Zinc and prostate cancer

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Etiologic factors that initiate and enhance the progression of prostate malignancy are beginning to emerge. One major research focus is the role of diet and nutrition. Dietary factors possibly linked to prostate cancer are numerous; however, the most provocative data focus attention upon those nutrients and phytochemicals involved in oxidative defense. A clear understanding of how anti-oxidants may protect the prostate from the genetic damage that is associated with tumor development remains unclear. It is well established that the consumption of fruit and vegetables is associated with reduced risk of many cancers.133,134 These strong and reproducible epidemiological associations have led to an interest in determining the specific components within whole foods responsible for this observed reduced risk. However, supplementation with certain anti-oxidant compounds has not been successful. The anti-oxidant ^-carotene which when provided as a dietary supplement to populations at high risk of lung cancer, in two independent trials, actually resulted in the early termination of these studies due to significantly increased incidence in the supplemented populations.135,136 As a result of the strikingly negative outcome of the ^-carotene trials, our own approach has shifted away from evaluating the health benefits of single dietary supplements to an approach with whole foods that contain an array of nutrients that are targeted to specific biological functions. Small clusters of cells representing the earliest stages of prostate cancer, in an apparently latent form, reside in millions of men (estimates up to 50%) of every race and culture of the world.137 Therefore, it can be deduced that initiating factors leading to changes in the local prostate environment can shift the balance in individuals whether to develop 'active' prostate cancer. Because prostate cancer is a disease of aging, hypotheses have been formulated that oxidative stress plays a potentially important role in the etiology of this disease, and thus most of the dietary intervention studies to date have focused on enhancing anti-oxidant status. This has been done by evaluating supplements of vitamin E,138 selenium139 or ^-carotene138,140 on risk of developing prostate cancer. Currently, a large chemoprevention trial, the selenium and Vitamin E Cancer Prevention Trial (SELECT), is underway to evaluate the effects of selenium and vitamin E either alone or in combination on prevention of prostate cancer.141 This study is based entirely on anti-oxidant function of these two nutrients using dietary supplementation. The outcome of this study will not be known for several years.

Zinc is a nutrient of particular interest in prostate cancer. Zinc plays an important role in protecting DNA from damage as an anti-oxidant and a component of many DNA repair proteins. Zinc is also unique in that it bears anti-oxidant,1 anti-inflammatory142 and pro-apoptotic activity.143,144 Thus, zinc supplementation has the potential to target multiple points of the carcino-genesis cascade (Figure 13.1). Normal human prostate accumulates the highest levels of zinc of any soft tissue in the body.145,146 However, a marked decrease in zinc content is associated with prostate cancer.147 149 Zinc deficiency also compromises hormone status and reproductive function in men.150 153 Several studies have implicated changes in zinc accumulation in the development and progression of prostate malignancy.154,155 There also exists some evidence that

PUTATIVE RISK FACTORS IN PROSTATE CANCER (GENETIC RISK, INFECTION, ELEVATED ESTROGEN & TESTOSTERONE)

OXIDATIVE DAMAGE TO PROSTATE DNA, PROTEIN AND LIPID

ZINC

(anti-inflammatory)

OXIDATIVE DAMAGE TO PROSTATE DNA, PROTEIN AND LIPID

ZINC

(anti-oxidant and T DNA repair)

INITIATION

TUMOR PROGRESSION

UNCONTROLLED PROLIFERATION

ZINC

(anti-proliferative)

PROSTATE CANCER

Figure 13.1 Potential inhibitory actions of zinc in prostate carcinogenesis increased dietary zinc is associated with a decrease in the incidence of prostate cancer.156 Currently it is unknown why the prostate accumulates high zinc concentrations. However, this phenomenon may render the prostate sensitive to changes in zinc intake. We have shown in various other cell types that changes in intracellular zinc have a dramatic effect on DNA damage and repair, and hence risk of cancer.105 It is possible that dietary zinc deficiency will increase an individual's risk of oxidative DNA damage in the prostate and prostate cancer. In addition, there appears to be a loss of zinc during prostate cancer. Thus, zinc need may be enhanced in prostate cancer patients. Zinc supplementation strategies may not only aid in the prevention of cancer, but could also play an important role in limiting its malignancy.

There is some controversy regarding the efficacy of zinc supplements for the prevention of prostate cancer. Several studies have shown that high cellular zinc levels inhibit prostate cancer cell growth.154,157,158 However, a recent epidemiological study has shown an increase in risk for prostate cancer with high zinc supplement use.159 Increased risk was seen in subjects with very high dose zinc supplement use (more than 100mg/day) or long-term zinc supplement use (10 or more years). The current upper level of intake for zinc is 40mg/day. Thus it is possible that these subjects could have been in the 'toxic' range for zinc intake. As with most therapeutics, higher doses do not always equate with an increase in efficacy.

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