Great hope for developing selenium as a practical approach for prostate cancer risk reduction was invested in SELECT, the largest-ever prostate cancer prevention trial [25
]. However, null findings dashed earlier optimism raised by the NPC Trial that daily selenium supplementation might lead to significant cancer risk reduction. Speculating on an explanation for these disappointing results, SELECT might have suffered from using SeMet, rather than Se-yeast employed in the NPC Trial [3
]. It was reasonable to believe that previously unforeseen differences in prostatic activity between SeMet and Se-yeast might be at the root of the discrepancy. Such a difference in cancer-protective potential might emanate from differences in their biodistribution [26
] or activity within the prostate (). We reasoned that a detailed, form-specific analysis of our selenium work in elderly dogs—the only non-human species to frequently develop prostate cancer during aging [28
]—would enable direct comparison of these two supplements, guiding a deeper search for potential form-dependent differences in prostatic distribution and activity of selenium in vivo
First, we probed for form-dependent differences in systemic selenium status after supplementation. We found equivalent increases in toenail selenium concentration after SeMet or Se-yeast supplementation at both low and high doses. Likewise, we found no form-dependent differences in intraprostatic selenium concentration. Thus, we found no evidence that supplementation with SeMet is less capable than Se-yeast to boost intraprostatic selenium level. Whether or not supplementation with SeMet or Se-yeast differentially alters the amount of particular selenium species within the prostate, such as methylselenol or selenoproteins [30
], could not be determined in our study, because only total selenium concentration was measured. Whether or not host factors, such as age or obesity [32
], impact the systemic and intraprostatic concentrations of selenium achievable after supplementation with different selenium forms could not be rigorously interrogated in our dogs due to small sample size, but deserves further evaluation.
But this result—SeMet and Se-yeast supplementation in an equivalent dose yield equivalent systemic and intraprostatic selenium concentrations—positioned us to probe the important question: Does supplementation with these two forms exert differential biological effects within the prostate in a context of equivalent selenium status
? Pursuant to that question, we conducted the first direct comparison of the potency of SeMet and Se-yeast on a suite of prostatic readouts that reflect alterations in multiple gene networks. To search for form-dependent differences in the capacity of selenium to influence prostatic responses, we conducted a tertile analysis of all selenium-supplemented dogs based on final intraprostatic selenium concentration. This potency analysis revealed that when dogs receiving SeMet or Se-yeast were standardized on the basis of their intraprostatic selenium concentration achieved after supplementation, there were no significant differences in the effect of either selenium form on epithelial cell DNA damage, proliferation, apoptosis, or intraprostatic androgen milieu. Across three different ranges of selenium status and six parameters, supplementation with SeMet or Se-yeast yielded equivalent outcomes. These results have strong translational implications. Our findings, which represent the first direct comparison of SeMet and Se-yeast on biological markers in the aging prostate that reflect flux through multiple gene networks, do not support the idea illustrated in that the null results of SELECT are attributable to a superior response of the aging prostate to daily supplementation with Se-yeast, rather than SeMet. Instead, based on the significant anticancer efficacy of Se-yeast in men with low baseline selenium in the NPC Trial [33
] together with the equipotent effects of the two forms of selenium reported here, we speculate that subgroup analysis of prostate cancer risk in SELECT will show that men with low baseline selenium concentration can achieve prostate cancer risk reduction from supplementation in the form of SeMet.
Lippman and colleagues [2
] pointed out that it was impossible to know whether Se-yeast would have been more active than SeMet had it been used in SELECT. No inferences could be made because SELECT did not test different formulations of selenium. Unfortunately, direct comparison of the effects of SeMet and Se-yeast on the prostate is not available from any human studies. Investigators have reported dose-dependent increases in intraprostatic selenium concentration in men after short-duration supplementation (2 to 6 weeks) with SeMet [23
] or Se-yeast [24
], but other prostatic responses to supplementation were not reported. Making hard conclusions based on between-study comparisons is difficult, owing to differences in dose and duration of supplementation, study subjects, and assays used to measure selenium. The power of the comparative analysis of SeMet and Se-yeast presented here is that potency was evaluated in a randomized, preclinical setting in which biological effects within the prostate could be evaluated in individuals having equivalent intraprostatic selenium status
. We believe this experimental approach affords the kind of hard-to-achieve estimate of form-dependent activity that is needed to reach sounder conclusions regarding potential differences in the effects of SeMet and Se-yeast on prostatic homeostasis and cancer risk reduction. The notion that a retreat to animal studies might yield a more complete understanding of disappointing human clinical trials has precedence in the CARET and ATBC lung cancer prevention trials. Subsequent studies in ferrets triggered an illuminating contextual re-think, revealing the dangerous combination of current smoking and high-dose beta-carotene, which ultimately led to increasing confidence that the 10% increase in lung cancer observed in β-carotene-supplemented smokers could be reconciled as an expected
, rather than an unexpected outcome
In summary, the null results of SELECT strengthened enthusiasm that there may be important form-dependent differences in selenium action within the prostate. The results of our novel potency analysis communicated here do not further support that notion. By guiding more informed speculations and provoking new questions, new data will continue to shape the ongoing dialogue about SELECT and its implications for defining the efficacy of selenium supplementation as a cancer-preventive strategy. By faithfully reporting our observations, we fortify that intellectual debate.