Selenium, an essential nutrient required for a number of metabolically important enzymes, can inhibit cancer development in a variety of experimental animal models. In 1996, Clark and co-workers reported the results of a 13-year, randomized, placebo-controlled study with older Americans that showed that the daily use of an oral supplement of selenium substantially reduced the risk of several cancers, most notably cancer of the prostate (67% risk reduction). These results suggested the exciting possibility that significant reductions in cancer risk may be realized with fairly low and certainly nontoxic doses of selenium that could readily be achieved by diet supplementation and/or food fortification. For this reason, the National Cancer Institute has committed substantial support for a further, large-scale clinical trial (the PCPT-2 SELECT trial) to evaluate whether selenium +/- vitamin E decreases the incidence of prostate cancer.

Despite the growing enthusiasm for selenium as a potential chemopreventive agent, the molecular mechanisms by which selenium modulates key events in the multistep process of prostate carcinogenesis remain unclear. Present understanding is that various selenium compounds can inhibit carcinogenesis in several ways. Some of these involve the nutritional role of selenium as an essential constituent of a number of antioxidant enzymes, including glutathione peroxidase. Other mechanisms appear to involve the conversion of selenium to non-protein bound anticarcinogenic metabolites, such as methylselenol.

In general, most information on the mechanisms of anticancer agents comes from studies using animal tumor models because these experiments, unlike human clinical trials, can yield a full complement of biological specimens (i.e., blood, tissues) for laboratory evaluation. In the case of prostate cancer, such work has been hampered by the fact that only one non-human species, the dog, develops this cancer spontaneously. Our research group is uniquely experienced in studying the naturally occurring prostate cancer of dogs. Our experience indicates that the dog provides a unique animal model system to study the effects of chemopreventive agents on cellular processes (e.g., regulation of cell death, cell proliferation, DNA damage) within the prostate that are critical to human prostate carcinogenesis. In our Phase I Idea Development Award, ¿In Vivo Testing of Chemopreventive Agents Using the Dog Model of Spontaneous Prostate Carcinogenesis,¿ we conducted laboratory studies that generated new information on possible mechanisms by which selenium exerts its prostate cancer protective effects: (1) daily selenium supplementation for 6 months in elderly, 9-10.5 year-old, sexually intact beagle dogs (physiologically equivalent to 62-69 year old men) results in a significant reduction in DNA damage in the prostate; and (2) the DNA damage sparing effect of selenium may be mediated by upregulation of the programmed cell death (apoptosis) of prostate epithelial cells and possibly by a reduction in the concentration of androgens within the prostate.

The goal of this Phase II Idea Development Award is to define further the possible mechanisms by which selenium supplementation exerts a prostate cancer protective effect. Specifically, we will address the possibility of an interaction between selenium and the antiandrogen drug finasteride, which is currently being evaluated as a chemopreventive agent in the PCPT-1 trial. The effects of selenium and antiandrogens on the aged dog prostate will be studied in terms of cellular processes involved in cancer development (cell death, cell proliferation, DNA damage) as well as those that are related to selenium metabolism (selenium levels and the activities of selenium-containing enzymes within the prostate). This type of work, which is necessary for understanding the mechanisms of the anticancer effects of selenium, is simply not feasible in human subjects. The innovation of this proposal is that we will utilize a unique animal model system to generate important and useful information necessary to develop selenium as a practical means of prostate cancer chemoprevention in humans. The importance of this proposal is that our studies complement ongoing human chemoprevention trials. The results of these studies will guide the design of future human trials in terms of selenium form and dose, and interactions with other chemopreventive agents.