Predisposition to any cancer can be considered in terms of environmental and extrinsic factors, such as foods and interventions, and intrinsic or inherent susceptibility related to the person’s genes apportioned at conception. For prostate cancer in particular, many people hold strong opinions regarding various strategies to avoid contracting it and for treatment of the condition, very often without any clear evidence of beneficial effect. It should be borne in mind that many advocated supplements and unconventional therapies are expensive and, although some ultimately may be proven to be of benefit, many will not and some may be harmful.
A body of epidemiological data links high meat consumption and a diet rich in saturated fats with an increased risk of prostate cancer. (175-177). As stated in the previous section, alpha-methylacyl-CoA racemase (AMCR), an enzyme involved in oxidation of fatty acid molecules, has been implicated in the link between high fat diets and prostate cancer (154).
Fatty acids in dietary fats can be divided into essential and non-essential with the former consisting of omega-6 (linoleic acid derived) and omega-3 fatty acids (which are linolenic acid in origin). Current evidence suggests that omega-3 fatty acids offer a protective role. (178, 179).
Mutagens in cooked meats and fat, which include heterocyclic amines and polycyclic aromatic hydrocarbons, are known to be activated by cytochrome p450 and N-acetyl transferase enzymes in the prostate to produce an increase in markers of dietary stress. (180). These, in turn, generate reactive oxygen species (ROS) leading to mutation of DNA base pairs and oncogene expression. Another mode of action invoked is degradation of omega-6 fatty acids via the arachidonic acid pathway production of prostaglandin and lipoxygenase products which, in addition to resulting in inflammation, are known to decrease apoptosis, stimulate proliferation and induce angiogenesis. (181-184).
The relevance of the anti-oxidant lycopene, an isomer of β-carotene, has been reported in relation to various cancers, including prostate, in a number of epidemiological studies. Lycopene, which is the carotenoid responsible for the red colour in tomatoes is thought to have a protective effect as an inverse relationship has been observed between tomato intake or blood lycopene level and the risk of cancer. (180, 185, 186)
The essential micronutrient selenium is present in water and food, especially seafood, meats and Brazil nuts. In countries with selenium-poor soils such as New Zealand, locally produced foodstuffs may be low in selenium content. A number of epidemiological studies have reported an increased risk of prostate and other cancers with selenium deficiency and, conversely, a reduced incidence of prostate cancer with selenium supplementation. (187, 188).
Selenium is a component of many proteins, such as glutathione peroxidase which is a key enzyme in surveillance against oxidative stress, involved in maintenance of genomic stability. (189). In addition to an effect in reducing tumour initiation, selenium is considered to have an inhibitory effect in relation to progression by blocking cell-cycle arrest through down-regulation of CDK1, CDK2 and cyclin A and activation of p19/INK4d and p21/WAF1. (190). Gianduzzo et al (2003) (191) demonstrated in a randomised, controlled trial that oral selenium supplementation resulted in significantly higher levels of this compound in prostatic tissue removed at transurethral resection of the prostate (TURP). Importantly, these investigators also found that blood and prostate levels correlated poorly, suggesting that peripheral blood measurements are a poor indicator of prostatic selenium content (191).
Vitamin E is present in a wide range of foods which include vegetables, vegetable oils, nuts and egg yolks. Through its most active form, α-tocopherol, vitamin E causes G1 cell-cycle arrest via cell regulatory proteins D1, D3 and E and cdk2 and cdk4. (190) In the Alpha-Tocopherol, Beta-Carotene study in the United States, a one-third reduction in prostate cancer incidence and a 40% reduction in prostate cancer deaths were reported in men taking vitamin E (The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, 1994)
Currently, 2 large prevention studies are in progress to evaluate selenium and vitamin E supplementation. SELECT (Selenium and Vitamin E Cancer Prevention Trial) is American based and APPOSE (Australian Prostate cancer Prevention Trial Using Selenium) are expected to produce results in the next few years (180, 192).
Dietary differences between people living in Asian countries and those in the West correlate with marked differences in prostate cancer incidence. However, with adoption of western dietary patterns, there is an increase incidence of diseases of affluence, such as diabetes mellitus, breast, colorectal and prostate cancer (193). These traditional differences have been attributed to the high content of soy, tofu and isoflavinoids in many traditional asian diets. (194, 195).
The major isoflavone components of soy, including genistein, daidzein and their metabolites, have been shown to inhibit benign and malignant prostatic epithelial cell growth, down-regulate androgen-related genes and reduce tumour growth in some animal models (190). Huang et al (2005) (94) reported inhibition of MMP-2 by genistein via MAPK and TGF-beta. This study suggested a physiological role for genestin and confirming epidemiological studies which demonstrated that dietary intake of genisten was associated with lower rates of metastatic prostate cancer . deVere-White et al (2005)(196) very recently presented their experience with GCP, a proprietary nutritional supplement, the major constituents of which are genestine and diadzin. The preparation functions as a tyrosine kinase inhibitor and facilitates entry of prostate cancer cells into apoptosis. For13 men on active surveillance for their prostate cancer, six months of GCP resulted in a lowering of PSA; the trial is ongoing (196).
Dalais et al (2004)(197) studied 29 men diagnosed with prostate cancer and scheduled to undergo RRP who were randomized to one of three groups; soy (high phytoestrogen), soy and linseed (high phytoestrogen), or wheat (low phytoestrogen) in the form of specially prepared breads. Their findings indicated that a daily diet containing four slices of a bread rich in soy grits favourably influenced the PSA level and the free/total PSA ratio in patients with prostate cancer, providing supportive evidence for epidemiological studies claiming that men who consume high phytoestrogen diets have a reduced risk of prostate cancer development and progression (197).
Schröder et al (2005) (198) reported on 49 patients with rising serum PSA levels after radical prostatectomy (n = 34) or radiotherapy (n = 15) who participated in a randomised, double-blind, placebo-controlled crossover study of a dietary supplement of soy, isoflavones, lycopene, silymarin and antioxidants as main ingredients. The soy-based dietary supplement delayed PSA progression in a significant fashion with a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods (198).
An integral part of most asian diets, green tea has had many benefits accorded to it, often through association with other dietary components. In terms of its affect on inhibiting prostate cancer development, it is thought to provide a benefit through the presence of polyphenols (also present in red wine) which induce apoptosis and inhibit proliferation via WAF1/p21 cell- cycle effects (190)
Continuous use of Nonsteroidal anti-inflammatory drugs (NSAIDs), in particular aspirin, has been reported to reduce the likelihood of development of several malignancies, including prostate cancer (199). Indeed, aspirin and other NSAIDs have been considered to decrease the risk of developing prostate cancer by 24-66% (200-2002)
Non-selective NSAIDS such as aspirin inhibit both cyclooxygenase (COX-1 & COX-2) enzymes with the COX-2 isoform believed to be the relevant one in terms of prostate cancer development. COX-2 converts arachidonic acid to prostaglandin so both non-specific and specific COX-2 inhibitors act at this site, although some specific COX-2 inhibitors may have other actions as well. Specific COX-2 inhibition by celecoxib and nimesulide has been reported to reduce expression of several androgen-inducible genes, repress androgen-receptor mediated activation of PSA and hK2 promoter activity and repress androgen receptor protein expression. (203).
Cost implications aside, the recent reporting of previously unappreciated serious side-effects with two prominent COX-2 inhibitors, rofecoxib and celecoxib, have resulted in some reluctance to change from using NSAIDS to selective COX-2 inhibitors for prostate cancer prophylaxis.
Based on the observations that androgens are necessary for the development of prostate cancer and that men with a congenital deficiency of the 5-α-reductase type 2 enzyme do not develop prostate cancer, a 7-year randomised, controlled trial with the drug finasteride was undertaken with 18 882 men who were >55 years, had a normal prostate on digital rectal examination and a PSA of <3 ng/ml.
The study was ended 15 months prematurely because the end-point had been reached and continuing the trial would not have changed the outcome. Men who received finasteride, which inhibits conversion of testosterone to dihydrotestosterone (DHT) by targeting the 5-α-reductase type 2 enzyme, had a prostate cancer prevalence reduction of 24.8% (24.4% to 18.4%. However, the prevalence of Gleason 7-10 tumours was higher in the finasteride arm (6.4% versus 5.1%) although 98% of the tumours were clinically localised. (204). Klein et al (2005) (205) have questioned the validity of the conclusion in relation to the rate of clinically-significant prostate cancer detection in this trial. They present a model of risk and benefit that estimates the potential influence of histological artefact (due to finasteride-induced effect on prostatic epithelial appearances) in the assignment of excess risk for high-grade disease and possible overdetection bias introduced by finasteride-induced volume reduction in prostates for the treated patients (205).
A further industry-sponsored study, the REDUCE (Reduction by DUtasteride in prostate cancer Events) trial is in progress. In this randomised, controlled study involving 8 000 men with PSA values between 2 and 10 ng/ml dutasteride, which inhibits both isoforms of the 5-α-reductase enzyme, is being used in the treatment arm. All patients in this trial are being biopsied at least twice during the study unlike the finasteride study in which prostatic biopsies were recommended if the annual PSA (adjusted for the effect of finasteride) exceeded 4 ng/ml or if the digital rectal examination was abnormal.
Recent research suggests that inhibition of the irreversible action of 5α-reductase to convert testosterone to the more transcriptionally active dihydrotestosterone may have untoward effects in relation to prostate cancer. Dihydrotestosterone in turn is hydroxylated to 3α-diol and 3β-Adiol which do not bind to the androgen receptor but have a strong affinity for oestrogen receptors, the result of which is thought to have a direct effect on prostate development and homeostasis (206). The binding of 3β-Adiol to oestrogen receptor beta (ERβ) induces expression of the cell adhesion molecule E-cadherin, loss of which is associated with a more aggressive phenotype in prostate cancer cells (38).
The genesis of prostate cancer is multifactorial, with changes arising over a considerable period of time. Consequently, with respect to preventative or ameliorating measures, it is axiomatic that these should be implemented early and sustained for longer rather than shorter duration if their beneficial effects are to be maximised.