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Purpose: Epidemiologic and clinical data suggest that selenium could prevent prostate cancer, but it has not been shown that supplemental selenium leads to an increased concentration of selenium in prostate tissue compared with adjacent tissue. Experimental Design: We conducted a randomized, controlled, short-term trial of l-selenomethionine (SeMet) versus observation in men with organ-confined prostate cancer. The primary endpoint was the measurement of selenium concentration in prostate tissue and seminal vesicle (SV). We assessed baseline selenium levels in serum and in toenail specimens (reflecting long-term intake) and post-intervention selenium levels in serum, and in prostate and SV tissues using hydride generation atomic fluorescence spectroscopy. Results: Sixty-six eligible patients were randomly assigned to the SeMet (n = 34) or observation (n = 32) arm; both arms had similar baseline patient characteristics. Baseline serum selenium was similar in the two groups (P = 0.64). Baseline toenail selenium levels were slightly higher in the SeMet group than in the control group (P = 0.07). After the intervention, the mean serum selenium level increased 15% in the SeMet arm and was higher than in the observation arm (P = 0.001). The selenium concentration in prostate tissue was 22% higher in the SeMet arm (n = 26) than in the observation arm (n = 25; 1.80 versus 1.47 ppm; P = 0.003, Wilcoxon rank sum test) and remained significantly higher after adjusting for chronic selenium intake (P = 0.021, ANCOVA). SV selenium concentration was similar in both groups (P = 0.384) and was lower than in prostate tissue. Conclusions: The present study is the first to show that selenium taken as oral supplementation accumulates preferentially in the human prostate gland as opposed to the SV. These findings support the hypothesis that oral selenium supplementation may contribute to the cancer preventive effects of selenium.

Fenretinide (4-HPR) is a retinoid analogue with antitumor and chemopreventive activities. In addition to 4-HPR, there are several other new phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [N-(2-hydroxyphenyl)retinamide (2-HPR), N-(3-hydroxyphenyl)retinamide, N-(2-carboxyphenyl)retinamide, N-(3-carboxyphenyl)retinamide, N-(4-carboxyphenyl)retinamide, and N-(4-methoxyphenyl)retinamide (4-MPR) ]. It is hypothesized that these agents can act independent of the nuclear retinoid receptor pathway. To test this hypothesis directly, we have analyzed the activity of these phenylretinamides in vitro on a panel of F9 murine embryonal carcinoma cell lines, which includes wild-type (F9-WT) and mutant cells that have disrupted genes for both retinoid X receptor alpha and retinoic acid receptor gamma retinoid receptors (F9-KO). The F9-KO cells lack almost all measurable response to all-trans-retinoic acid, the primary biologically active retinoid. Two distinct effects of retinamides were identified. The first is a rapid, dose-dependent induction of cell growth inhibition (reduced cell viability), and the second is a slower induction of differentiation and accumulation of cells in the G(1) phase of the cell cycle that was observed with a concentration of 1 micro M, for only those phenylretinamides bearing charged (hydroxyl or carboxyl) groups on the terminal phenylamine ring. The induction of differentiation and G(1) accumulation was only observed in the F9-WT cells, indicating that this effect is receptor-dependent. 4-MPR, a major metabolite of 4-HPR, lacks a charged group on the terminal phenylamine ring and did not induce retinoid receptor-dependent effects, but did induce cell growth inhibition. Thus, 4-MPR may play a role in the clinical activity of 4-HPR. This study further reveals the mechanism of action of these novel phenylretinamides and supports continued investigation into their development as chemopreventive drugs.

The synthetic retinoid N-(4-hydroxyphenyl)retinamide [4-HPR (or fenretinide)] has preclinical and clinical preventive activity in breast carcinogenesis. 4-HPR and its metabolites have been shown to accumulate in the mammary tissue of rodents. We assessed levels of 4-HPR and its major metabolite, N-(4-methoxyphenyl)retinamide (4-MPR), in plasma and in normal and neoplastic breast tissue obtained from women treated with 4-HPR.We randomly assigned 14 women with suspected or very recently diagnosed breast cancer to receive 100, 200, or 300 mg of 4-HPR daily for 3-12 days before scheduled biopsy, lumpectomy, or mastectomy. Using high-performance liquid chromatography, we measured post-4-HPR-treatment concentrations of 4-HPR and 4-MPR in plasma and breast tissue obtained during surgery.Breast tissue and plasma retinamide (4-HPR plus 4-MPR) concentrations increased significantly with short-term oral administration of 4-HPR. Retinamide levels increased in a linear and dose-related fashion in plasma, whereas they peaked and plateaued at 200 mg/day in breast tissue. The total retinamide concentration in breast tissue exceeded that in plasma at each 4-HPR dose. The highest mean tissue:plasma retinamide ratios were achieved at 200 mg/day: 639.5 +/- 253.8 to 190.6 +/- 91.9 ng/ml (4.8:1) for 4-HPR and 594.4 +/- 201.9 to 130.5 +/- 37.8 ng/ml (6.6:1) for 4-MPR. Plasma retinol levels decreased in association with increasing 4-HPR doses. Two patients experienced grade 1 toxicity at the 300 mg/day dose.These findings indicate that retinamides preferentially accumulate in human breast tissue (versus plasma). 4-HPR tissue concentrations at 200 mg/d were equivalent to those that inhibit growth and induce apoptosis of breast cancer cells in vitro. Previous clinical and correlative laboratory results suggest that 4-HPR may reduce risk in premenopausal women, who are more prone (than are postmenopausal women) to estrogen receptor (ER)-negative breast cancer development. The present results and previous data (including in vitro 4-HPR activity against ER-negative breast cancer) support further study of 4-HPR in the setting of premenopausal/ER-negative breast cancer prevention.