer preventive activity of several antioxidants. This notion has been the basis of the hypothesis that dietary antioxidants may prevent cancer, which has been tested in several randomized clinical trials (RCTs) and preclinical model studies. The ability to prevent lung cancer of beta-carotene, which quenches ROS, and alpha-tocopherol (vitamin E), that interferes with ROS-induced lipid peroxidation, has been tested in an RCT with smokers. However, beta-carotene increased the risk of lung cancer, [93] although this adverse effect disappeared after a longer follow-up. [94] Vitamin E did not protect against lung cancer in this study, but reduced the risk of prostate cancer in smokers. [93] Selenium is an essential component of a range of selenoproteins. Several of these proteins have an antioxidant activity or are involved in antioxidant mechanisms and detoxify ROS, such as glutathione peroxidase (GPx), which acts either alone or in combination with other enzymes, such as superoxide dismutase (SOD). [95],[96] In a clinical trial of subjects with an increased risk for skin cancer, the ability to prevent such tumors of selenium in the form of a selenium-rich yeast dietary supplement was tested. It did not prevent, but slightly increased the risk of non-melanoma skin cancer, while the risk of colon and particularly prostate cancer was reduced. [97],[98],[99]

Selenium and vitamin E

As the above-mentioned RCTs suggested preventive activity of selenium and vitamin E for prostate cancer as a secondary endpoint, the ability to prevent prostate cancer was evaluated in a very large RCT, the Selenium and Vitamin E Cancer Prevention Trial (SELECT). However, selenomethionine, one of the forms of selenium in the human diet, and alpha-tocopherol either alone or in combination did not have a preventive activity. [100] In a much smaller RCT of men with high-grade PIN on biopsy, subjects were provided for three years with a mixture of selenium and soy (exact preparation was not defined for either in the article) together with alpha-tocopherol or with placebo, but no preventive effect was observed on the cumulative incidence of prostate cancer. [57] Using two animal models, we tested the ability of selenomethionine, selenized yeast, alpha-tocopherol, and combinations thereof, to prevent prostate cancer, but we did not detect any preventive activity of these agents. [101],[102] However, there is epidemiological and animal model evidence to suggest that not alpha tocopherol, but gamma-tocopherol, the major tocopherol in the human diet, [103] might be protective against prostate cancer. [104],[105]

Lycopene

Lycopene, a very strong ROS-quenching antioxidant present in tomatoes, water melons, and other vegetables / fruits, has been associated with reduced risk of prostate cancer in some epidemiological studies, but not in several others and the overall evidence for a protective effect of lycopene is very limited at best. [106] Lycopene was negative in two rat models using a carcinogen plus testosterone protocol for prostate cancer induction [107],[108] and in a chemically-induced prostate cancer model in rats, [68] but tomato powder increased prostate cancer-specific survival in rats treated with carcinogen plus testosterone (the effect of lycopene or tomato powder on tumor incidence was not assessed in this study). [108] In contrast, feeding lycopene, but not tomato paste, from four to twenty weeks of age inhibited the development of prostate tumors in TRAMP mice, but did not affect the weight of the prostate complex. [109] Adding lycopene to a diet containing supplemental selenium and vitamin E, retarded tumor development in a mildly aggressive TRAMP-like mouse model (LADY) and reduced the expression of the oncogenic SV-40 transgene, which may explain its tumor inhibitory effect. [110] Thus, the results of most animal studies appear to indicate a lack of preventive activity of lycopene. There are no reports yet of lycopene tested in a RCT with prostate cancer as the endpoint. However, lycopene may have antioxidant-like effects in the human prostate; feeding a lycopene-rich tomato sauce reduced the level of oxidative DNA damage in the prostate in one Phase II study, but a lycopene-rich tomato extract did not do so in another study from the same group. [111],[112],[113] Consumption of lycopene-rich tomato sauce also increased apoptosis in prostate tissue and reduced serum PSA in one of these studies. [111] Other clinical trials are ongoing.

Considerations

There are probably many reasons why antioxidants may have such diverse effects and did not prevent cancer in several studies; some of the more important reasons include:

  • It has been proposed that some or many antioxidants have biphasic effects that differ at lower and higher doses. [114],[115],[116]
  • There are diverse mechanisms by which antioxidants exert their antioxidant effect that may, in part, be affected by genetic polymorphisms in genes encoding for antioxidant proteins, which may lead to different effects in different people exposed to the same antioxidant dose. [90],[117],[118],[119]
  • Many antioxidant agents have biologically significant effects of a non-antioxidant nature and are known or likely to interact with each other. For example we found that at low, physiologically relevant concentrations, selenium can stimulate in vitro proliferation of prostate cancer cells, while it inhibits cell proliferation and indices of apoptosis only at higher concentrations; effects that are probably not related to its incorporation in antioxidant selenoproteins. [120]
  • A critical issue is the dietary supply of antioxidants before intervention with these agents is started in RCTs and animal studies. For example, in the aforementioned RCT with selenized yeast, the risk of prostate cancer was only reduced in men who had low baseline selenium levels. [121] Data on this issue from the SELECT trial are not (yet) available. In most animal studies, baseline diets were fully selenium-sufficient and supplementation might not have increased the antioxidant status further. [85],[101] Indeed, we did not discover that selenomethionine prevented oxidative DNA damage or that it induced expression or activity of GPx or SOD antioxidant enzymes in such an experiment with rats [Ozten and Bosland, unpublished data].
  • For selenium, another important issue is the dietary forms of this agent that are studied, because they can differ in bioactivation pathways. [122] Selenium has different forms, including various organoselenium compounds such as selenomethionine, Se-methylselenocysteine, and methylseleninic acid, which does not naturally occur, as well as inorganic selenium compounds such as selenite. [123] Each form can trigger different metabolic pathways, leading to differences in their cancer suppressing activity. [124]
  • There are many dietary factors that have significant antioxidant activity, in addition to their major biological effects, even though they are not commonly considered antioxidants. The soy isoflavone genistein is one such factor that has substantive antioxidant activity, through ROS scavenging and via up-regulation of the expression and activity of antioxidant enzymes at physiologically relevant doses, [35],[40],[41],[42] whereas many of its other potential anti-cancer properties, such as tyrosine kinase inhibition, may predominate only at unrealistically high dietary levels. [35],[36]

In conclusion, important antioxidants are likely to have highly non-linear dose-response relationships with respect to their anticancer activity and to have significant interactions with factors that are difficult or impossible to control in RCTs and even animal studies, but substantially modify antioxidant efficacy. Most troubling is the possibility that some antioxidants at physiologically achievable doses may have adverse, cancer-enhancing activity that may unpredictably vary among humans.


Translation of Preclinical Chemoprevention Efficacy Data

For translation of preclinical chemoprevention data to human testing in randomized clinical trials, several critical issues need to be considered, such as dose, form, and bioavailability of the agent, timing of treatment, clinical trial design, and predictive value of the preclinical models. The agent dose in preclinical studies is usually 40 – 80% of the maximally tolerated dose, but in humans lower doses may be required by regulatory agencies or deemed prudent by investigators. Naturally occurring chemoprevention agents are also often tested in animal models at doses higher than those physiologically relevant in humans, which may have different, sometimes potentially harmful effects. A recent report on such biphasic effects of genistein in preclinical models suggests the potential for harm at low, physiologically relevant doses. [34] The form of the agent used in animal studies, often mixed into the diet, may not be feasible in humans, for whom administration in tablets or capsules is typically used. The bioavailability of some agents with considerable in vitro cancer-inhibitory activity is poor, such as is the case for curcumin. [66] In addition, there is very little information about the bioavailability of any agent to the relevant target, prostate tissue. Only for lycopene are there data in this respect, but the metabolism of this and other compounds may be complex and result in the presence of metabolites with unknown activity in prostate tissue. [113] Thus, preclinical studies and subsequent RCTs must be coordinated, such that both form and bioavailability of the agents tested are considered and agent metabolism is addressed as well. Importantly, the timing of agent administration in animal studies and human clinical trials typically differs considerably; chemopreventive treatment of humans is typically not considered until middle age. Therefore, delayed administration of the agent under test must be included in the preclinical research phase, which has been proven feasible. [82] For some agents, such as green tea polyphenols and genistein, preventive activity in preclinical models has only been identified when treatment occurred early in life, [7],[8] which is obviously not feasible in humans.

Other important issues in translating preclinical data pertain to the study design of clinical prevention trials. [3],[125],[126] Following Phase I safety studies, short-term Phase II studies, with agent administration before radical prostatectomy, are needed, to further establish safety and generate data on efficacy using relevant intermediate end-points in the prostate tissue. Beyond the Phase II studies, trials of intermediate duration are needed prior to embarking on large Phase III studies. Several study designs have been proposed, most of which are applied to populations at high risk for prostate cancer, such as men with elevated PSA, but negative biopsies, men with high-grade PIN, but no cancer on biopsy, or men with a family history of prostate cancer. [3],[125],[126] One such type of intermediate trial involves treatment of men with recurring prostate cancer, with reduction in the rise of PSA in these men as the end-point. [3],[125],[126] The problem with this study design is that one cannot differentiate between the effects of the test agent on prostate cancer cell growth and effects on PSA expression, which are not necessarily linked and can even occur in opposite directions. One other intermediate trial design involves treatment of men at high risk of recurrence after radical prostatectomy. [3] This design not only includes a relatively low sample size (250 – 300 subjects) and short duration (two to three years of treatment), but focuses on prostate cancer that is clinically significant and potentially lethal. This is important because many prostate cancers currently detected in the USA have questionable or low clinical significance and may not need to be prevented. Thus, clinical trials that focus on clinically significant prostate cancer are crucial in developing chemopreventive agents that are active against aggressive, potentially lethal forms of prostate cancer. However, no such studies have been completed to date. Of note, two of the currently completed Phase III RCTs for the chemoprevention of prostate cancer, SELECT and PCPT, involve average risk men, whereas participants of the REDUCE trial had elevated risk of prostate cancer associated with elevated PSA levels. In one other RCT with men at increased risk of prostate cancer because of the presence of high grade PIN on biopsy, but no cancer [127] , the antiestrogen toremifene did not significantly reduce prostate cancer development in three years of follow-up [http://prostatecancerinfolink.net/risk-prevention/prevention-prostatecancer/other-trials/]. In all four studies, the majority of detected cancers were likely of low clinical significance but not distinguishable from potentially lethal cancers.

Predictive ability of preclinical models

The ability of preclinical models to predict the outcome of subsequent clinical trials is one of the most important issues in the translation of preclinical chemoprevention data. Preclinical studies of selenium and vitamin E, with rat models, have been uniformly negative, as indicated earlier, and were thus fully predictive of the negative outcome of SELECT. Similar preclinical model studies with antiandrogens [73],[74] were also predictive of the reduction in prostate cancer development in the PCPT and REDUCE trials with 5α-reductase inhibitors. [77],[78] Tamoxifen was not active in preventing prostate cancer in a rat model study, [74] predictive of the lack of significant efficacy of the antiestrogen toremifene. The predictive value of animal models for other chemoprevention agents is not clear because of the lack of definitive clinical trials. The limited clinical trials with silibinin, green tea polyphenols, lycopene, soy, and 4-HPR are insufficient to allow a formal definitive evaluation of the predictive ability of preclinical animal models for these agents.


Concluding Remarks

A well-coordinated and concerted effort to developing chemoprevention agents for prostate cancer, by applying a rational approach to translating relevant and reproducible preclinical data to validated clinical trials, focusing on agents that hold substantial promise, will be essential for producing preventive treatments that are substantially active against clinically significant disease without the potential for harm. Bioavailability of agents for the prostate, and systemic and prostatic metabolism of agents, may be critically important, but remains underappreciated, as there are few pertinent data from both preclinical models and human clinical trials. Antioxidants have not emerged as being active against prostate cancer development, while several naturally occurring agents have not been moved forward in translational approaches. Agents that target androgen mechanisms have reduced detection of prostate cancer, but it is uncertain whether these compounds reduce prostate cancer-specific mortality or significantly slow the disease progression. Other agents have met with a poorly coordinated approach to their development as chemopreventives and / or have been tested in limited or inconclusive clinical trials. Problems in this regard are: (1) Negative results (i.e., lack of activity) and potentially harmful effects of candidate agents are often not published, (2) chemoprevention is often not considered profitable by the pharmaceutical and food industries, limiting targeted investment, and (3) funding agencies are hesitant to put together cohesive and well-coordinated approaches to chemopreventive agent development, relying instead on investigator-initiated approaches that, almost by definition, are doomed to be uncoordinated. In addition, prostate cancer is a highly heterogeneous disease at the molecular level, impeding targeted chemopreventive drug development. Moreover, most chemopreventive agents have multiple complex activities that can be profoundly non-linear in relation to dose and interaction with other factors, of both genetic (e.g., polymorphisms in critical genes) and environmental nature (e.g., diet). Finally, prostate cancer, as a disease, presents us with some additional problems that pose significant challenges to designing chemoprevention clinical trials and interpreting their results: (a) Most prostate malignancies clinically detected in the US and other western countries are not clinically significant, in the sense that they do not lead to cancer-specific mortality; (b) the prevalence of microscopic-size prostate cancers often of doubtful clinical significance is very high in middle-aged and older men around the world; and (c) at present, it is difficult to differentiate clinically significant from insignificant cancers in a majority of the cases. The good news is that some of the currently available preclinical models appear to be predictive of the outcome of clinical trials and will provide useful data for the development of rational approaches to the chemoprevention of prostate cancer.


Note Added in Proof

In a just published article, dietary supplementation of healthy men with vitamin E was reported to significantly increase risk of prostate cancer in the SELECT study, with a hazard ratio of 1.17 (99% confidence interval 1.004-1.36; P = 0.008). [128]


Acknowledgments

The authors want to acknowledge their collaborations with David L. McCormick reflected in some of the studies referred to in this article. The study described in this review was supported in part by NIH grant Nos. CA103215, CA104334, CA 116195, and R03 CA136027 (to M.C. Bosland) and NCI contract No.1-CN-251017 (to D.L. McCormick).

 

References

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.  Back to cited text no. 1
    
2. Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ, et al. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: An autopsy study of 249 cases. In Vivo 1994;8:439-43.  Back to cited text no. 2
    
3. Bosland MC, McCormick DL, Melamed J, Walden PD, Zeleniuch-Jacquotte A, Lumey LH. Chemoprevention strategies for prostate cancer. Eur J Cancer Prev 2002;11 Suppl 2:S18-27.  Back to cited text no. 3
    
4. Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, Kopelovitch L, et al. Chemoprevention of prostate cancer: Concepts and strategies. Eur Urol 1999;35:342-50.  Back to cited text no. 4
    
5. Steele VE, McCormick DL, Bosland MC, Rao KVN, Lubet RA. Identification of new agents for the prevention of prostate cancer using preclinical animal models. AACR Meeting Abstracts 2004;2004:938-c-.  Back to cited text no. 5
    
6. Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A 2001;98:10350-5.  Back to cited text no. 6
    
7. Adhami VM, Siddiqui IA, Sarfaraz S, Khwaja SI, Hafeez BB, Ahmad N, et al. Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease. Clin Cancer Res 2009;15:1947-53.  Back to cited text no. 7
    
8. Harper CE, Patel BB, Wang J, Eltoum IA, Lamartiniere CA. Epigallocatechin-3-Gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: Mechanisms of action. Prostate 2007;67:1576-89.  Back to cited text no. 8
    
9. Bosland MC, Horton L, Weir R. Green tea extract does not protect against prostate cancer induction by MNU and testosterone in WU rats. AACR Meeting Abstracts 2005;2005:1428.  Back to cited text no. 9
    
10. Condon MS, Agarwal S, van Weerden W, Bosland MC. Effects of green tea extract and caffeine on the growth of rat prostate cancer cells and the human prostate cancer xenograft PC346. Proc Am Assoc Res 2003;44:1100-1.  Back to cited text no. 10
    
11. Liao S, Hiipakka RA. Selective inhibition of steroid 5 alpha-reductase isozymes by tea epicatechin-3-gallate and epigallocatechin-3-gallate. Biochem Biophys Res Commun 1995; 214:833-8.  Back to cited text no. 11
    
12. Chuu CP, Chen RY, Kokontis JM, Hiipakka RA, Liao S. Suppression of androgen receptor signaling and prostate specific antigen expression by (-)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett 2009;275:86-92.  Back to cited text no. 12
    
13. Siddiqui IA, Asim M, Hafeez BB, Adhami VM, Tarapore RS, Mukhtar H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. Faseb J 2011;25:1198-207.  Back to cited text no. 13
    
14. Cho YM, Takahashi S, Asamoto M, Suzuki S, Tang M, Shirai T. Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model. Prostate Cancer Prostatic Dis 2007;10:378-83.  Back to cited text no. 14
    
15. Caporali A, Davalli P, Astancolle S, D’Arca D, Brausi M, Bettuzzi S, et al. The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. Carcinogenesis 2004;25:2217-24.  Back to cited text no. 15
    
16. Chiaverotti T, Couto SS, Donjacour A, Mao JH, Nagase H, Cardiff RD, et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol 2008;172:236-46.  Back to cited text no. 16
    
17. Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 2006;66:1234-40.  Back to cited text no. 17
    
18. Brausi M, Rizzi F, Bettuzzi S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol 2008;54:472-3.  Back to cited text no. 18
    
19. Raina K, Blouin MJ, Singh RP, Majeed N, Deep G, Varghese L, et al. Dietary feeding of silibinin inhibits prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 2007;67:11083-91.  Back to cited text no. 19
    
20. Singh RP, Raina K, Sharma G, Agarwal R. Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice. Clin Cancer Res 2008;14:7773-80.  Back to cited text no. 20
    
21. Raina K, Rajamanickam S, Singh RP, Deep G, Chittezhath M, Agarwal R. Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 2008;68:6822-30.  Back to cited text no. 21
    
22. National Toxicology Program. Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20-6) in F344 / N rats and B6C3F1 mice (Feed Studies). Natl Toxicol Program Tech Rep Ser 2011:1-177.  Back to cited text no. 22
    
23. Flaig TW, Glodé M, Gustafson D, van Bokhoven A, Tao Y, Wilson S, et al. A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate 2010;70:848-55.  Back to cited text no. 23
    
24. Harper CE, Cook LM, Patel BB, Wang J, Eltoum IA, Arabshahi A, et al. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats. Prostate 2009;69:1668-82.  Back to cited text no. 24
    
25. Wang J, Eltoum IE, Carpenter M, Lamartiniere CA. Genistein mechanisms and timing of prostate cancer chemoprevention in lobund-wistar rats. Asian Pac J Cancer Prev 2009;10:143-50.  Back to cited text no. 25
    
26. Wang J, Eltoum IE, Lamartiniere CA. Genistein chemoprevention of prostate cancer in TRAMP mice. J Carcinog 2007;6:3.  Back to cited text no. 26
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27. Wang J, Eltoum IE, Lamartiniere CA. Dietary genistein suppresses chemically induced prostate cancer in Lobund-Wistar rats. Cancer Lett 2002;186:11-8.  Back to cited text no. 27
    
28. Lamartiniere CA, Cotroneo MS, Fritz WA, Wang J, Mentor-Marcel R, Elgavish A. Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr 2002;132:552S-8S.  Back to cited text no. 28
    
29. McCormick DL, Johnson WD, Bosland MC, Lubet RA, Steele VE. Chemoprevention of rat prostate carcinogenesis by soy isoflavones and by Bowman-Birk inhibitor. Nutr Cancer 2007; 57:184-93.  Back to cited text no. 29
    
30. Pollard M, Wolter W. Prevention of spontaneous prostate-related cancer in Lobund-Wistar rats by a soy protein isolate / isoflavone diet. Prostate 2000;45:101-5.  Back to cited text no. 30
    
31. Mentor-Marcel R, Lamartiniere CA, Eltoum IE, Greenberg NM, Elgavish A. Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP). Cancer Res 2001;61:6777-82.  Back to cited text no. 31
    
32. Onozawa M, Kawamori T, Baba M, Fukuda K, Toda T, Sato H, et al. Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats. Jpn J Cancer Res 1999;90:393-8.  Back to cited text no. 32
    
33. El Touny LH, Banerjee PP. Akt GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype. Carcinogenesis 2007;28:1710-7.  Back to cited text no. 33
    
34. El Touny LH, Banerjee PP. Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Res 2009;69:3695-703.  Back to cited text no. 34
    
35. Peterson G. Evaluation of the biochemical targets of genistein in tumor cells. J Nutr 1995;125(3 Suppl):784S-9S.  Back to cited text no. 35
    
36. Linassier C, Pierre M, Le Pecq JB, Pierre J. Mechanisms of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem Pharmacol 1990;39:187-93.  Back to cited text no. 36
    
37. Holzbeierlein JM, McIntosh J, Thrasher JB. The role of soy phytoestrogens in prostate cancer. Current Opin Urol 2005;15:17-22.  Back to cited text no. 37
    
38. Sarkar FH, Li Y. Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer Metastasis Rev 2002;21:265-80.  Back to cited text no. 38
    
39. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998;139:4252-63.  Back to cited text no. 39
    
40. Guo Q, Rimbach G, Moini H, Weber S, Packer L. ESR and cell culture studies on free radical-scavenging and antioxidant activities of isoflavonoids. Toxicology 2002;179:171-80.  Back to cited text no. 40
    
41. Ruiz-Larrea MB, Mohan AR, Paganga G, Miller NJ, Bolwell GP, Rice-Evans CA. Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res 1997;26:63-70.  Back to cited text no. 41
    
42. Suzuki K, Koike H, Matsui H, Ono Y, Hasumi M, Nakazato H, et al. Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer 2002;99:846-52.  Back to cited text no. 42
    
43. Setchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr 2010;140:1355S-62S.  Back to cited text no. 43
    
44. Setchell KD, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr 2002;132:3577-84.  Back to cited text no. 44
    
45. Lund TD, Munson DJ, Haldy ME, Setchell KD, Lephart ED, Handa RJ. Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reprod 2004;70:1188-95.  Back to cited text no. 45
    
46. Setchell KD, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, et al. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr 2005;81:1072-9.  Back to cited text no. 46
    
47. Bovee TF, Schoonen WG, Hamers AR, Bento MJ, Peijnenburg AA. Screening of synthetic and plant-derived compounds for (anti)estrogenic and (anti)androgenic activities. Anal Bioanal Chem 2008;390:1111-9.  Back to cited text no. 47
    
48. Maskarinec G, Morimoto Y, Hebshi S, Sharma S, Franke AA, Stanczyk FZ. Serum prostate-specific antigen but not testosterone levels decrease in a randomized soy intervention among men. Eur J Clin Nutr 2006;60:1423-9.  Back to cited text no. 48
    
49. Adams KF, Chen C, Newton KM, Potter JD, Lampe JW. Soy isoflavones do not modulate prostate-specific antigen concentrations in older men in a randomized controlled trial. Cancer Epidemiol Biomarkers Prev 2004;13:644-8.  Back to cited text no. 49
    
50. Kwan W, Duncan G, Van Patten C, Liu M, Lim J. A phase II trial of a soy beverage for subjects without clinical disease with rising prostate-specific antigen after radical radiation for prostate cancer. Nutr Cancer 2010;62:198-207.  Back to cited text no. 50
    
51. Pendleton JM, Tan WW, Anai S, Chang M, Hou W, Shiverick KT, et al. Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy. BMC Cancer 2008;8:132.  Back to cited text no. 51
    
52. deVere White RW, Tsodikov A, Stapp EC, Soares SE, Fujii H, Hackman RM. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer 2010;62:1036-43.  Back to cited text no. 52
    
53. Grainger EM, Schwartz SJ, Wang S, Unlu NZ, Boileau TW, Ferketich AK, et al. A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen. Nutr Cancer 2008;60:145-54.  Back to cited text no. 53
    
54. Schröder FH, Roobol MJ, Boevé ER, de Mutsert R, Zuijdgeest-van Leeuwen SD, Kersten I, et al. Randomized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement. Eur Urol 2005;48:922-30; discussion 930-1.  Back to cited text no. 54
    
55. Joniau S, Goeman L, Roskams T, Lerut E, Oyen R, Van Poppel H. Effect of nutritional supplement challenge in patients with isolated high-grade prostatic intraepithelial neoplasia. Urology 2007;69:1102-6.  Back to cited text no. 55
    
56. Dalais FS, Meliala A, Wattanapenpaiboon N, Frydenberg M, Suter DA, Thomson WK, et al. Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology 2004;64:510-5.  Back to cited text no. 56
    
57. Fleshner NE, Kapusta L, Donnelly B, Tanguay S, Chin J, Hersey K, et al. Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium. J Clin Oncol 2011;29:2386-90.  Back to cited text no. 57
    
58. Swami S, Krishnan AV, Moreno J, Bhattacharyya RS, Gardner C, Brooks JD, et al. Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients. Int J Cancer 2009;124:2050-9.  Back to cited text no. 58
    
59. Hamilton-Reeves JM, Rebello SA, Thomas W, Kurzer MS, Slaton JW. Effects of soy protein isolate consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer. Nutr Cancer 2008;60:7-13.  Back to cited text no. 59
    
60. Hamilton-Reeves JM, Rebello SA, Thomas W, Slaton JW, Kurzer MS. Isoflavone-rich soy protein isolate suppresses androgen receptor expression without altering estrogen receptor-beta expression or serum hormonal profiles in men at high risk of prostate cancer. J Nutr 2007;137:1769-75.  Back to cited text no. 60
    
61. Schwartz GG. Vitamin D and intervention trials in prostate cancer: from theory to therapy. Ann Epidemiol 2009;19:96-102.  Back to cited text no. 61
    
62. Mucci LA, Spiegelman D. Vitamin D and prostate cancer risk–a less sunny outlook? J Natl Cancer Inst 2008;100:759-61.  Back to cited text no. 62
    
63. Gilbert R, Martin RM, Beynon R, Harris R, Savovic J, Zuccolo L, et al. Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 2011;22:319-40.  Back to cited text no. 63
    
64. Perez-Stable CM, Schwartz GG, Farinas A, Finegold M, Binderup L, Howard GA, et al. The G gamma / T-15 transgenic mouse model of androgen-independent prostate cancer: target cells of carcinogenesis and the effect of the vitamin D analogue EB 1089. Cancer Epidemiol Biomarkers Prev 2002;11:555-63.  Back to cited text no. 64
    
65. Banach-Petrosky W, Ouyang X, Gao H, Nader K, Ji Y, Suh N, et al. Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice. Clin Cancer Res 2006;12:5895-901.  Back to cited text no. 65
    
66. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm 2007;4:807-18.  Back to cited text no. 66
    
67. Barve A, Khor TO, Hao X, Keum YS, Yang CS, Reddy B, et al. Murine prostate cancer inhibition by dietary phytochemicals–curcumin and phenyethylisothiocyanate. Pharm Res 2008;25:2181-9.  Back to cited text no. 67
    
68. Imaida K, Tamano S, Kato K, Ikeda Y, Asamoto M, Takahashi S, et al. Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis. Carcinogenesis 2001;22:467-72.  Back to cited text no. 68
    
69. Harper CE, Patel BB, Wang J, Arabshahi A, Eltoum IA, Lamartiniere CA. Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis 2007;28:1946-53.  Back to cited text no. 69
    
70. Seeni A, Takahashi S, Takeshita K, Tang M, Sugiura S, Sato SY, et al. Suppression of prostate cancer growth by resveratrol in the transgenic rat for adenocarcinoma of prostate (TRAP) model. Asian Pac J Cancer Prev 2008;9:7-14.  Back to cited text no. 70
    
71. Adhami VM, Khan N, Mukhtar H. Cancer chemoprevention by pomegranate: laboratory and clinical evidence. Nutr Cancer 2009;61:811-5.  Back to cited text no. 71
    
72. Akaza H, Tsukamoto S, Morita T, Yamauchi A, Onozawa M, Shimazui T, Ideyama Y, Shirai T. Promoting effects of antiandrogenic agents on rat ventral prostate carcinogenesis induced by 3,2′-dimethyl-4-aminobiphenyl (DMAB). Prostate Cancer Prostatic Dis 2000;3:115-119.  Back to cited text no. 72
    
73. Tsukamoto S, Akaza H, Onozawa M, Shirai T, Ideyama Y. A five-alpha reductase inhibitor or an antiandrogen prevents the progression of microscopic prostate carcinoma to macroscopic carcinoma in rats. Cancer 1998;82:531-7.  Back to cited text no. 73
    
74. McCormick DL, Johnson WD, Lubet RA, Steele VE, Bosland MC. Differential chemopreventive activity of the antiandrogen, flutamide, and the antiestrogen, tamoxifen, in the rat prostate. Proc Am Assoc Cancer Res 2002;43:640.  Back to cited text no. 74
    
75. Goodman PJ, Tangen CM, Crowley JJ, Carlin SM, Ryan A, Coltman CA Jr, et al. Implementation of the Prostate Cancer Prevention Trial (PCPT). Control Clin Trials 2004;25:203-22.  Back to cited text no. 75
    
76. Andriole G, Bostwick D, Brawley O, Gomella L, Marberger M, Tindall D, et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol 2004;172:1314-7.  Back to cited text no. 76
    
77. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010;362:1192-202.  Back to cited text no. 77
    
78. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-24.  Back to cited text no. 78
    
79. Gann PH. Prostate cancer. A closer look at the initial results from the REDUCE trial. Nat Rev Urol 2010;7:535-7.  Back to cited text no. 79
    
80. Cohen YC, Liu KS, Heyden NL, Carides AD, Anderson KM, Daifotis AG, et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2007;99:1366-74.  Back to cited text no. 80
    
81. Bosland MC, Cremers RG, Kiemeney LA. Words of wisdom. Re: effect of dutasteride on the risk of prostate cancer. Eur Urol 2010;58:631-2.  Back to cited text no. 81
    
82. Rao KV, Johnson WD, Bosland MC, Lubet RA, Steele VE, Kelloff GJ, et al. Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone. Cancer Res 1999;59:3084-9.  Back to cited text no. 82
    
83. McCormick DL, Johnson WD, Kozub NM, Rao KV, Lubet RA, Steele VE, et al. Chemoprevention of rat prostate carcinogenesis by dietary 16alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone. Carcinogenesis 2007;28:398-403.  Back to cited text no. 83
    
84. McCormick DL, Rao KV, Steele VE, Lubet RA, Kelloff GJ, Bosland MC. Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid. Cancer Res 1999;59:521-4.  Back to cited text no. 84
    
85. McCormick DL, Rao KV, Dooley L, Steele VE, Lubet RA, Kelloff GJ, et al. Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats. Cancer Res 1998;58:3282-8.  Back to cited text no. 85
    
86. Pienta KJ, Esper PS, Zwas F, Krzeminski R, Flaherty LE. Phase II chemoprevention trial of oral fenretinide in patients at risk for adenocarcinoma of the prostate. Am JClin Oncol 1997;20:36-9.  Back to cited text no. 86
    
87. Urban D, Myers R, Manne U, Weiss H, Mohler J, Perkins D, et al. Evaluation of biomarker modulation by fenretinide in prostate cancer patients. Eur Urol 1999;35:429-38.  Back to cited text no. 87
    
88. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 2011;711:193-201.  Back to cited text no. 88
    
89. Khandrika L, Kumar B, Koul S, Maroni P, Koul HK. Oxidative stress in prostate cancer. Cancer Lett 2009;282:125-36.  Back to cited text no. 89
    
90. Klaunig JE, Wang Z, Pu X, Zhou S. Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicology Appl Pharmacol 2011;254:86-99.  Back to cited text no. 90
    
91. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007;7:256-69.  Back to cited text no. 91
    
92. Lonkar P, Dedon PC. Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates. Int J Cancer 2011;128:1999-2009.  Back to cited text no. 92
    
93. Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995;62(6 Suppl):1427S-30S.  Back to cited text no. 93
    
94. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 2003;290:476-85.  Back to cited text no. 94
    
95. Zhuo P, Diamond AM. Molecular mechanisms by which selenoproteins affect cancer risk and progression. Biochim Biophys Acta 2009;1790:1546-54.  Back to cited text no. 95
    
96. Steinbrenner H, Sies H. Protection against reactive oxygen species by selenoproteins. Biochim Biophys Acta 2009;1790:1478-85.  Back to cited text no. 96
    
97. Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:1957-63.  Back to cited text no. 97
    
98. Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull BW, Slate EH, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 1998;81:730-4.  Back to cited text no. 98
    
99. Duffield-Lillico AJ, Slate EH, Reid ME, Turnbull BW, Wilkins PA, Combs GF Jr, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. J Natl Cancer Inst 2003;95:1477-81.  Back to cited text no. 99
    
100. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301:39-51.  Back to cited text no. 100
    
101. Ozten N, Horton L, Lasano S, Bosland MC. Selenomethionine and alpha-tocopherol do not inhibit prostate carcinogenesis in the testosterone plus estradiol-treated NBL rat model. Cancer Prev Res (Phila) 2010;3:371-80.  Back to cited text no. 101
    
102. McCormick DL, Rao KV, Johnson WD, Bosland MC, Lubet RA, Steele VE. Null activity of selenium and vitamin e as cancer chemopreventive agents in the rat prostate. Cancer Prev Res (Phila) 2010;3:381-92.  Back to cited text no. 102
    
103. Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74:714-22.  Back to cited text no. 103
    
104. Barve A, Khor TO, Nair S, Reuhl K, Suh N, Reddy B, et al. Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice. Int J Cancer 2009;124:1693-9.  Back to cited text no. 104
    
105. Takahashi S, Takeshita K, Seeni A, Sugiura S, Tang M, Sato SY, et al. Suppression of prostate cancer in a transgenic rat model via gamma-tocopherol activation of caspase signaling. Prostate 2009;69:644-51.  Back to cited text no. 105
    
106. Kavanaugh CJ, Trumbo PR, Ellwood KC. The U.S. Food and Drug Administration’s evidence-based review for qualified health claims: tomatoes, lycopene, and cancer. J Natl Cancer Inst 2007;99:1074-85.  Back to cited text no. 106
    
107. Bosland MC, Johnson WD, Cwik MJ, Lubet RA, Steele VE, McCormick DL. Lack of chemopreventive activity of lycopene in the Wistar-Unilever rat prostate cancer model. AACR Meeting Abstracts 2004;2004:900-c-.  Back to cited text no. 107
    
108. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK. Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst 2003;95:1578-86.  Back to cited text no. 108
    
109. Konijeti R, Henning S, Moro A, Sheikh A, Elashoff D, Shapiro A, et al. Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 2010;70:1547-54.  Back to cited text no. 109
    
110. Venkateswaran V, Klotz LH, Ramani M, Sugar LM, Jacob LE, Nam RK, et al. A combination of micronutrients is beneficial in reducing the incidence of prostate cancer and increasing survival in the Lady transgenic model. Cancer Prev Res (Phila) 2009;2:473-83.  Back to cited text no. 110
    
111. Bowen P, Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood) 2002;227:886-93.  Back to cited text no. 111
    
112. van Breemen RB. How do intermediate endpoint markers respond to lycopene in men with prostate cancer or benign prostate hyperplasia? J Nutr 2005;135:2062S-4S.  Back to cited text no. 112
    
113. van Breemen RB, Sharifi R, Viana M, Pajkovic N, Zhu D, Yuan L, et al. Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial. Cancer Prev Res (Phila) 2011;4:711-8.  Back to cited text no. 113
    
114. Lee KW, Lee HJ. Biphasic effects of dietary antioxidants on oxidative stress-mediated carcinogenesis. Mech Ageing Dev 2006;127:424-31.  Back to cited text no. 114
    
115. Calabrese V, Cornelius C, Trovato A, Cavallaro M, Mancuso C, Di Rienzo L, et al. The hormetic role of dietary antioxidants in free radical-related diseases. Curr Pharm Des 2010;16:877-83.  Back to cited text no. 115
    
116. Chiang EC, Shen S, Kengeri SS, Xu H, Combs GF, Morris JS, et al. Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis. Dose-response 2009;8:285-300.  Back to cited text no. 116
    
117. Li H, Kantoff PW, Giovannucci E, Leitzmann MF, Gaziano JM, Stampfer MJ, et al. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Res 2005;65:2498-504.  Back to cited text no. 117
    
118. Mao C, Qiu LX, Zhan P, Xue K, Ding H, Du FB, et al. MnSOD Val16Ala polymorphism and prostate cancer susceptibility: a meta-analysis involving 8,962 subjects. J Cancer Res Clin Oncol 2010;136:975-9.  Back to cited text no. 118
    
119. Liwei L, Chunyu L, Ruifa H: Association between manganese superoxide dismutase gene polymorphism and risk of prostate cancer: a meta-analysis. Urology 2009, 74(4):884-888.  Back to cited text no. 119
    
120. Kandas NO, Randolph C, Bosland MC. Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutr Cancer 2009;61:251-64.  Back to cited text no. 120
    
121. Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int 2003;91:608-12.  Back to cited text no. 121
    
122. Navarro-Alarcon M, Cabrera-Vique C. Selenium in food and the human body: a review. Sci Total Environ 2008;400:115-41.  Back to cited text no. 122
    
123. Abdulah R, Miyazaki K, Nakazawa M, Koyama H. Chemical forms of selenium for cancer prevention. J Trace Elem Med Biol 2005;19:141-50.  Back to cited text no. 123
    
124. Zhang J, Wang L, Li G, Anderson LB, Xu Y, Witthuhn B, et al. Mouse prostate proteomes are differentially altered by supranutritional intake of four selenium compounds. Nutr Cancer 2011;63:778-89.  Back to cited text no. 124
    
125. Lee JJ, Lieberman R, Sloan JA, Piantadosi S, Lippman SM. Design considerations for efficient prostate cancer chemoprevention trials. Urology 2001;57(4 Suppl 1):205-12.  Back to cited text no. 125
    
126. Lieberman R. Prostate cancer chemoprevention: Strategies for designing efficient clinical trials. Urology 2001;57(4 Suppl 1):224-9.  Back to cited text no. 126
    
127. Price D, Stein B, Sieber P, Tutrone R, Bailen J, Goluboff E, et al. Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol 2006;176:965-70; discussion 970-1  Back to cited text no. 127
    
128. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306:1549-56.  Back to cited text no. 128
    


 Authors


Dr. Nur Özten, Nur Ozten Department of Pathology University of Illinois at Chicago 840 South Wood Street, Room 130 CSN, MC 847 Chicago, IL 60612 USA
Dr. Maarten C. Bosland, Maarten C. Bosland Department of Pathology University of Illinois at Chicago 840 South Wood Street, Room 130 CSN, MC 847 Chicago, IL 60612 USA