Proliferative tumor doubling times of prostatic carcinoma.

Prostate cancer (PCa) has a variable biology ranging from latent cancer to extremely aggressive tumors. Proliferative activities of cancers may indicate their biological potential. A flow cytometric assay to calculate maximum proliferative doubling times (T(max)) of PCa in radical prostatectomy specimens after preoperative in vivo bromodeoxyuridine (BrdU) infusion is presented. Only 4/17 specimens had tumors large enough for flow cytometric analysis. The T(max) of tumors was similar and ranged from 0.6 to 3.6 months. Tumors had calculated doubling times 2- to 25-fold faster than their matched normal tissue. Variations in labeling index and T(max) were observed within a tumor as well as between different Gleason grades. The observed PSA doubling times (PSA-DT) ranged from 18.4 to 32.0 months, considerably slower than the corresponding T(max) of tumors involved. While lack of data for apoptotic rates is a limitation, apparent biological differences between latent versus aggressive PCa may be attributable to variations in apoptotic rates of these tumors rather than their cell proliferative rates.

The metabolites citrate, myo-inositol, and spermine are potential age-independent markers of prostate cancer in human expressed prostatic secretions.

OBJECTIVES: Due to specific physiological functions, prostatic tissues and fluids have unique metabolic profiles. In this study, proton nuclear magnetic resonance spectroscopy ((1)H-NMRS) is used to assess potential metabolic markers of prostate cancer (PCa) in human expressed prostatic secretions (EPS). METHODS: Metabolic profiles of EPS from 52 men with PCa and from 26 healthy controls were analyzed using quantitative (1)H-NMRS. The metabolites quantified included citrate, spermine, myo-inositol, lactate, alanine, phosphocholine, glutamine, acetate, and hydroxybutyrate. Logistic regression (LR) was used to model the risk of PCa based on metabolite concentrations while adjusting for age. RESULTS: The average age of the EPS donors with PCa was 58.0+/-7.0 years and 52.2+/-12.1 for the healthy donors. The median Gleason score for the men with PCa was 7 (range 5-9). The LR models indicated that the absolute concentrations of citrate, myo-inositol, and spermine were highly predictive of PCa and inversely related to the risk of PCa. The areas under the receiver operating characteristic curves (AUROC) for citrate, myo-inositol and spermine were 0.89, 0.87, and 0.79, respectively. At 90% sensitivity, these metabolites had specificities of 74%, 51%, and 34%, respectively. The LR analysis indicated that absolute levels of these three metabolites were independent of age. CONCLUSIONS: The results indicate that citrate, myo-inositol and spermine are potentially important markers of PCa in human EPS. Further, the absolute concentrations of these metabolites in EPS appear to be independent of age, increasing the potential utility of these markers due to elimination of age as a confounding variable.

Prostatic fluid concentrations of isoflavonoids in soy consumers are sufficient to inhibit growth of benign and malignant prostatic epithelial cells in vitro.

BACKGROUND: The differential intestinal metabolism of the soy isoflavones is likely to influence the ability of soy to prevent prostate cancer. While daidzein, genistein, and equol have direct antiproliferative effects on prostatic epithelial cells in vitro, there are no such data for the isoflavone glycitein, or seven metabolites: O-desmethylangolensin (ODMA), 6-hydroxyODMA (6H-ODMA), dihydrodaidzein (DHD), cis-4-hydroxyequol (C4HE), 3'-hydroxydaidzein (3HD), 6-hydroxydaidzein (6HD), and 8-hydroxydaidzein (8HD). In the current study, the in vitro activities of these compounds were elucidated, and the active ranges of concentrations were compared to that found in Caucasian prostatic fluid (PF) and plasma samples. METHODS: The effects of isoflavonoids on cell growth, cell cycle distribution, and apoptosis (active Caspase 3) were examined on benign prostatic epithelial cells (PrEC), and the prostate cancer cell line LNCaP. RESULTS: PF concentrations of genistein, equol, and daidzein (but not ODMA or DHD) were often within the ranges that reduce PrEC growth in vitro. Profound differences in sensitivities were observed with LNCaP. The hydroxydaidzeins, C4HE, and 6H-ODMA had significant inhibitory effects at 10(-5)M on PrEC growth (but not LNCaP). Glycitein had significant effects on both. Reductions in cell growth were typically associated with both changes in cell cycle distribution and Caspase 3 activation. When five isoflavonoids were used in combination at concentrations present in PF samples, synergistic effects were observed. CONCLUSION: The profound differences in sensitivities of prostatic epithelial cells to these compounds along with their synergistic effects suggest that multiple metabolites in vivo may be optimal for preventing prostate cancer.

Long-term dietary habits affect soy isoflavone metabolism and accumulation in prostatic fluid in caucasian men.

The soy isoflavones daidzein and genistein are believed to reduce prostate cancer risk in soy consumers. However, daidzein can be metabolized by the intestinal flora to form a variety of compounds with different bioactivities. In the current study, we investigated the influence of long-term dietary habits on daidzein metabolism in healthy Caucasian men (19-65 y old). A secondary goal was to compare plasma and prostatic fluid concentrations of 5 isoflavonoids: genistein, daidzein, equol, dihydrodaidzein, and O-desmethylangolensin. Baseline plasma levels of isoflavonoids were quantitated in 45 men by HPLC-electrospray ionization-MS. Participants then consumed a soy beverage daily for 1 wk, and post-soy isoflavonoid levels were quantitated in plasma and prostatic fluid. Equol was the only metabolite that appeared to be influenced by routine dietary habits. Stratified analyses revealed that men who had consumed > or =30 mg soy isoflavones/d for at least 2 y had 5.3-times the probability of producing equol than men who had consumed < or =5 mg/d (P = 0.014). Additionally, those men who consumed animal meat regularly had 4.7-times the probability of producing equol than men who did not consume meat (P = 0.023). Equol production was not linked to age, BMI, or the consumption of yogurt, dairy, fruit, or American-style fast food. Daidzein and its metabolites (but not genistein) were typically present at higher levels in prostate fluid than plasma (median = 4-13 times that in plasma). In conclusion, our data suggest that the ability of Caucasian men to produce equol is favorably influenced by the long-term consumption of high amounts of soy and the consumption of meat. Last, the high concentrations of isoflavonoids in prostatic fluid increases the potential for these compounds to have direct effects in the prostate.

Soy isoflavonoid equol modulates the growth of benign and malignant prostatic epithelial cells in vitro.

BACKGROUND: The dietary consumption of high levels of soy has been linked to reduced risks for prostate cancer (PC) in Asians and vegetarians. In vitro studies have focused on the two most abundant isoflavones in soy, genistein and daidzein. However, daidzein is differentially metabolized by gut microflora in humans, yielding compounds with very different bioactivities and half-lives. Asians are significantly more likely to produce the metabolite equol than Caucasians, suggesting its role in the prevention of PC. We hypothesize that equol is a bioactive metabolite that exerts direct antiproliferative effects on prostatic epithelial cells. METHODS: Benign and malignant prostatic epithelial cells were treated in vitro with equol, genistein, and daidzein by using the range of concentrations found in the prostatic fluids of Asians consuming soy. Growth and cell cycle distribution were analyzed over time. RESULTS: After 9 days of treatment, equol inhibited growth of benign human prostatic epithelial cells (PrEC) by 37% at 10(-6) M and 80% at 10(-5) M. Although genistein also had profound effects, daidzein appeared only one tenth as potent as equol. Equol and daidzein caused an accumulation of cells in G0/G1, whereas genistein arrested cells in G2/M. The isoflavonoids demonstrated differential effects on the established PC cell lines 22Rv1, LNCaP, LAPC-4, PC-3, and DU 145. PC-3 cells showed the greatest resistance. CONCLUSION: Equol is a biologically active metabolite of daidzein that has potent antiproliferative effects on benign and malignant prostatic epithelial cells at concentrations that can be obtained naturally through dietary soy consumption.