Antihormone treatment differentially regulates PSA secretion, PSMA expression and 68Ga-PSMA uptake in LNCaP cells.

BACKGROUND: In recent years, a variety of innovative therapeutics for castration-resistant prostate cancer have been developed, including novel anti-androgenic drugs, such as abiraterone or VPC-13566. Therapeutic monitoring of these pharmaceuticals is performed either by measuring PSA levels in serum or by imaging. PET using PSMA ligands labeled with Fluor-18 or Gallium-68 is the most sensitive and specific imaging modality for detection of metastases in advanced prostate cancer. To date, it remains unclear how PSMA expression is modulated by anti-hormonal treatment and how it correlates with PSA secretion. METHODS: We analyzed modulation of PSMA-mRNA and protein expression, 68Ga-PSMA uptake and regulation of PSA secretion by abiraterone or VPC-13566 in LNCaP cells in vitro. RESULTS: We found that abiraterone and VPC-13566 upregulate PSMA protein and mRNA expression but block PSA secretion in LNCaP cells. Both anti-androgens also enhanced 68Ga-PSMA uptake normalized by the number of cells, whereas abiraterone and VPC-13566 reduced 68Ga-PSMA uptake in total LNCaP monolayers treated due to cell death. CONCLUSION: Our data indicate that PSA secretion and PSMA expression are differentially regulated upon anti-androgen treatment. This finding might be important for the interpretation of 68Ga-PSMA PET images in monitoring therapies with abiraterone and VPC-13566 in prostate cancer patients, but needs to be validated in vivo.

Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 µg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 µg/ml of red Maca plus Taxol or 2ME 5 µM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 µg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 µg/ml, but not at 80 µg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells.

Does PSA reduction after antibiotic therapy permits postpone prostate biopsy in asymptomatic men with PSA levels between 4 and 10 ng/mL?

PURPOSE: We investigated the effect of antibiotics on PSA in asymptomatic patients with mild PSA elevation. MATERIALS AND METHODS: We prospectively evaluated, in a non-randomized design, 106 asymptomatic patients with PSA of 4-10 ng/mL, with a negative digital rectal examination and with no urinary tract infection evidence for 2 years. Patients were divided into two groups: those treated with antibiotics for 3 weeks (G1) and those who were not treated (G2). PSA was taken six weeks after and prostate biopsy was performed in all patients. RESULTS: PCa was diagnosed in 25 of 106 patients (23.6%): 16 (25.0%) in G1 and 9 (21.4%) in G2 (p>0.05). PSA normalization was experienced in 24.5%. In G1, PSA returned to <4 ng/mL in 15 (23.4%) patients compared to 11 (26%) patients in G2. In the patients with a positive biopsy, no significant variation was noted in PSA, fPSA, %fPSA and DPSA after antibiotic treatment. A significantly lower cancer detection rate was noted with decreased PSA, fPSA, and DPSA after antibiotic use. A PSA reduction rate of ≥ 10% occurred in 58.5%, and this was similar in both G1 and G2 groups. The sensibility, specificity and accuracy of PSA reduction of ≥ 10% were 31%, 23% and 25%, respectively. CONCLUSION: Empirical antibiotic therapy in asymptomatic male patients is not related to PSA reduction. The greater than 10% PSA reduction after antibiotic in this population cannot postpone prostate biopsy.

Inhibition of the DHT-induced PSA secretion by Verbascum xanthophoeniceum and Serenoa repens extracts in human LNCaP prostate epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Verbascum xanthophoeniceum is a mullein plant, typical of Balkan region and some parts of Turkey, traditionally used as phytotherapeutic agent due to its anti-inflammatory properties. It is rich in phenylethanoid and iridoid metabolites whose anti-inflammatory properties are under characterization. MATERIALS AND METHODS: The role of Verbascum xanthophoeniceum crude methanolic extract and its isolated phenylethanoid glycoside verbascoside have been evaluated, in comparison to a saw palmetto extract, on a human in vitro model of androgen-regulated prostate epithelium, the LNCaP cell line. Cytotoxicity and DHT-induced free and total PSA secretion have been thoroughly studied. RESULTS: We have found that similar to saw palmetto, Verbascum xanthophoeniceum extract and its isolated phenylethanoid glycoside verbascoside have no cytotoxicity in human LNCaP prostate epithelial cells, whereas an inhibitory effect on the DHT-induced free and total PSA secretion, a recognized anti-androgen like activity, has been shown in case of both Verbascum xanthophoeniceum extract and pure verbascoside. Furthermore, in the absence of the endogenous androgen DHT, an androgen-like activity in Verbascum xanthophoeniceum is detectable as it is for saw palmetto, suggesting that a mixed androgen-antiandrogen activity is present. CONCLUSIONS: For the first time, Serenoa repens and Verbascum xanthophoeniceum extracts have shown an absence of cytotoxicity and an inhibitory effect on DHT-induced PSA secretion in an in vitro model of human prostate epithelium, whereas the phenylethanoid glycoside verbascoside appeared to explain only part of the Verbascum xanthophoeniceum inhibitory activity on PSA secretion.

Dietary flavonoid intake, black tea consumption, and risk of overall and advanced stage prostate cancer.

Flavonoids are natural antioxidants found in various foods, and a major source is black tea. Some experimental evidence indicates that flavonoids could prevent prostate cancer. We investigated the associations between flavonoid intake, black tea consumption, and prostate cancer risk in the Netherlands Cohort study, which includes 58,279 men who provided detailed baseline information on several cancer risk factors. From 1986 to 2003, 3,362 prostate cancers were identified, including 1,164 advanced (stage III/IV) cancers. Cox proportional hazards regression using the case-cohort approach was used to estimate hazard ratios and 95% confidence intervals. Intake of total catechin, epicatechin, kaempferol, and myricetin and consumption of black tea were associated with a decreased risk of stage III/IV or stage IV prostate cancer. Hazard ratios of stage III/IV and stage IV prostate cancer for the highest versus the lowest category of black tea consumption (≥5 versus ≤1 cups/day) were 0.75 (95% confidence interval: 0.59, 0.97) and 0.67 (95% confidence interval: 0.50, 0.91), respectively. No associations were observed for overall and nonadvanced prostate cancer. In conclusion, dietary flavonoid intake and black tea consumption were associated with a decreased risk of advanced stage prostate cancer.

Improving the management of patients with prostate cancer receiving long-term androgen deprivation therapy.

In many patients with prostate cancer, androgen deprivation therapy (ADT) is administered over prolonged periods of time. The benefits of long-term ADT in patients with advanced disease are well established and, more recently, studies have shown that long-term adjuvant ADT used in combination with radiotherapy improves survival in patients with earlier stages of disease. Nevertheless, clinicians should remain aware of the potential long-term side effects of ADT and the strategies that can be used to manage or prevent long-term complications. One such strategy is intermittent androgen deprivation (IAD), in which patients receive cycles of ADT, the duration of which is usually determined by PSA levels. Accumulating data indicate that this approach improves the tolerability of ADT (particularly sexual dysfunction) and patients' quality of life, without compromising clinical outcomes (progression and survival). Indeed, the latest European Association of Urology guidelines state that IAD should no longer be considered investigational. Nevertheless, some questions remain unanswered, including: who are the most suitable patients for IAD and what are the optimal PSA levels for stopping and restarting treatment? Osteoporosis (and the resultant increased risk of fractures) is a well-recognized complication of long-term ADT. Bone mineral density should be measured before and during long-term ADT and patients advised to make appropriate lifestyle changes to help preserve bone health. Pharmacological intervention is also an option. Denosumab (an NF-κB ligand inhibitor) significantly reduces ADT-induced bone loss and the risk of fractures in patients with non-metastatic disease. In those whose disease has metastasized, zoledronate and denosumab are licensed to prevent skeletal-related events and a large randomized study has shown that denosumab is more effective than zoledronate in this setting.

Impact of common medications on serum total prostate-specific antigen levels and risk group assignment in patients with prostate cancer.

A recent study in men without prostate cancer suggested that extended use of common medications (nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide diuretics and statins) may lower serum total prostate-specific antigen (PSA) levels by clinically relevant amounts. The present study evaluated the impact of these drugs in patients with clinically localized prostate cancer. A retrospective analysis of 177 patients was performed. The multivariate regression analyses were adjusted for age, prostate volume, Gleason score, T stage, diagnostic setting (clinical symptoms versus elevated PSA only) and presence of diabetes mellitus. Drug use increased with age, e.g. to 50% in patients ≥70 years. The most commonly used drugs were statins (32% of all patients, including those who used drug combinations), followed by NSAIDs (21%) and thiazide diuretics (13%). Drug use was associated with a statistically significant PSA reduction (12%, when comparing 104 non-users to 73 users of any of the three drug types; adjusted analysis, p=0.01). Compared to the U.S.A. National Comprehensive Cancer Network risk group assignment based on measured PSA level, reassignment after correcting for medication use resulted in 8 changes among 57 patients with low or intermediate risk (14%). No such changes can be expected in patients belonging to the high-risk group. These results support the concerns expressed previously, given that risk group assignment, which may be inaccurate in patients using concomitant medications, eventually guides choice of treatment.

Alternative antiandrogen therapy in patients with castration-resistant prostate cancer: a single-center experience.

Outcomes of alternative (second-line) antiandrogen therapy in 112 patients with relapsing prostate cancer after first-line hormonal therapy were analyzed. A good response (prostate-specific antigen [PSA] decrease 50%) and a partial response (PSA decrease of 0­50%) by switching from bicalutamide (BCL) to flutamide (FLT) and from FLT to BCL were achieved in 35.4% (28/79) and 30.4% (24/79), and in 45.0% (9/20) and 20.0% (4/20) of cases, respectively. A good response and a partial response with the change from chlormadinone acetate (CMA) to a non-steroidal antiandrogen (FLT or BCL)and from a non-steroidal antiandrogen to CMA were obtained in 25.0% (2/8) and 37.5% (3/8), and in 20.0% (1/5) and 0% (0/5)of cases, respectively. In multivariate analyses, a second-line good response was significantly predictive of cause-specific survival from first therapy relapse to cancer death in all patients. Patients (52/112, 46.4%) with 30% decrease in PSA levels were associated with significantly better cause-specific survival as measured from the start of first-line treatment and first-line relapse.

Selenium enrichment of broccoli sprout extract increases chemosensitivity and apoptosis of LNCaP prostate cancer cells.

BACKGROUND: Broccoli is a Brassica vegetable that is believed to possess chemopreventive properties. Selenium also shows promise as an anticancer agent. Thus, selenium enrichment of broccoli has the potential to enhance the anticancer properties of broccoli sprouts. METHOD: Selenium-enriched broccoli sprouts were prepared using a sodium selenite solution. Their anticancer properties were evaluated in human prostate cancer cell lines and compared with those of a control broccoli sprout extract. RESULTS: Selenium-enriched broccoli sprouts were superior to normal broccoli sprouts in inhibiting cell proliferation, decreasing prostate-specific antigen secretion, and inducing apoptosis of prostate cancer cells. Furthermore, selenium-enriched broccoli sprouts but, not normal broccoli sprouts, induced a downregulation of the survival Akt/mTOR pathway. CONCLUSION: Our results suggest that selenium-enriched broccoli sprouts could potentially be used as an alternative selenium source for prostate cancer prevention and therapy.

Selenium supplementation does not affect testicular selenium status or semen quality in North American men.

Selenium (Se) is essential for sperm function and male fertility, but high Se intake has been associated with impaired semen quality. We reported previously a decrease in sperm motility in men fed high-Se foods, but we could not rule out the influence of other environmental and dietary factors. We now report on a randomized, controlled study on the potential adverse effects of Se supplementation on semen quality in 42 free-living men administered Se (300 microg/d) as high-Se yeast for 48 weeks. Semen analysis was performed 4 times before treatment began, then twice each week during treatment at 6, 12, 24, 36, and 48 weeks, and then after treatment at 72 and 96 weeks. Blood samples were collected 3 times before treatment and at each subsequent visit. Se concentration increased 61% in blood plasma and 49% in seminal plasma. However, Se supplementation had no effect on sperm Se, serum androgen concentrations, or sperm count, motility, progressive velocity, or morphology. We observed progressive decreases in serum luteinizing hormone, semen volume, and sperm Se in both the high-Se and placebo groups. Moreover, sperm straight-line velocity and percent normal morphology increased in Se-treated and placebo-treated participants. The lack of an increase in sperm Se suggests that testicular Se stores were unaffected, even though the participants' dietary Se intake was tripled and their total body Se approximately doubled by supplementation. These results are consistent with animal studies showing the Se status of testes to be unresponsive to dietary Se intake.

Prostate-specific antigen levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen: results from the 2001-2002 National Health and Nutrition Examination Survey.

BACKGROUND: Inflammation has been implicated in prostate carcinogenesis; therefore, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has the potential of decreasing the risk of prostate cancer. However, to the authors' knowledge the precise correlation between oral NSAID use, serum prostate-specific antigen (PSA), and prostate cancer risk is unknown. To further characterize this association, the authors evaluated serum PSA levels with regard to NSAID and acetaminophen consumption in a large cross-sectional study of men in the US. METHODS: PSA levels were determined in 1319 men aged >40 years in the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Linear regressions were performed on log-transformed PSA levels, accounting for the complex survey design, to evaluate the relations between PSA and the use of NSAIDs and acetaminophen after adjusting for the effects of age, race, educational level, smoking status, body mass index, coexisting inflammatory conditions, and heart disease. RESULTS: NSAID and acetaminophen consumption displayed a negative association with PSA levels, namely, individuals who reported using NSAIDs (19.8%) or acetaminophen (1.3%) regularly had lower PSA levels than individuals who did not take these drugs, although the impact of acetaminophen was not statistically significant. PSA levels among NSAID users were 0.9 times the levels among nondrug takers (P = .038), whereas PSA levels among acetaminophen users were 0.76 times the levels in nondrug takers (P = .14). Individuals who stated they took both NSAIDs and acetaminophen (0.99%) on a regular basis had higher PSA levels (1.8 times greater), although not statistically significantly so (P = .24), than individuals who stated they did not take either of these drugs regularly. CONCLUSIONS: The findings of the current study suggest that regular NSAID consumption may reduce serum PSA levels. Whether this is indicative of a protective effect on prostate cancer risk or masks possible prostate injury resulting in reduced detection of prostate cancer is unclear. Given the widespread consumption of NSAIDs and the regular use of PSA for the assessment of prostate cancer risk, the potential implications of the current study's findings may be substantial and warrant further investigation.

A detailed safety assessment of a saw palmetto extract.

BACKGROUND: Saw palmetto is commonly used by men for lower-urinary tract symptoms. Despite its widespread use, very little is known about the potential toxicity of this dietary supplement. METHODS: The Saw palmetto for Treatment of Enlarged Prostates (STEP) study was a randomized clinical trial performed among 225 men with moderate-to-severe symptoms of benign prostatic hyperplasia, comparing a standardized extract of the saw palmetto berry (160 mg twice daily) with a placebo over a 1-year period. As part of this study, detailed data were collected on serious and non-serious adverse events, sexual functioning, and laboratory tests of blood and urine. Between-group differences were assessed with mixed-effects regression models. RESULTS: There were no significant differences observed between the saw palmetto and placebo-allocated participants in the risk of suffering at least one serious adverse event (5.4% vs. 9.7%, respectively; p=0.31) or non-serious symptomatic adverse event (34.8% vs. 30.1%, p=0.48). There were few significant between-group differences in sexual functioning or for most laboratory analyses, with only small differences observed in changes over time in total bilirubin (p=0.001), potassium (p=0.03), and the incidence of glycosuria (0% in the saw palmetto group vs. 3.7% in the placebo group, p=0.05). CONCLUSIONS: Despite careful assessment, no evidence for serious toxicity of saw palmetto was observed in this clinical trial. Given the sample size and length of this study, however, these data do not rule out potential rare adverse effects associated with the use of saw palmetto.

Enterolactone restricts the proliferation of the LNCaP human prostate cancer cell line in vitro.

Ecological data suggest a long-term diet high in plant material rich in biologically active compounds, such as the lignans, can significantly influence the development of prostate cancer over the lifetime of an individual. The capacity of a pure mammalian lignan, enterolactone (ENL), to influence the proliferation of the LNCaP human prostate cancer cell line was investigated as a function of cell density, metabolic activity, expression and secretion of prostate specific antigen (PSA), cell cycle profile, and the expression of genes involved in development and progression of prostate cancer. Treatment with a subcytotoxic concentration of ENL (60 muM for 72 h) was found to reduce: cell density (57.5%, SD 7.23, p < 0.001), metabolic activity (55%, SD 0.03, p < 0.001), secretion of PSA (48.50% SD 4.74, p = 0.05) and induce apoptosis (8.33-fold SD 0.04, p = 0.001) compared to untreated cells. Cotreatment with 10 muM etoposide was found to increase apoptosis by 50.17% (SD 0.02, p < 0.001). Additionally, several key genes (e. g. MCMs, survivin and CDKs) were beneficially regulated by ENL treatment (p < 0.05). The data suggest that the antiproliferative activity of ENL is a consequence of altered expression of cell cycle associated genes and provides novel molecular evidence for the antiproliferative properties of a pure lignan in prostate cancer.

A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen.

Tomato and soy products are hypothesized to reduce the risk of prostate cancer or enhance efficacy of therapy. A study was completed to determine if men with active prostate cancer will adhere to a dietary intervention rich in tomato products and a soy protein supplement men (n = 41) with recurrent, asymptomatic prostate cancer were randomized among 2 groups: Group A (n = 20) consumed tomato products (no soy) for Weeks 0 through 4, targeting a minimum of 25 mg of lycopene/day. Group B (n = 21) consumed soy (no tomatoes) for Weeks 0 through 4, providing 40 g of soy protein/day. For Weeks 4 through 8, all men consumed a combined tomato-rich diet and soy supplements. No grade II through IV toxicities were observed. During Weeks 0 through 4, mean daily lycopene intake for Group A was 43 mg (+/- 15 mg) and mean soy intake for Group B was 39 g (+/- 1 g), remaining similar during Weeks 4 through 8. Serum lycopene increased from 0.72 +/- 0.09 micromol/l to 1.21 +/- 0.10 micromol/l (P < 0.0001) and urinary isoflavone excretion increased from not detectable to 54.1 +/- 5.7 micromol/l (P < 0.05) with 8 wk of diet intervention. Serum prostate-specific antigen decreased between Weeks 0 and 8 for 14 / 41 men (34%). Mean serum vascular endothelial growth factor for the entire group was reduced from 87 to 51 ng/ml (P < 0.05) over 8 wk. In conclusion, prostate cancer patients will consume diets rich in tomato products and soy with excellent compliance and bioavailability of phytochemicals. Further studies combining tomato and soy foods to determine efficacy for prostate cancer prevention or management are encouraged.

The postchemotherapy PSA surge syndrome.

BACKGROUND: Chemotherapy has emerged as a standard treatment in patients with castration-refractory prostate cancer (CRPC). Consensus criteria are available to define response in CRPC as at least a 50% decline in serum prostate-specific antigen (PSA) confirmed 4 weeks later. The objective of this work was to study early serum PSA changes in patients under chemotherapy and to correlate these changes with subsequent response assessment. PATIENTS AND METHODS: Serum PSA levels were monitored every 3 weeks in 79 patients with CRPC treated with chemotherapy and a time course of serum PSA levels was obtained. Correlation with response was studied. RESULTS: According to consensus criteria, 21 (40%) and 20 (38%) patients achieved a PSA response and stabilization, respectively, after first-line chemotherapy. Among patients who achieved either a response or a stabilization, 8 of 41 (20%) had a serum PSA rise during the first 8 weeks of chemotherapy, followed by a subsequent decline in serum PSA. The same observation was made in patients receiving second-line chemotherapy: 6 of 20 patients achieving a response or stabilization had an initial serum PSA rise. The postchemotherapy increase in serum PSA could reach more than twice the baseline value. The duration of the PSA surge ranged from 1 to 8 weeks. When considering responders only, 6 of 30 (20%) had a postchemotherapy serum PSA surge, followed by a drop. CONCLUSION: Postchemotherapy PSA surges occur not infrequently in patients with CRPC who respond to chemotherapy. Physicians should be aware of this effect to avoid inadequate early discontinuation of chemotherapy.

Serum PSA and percent free PSA value changes after antibiotic treatment. A diagnostic method in prostate cancer suspects with asymptomatic prostatitis.

INTRODUCTION: An association between inflammatory foci in prostatic tissues and elevated serum prostate-specific antigen (PSA) levels has been a controversial issue. We studied the effects of antibiotics on elevated PSA levels to improve the diagnostic value of prostate cancer findings. PATIENTS AND METHODS: Of 65 asymptomatic men with inconstant PSA elevation, 51 with laboratory signs of prostatitis received antibiotics instead of undergoing a prompt prostate biopsy. Asymptomatic prostatic inflammation was defined as the presence of >10 white blood cells/high-power field in the post-prostate massage urine. Follow-up measurements of PSA and percent free PSA values were obtained. RESULTS: Approximately 30% of the patients had a treatment response, defined as PSA decrease >20% from baseline. The range of the variations of PSA and percent free PSA values, expressed as coefficient of variation, also decreased significantly. Moreover, antibiotic treatment lowered the extent of histological prostatic inflammation in some patients. CONCLUSIONS: Subclinical prostatic inflammation potentially contributes to an elevated PSA level and its variation among prostate cancer suspects. Watchful observation may be an optional tool for patients showing a significant PSA decrease following antibiotic treatment.

A phase II clinical trial of sorafenib in androgen-independent prostate cancer.

PURPOSE: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). EXPERIMENTAL DESIGN: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. RESULTS: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (t(max)) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. CONCLUSIONS: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

Lycopene and soy isoflavones in the treatment of prostate cancer.

Dietary intake of lycopene and soy has been associated with a lower risk of prostate cancer. In vitro studies with lycopene and genistein, a soy isoflavone, have shown induction of apoptosis and inhibition of cell growth in androgen-sensitive (LNCaP) and androgen-independent (PC3 and VeCaP) prostate cancer cell lines. In a previous Phase II clinical trial in prostate cancer patients, we observed prostate-specific antigen (PSA) stabilization with soy isoflavone intake. In this Phase II clinical trial, we investigated the efficacy of lycopene alone or in combination with soy isoflavones on serum PSA levels in men with prostate cancer. To be eligible for the study, men with prostate cancer had to have rising serum PSA following local therapy or while on hormone therapy. Study population included 71 eligible patients who had 3 successive rising PSA levels or a minimum PSA of 10 ng/ml at 2 successive evaluations prior to starting therapy. Subjects were randomly assigned to receive a tomato extract capsule containing 15 mg of lycopene alone (n = 38) or together with a capsule containing 40 mg of a soy isoflavone mixture (n = 33) twice daily orally for a maximum of 6 mo. One patient on the lycopene arm did not receive therapy due to his inability to ingest the study pill. There was no decline in serum PSA in either group qualifying for a partial or complete response. However, 35 of 37 (95%) evaluable patients in the lycopene group and 22 of 33 (67%) evaluable patients in the lycopene plus soy isoflavone group achieved stable disease described as stabilization in serum PSA level. The data suggest that lycopene and soy isoflavones have activity in prostate cancer patients with PSA relapse disease and may delay progression of both hormone-refractory and hormone-sensitive prostate cancer. However, there may not be an additive effect between the 2 compounds when taken together. Future studies are warranted to further investigate the efficacy of lycopene and soy isoflavones in prostate cancer as well as the mechanism of potential negative interaction between them.

Reduction of PSA values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection.

We identified from our clinical database a total of 471 patients affected by cat. II chronic bacterial prostatitis (CBP), cat. III (IIIa and IIIb) chronic pelvic pain syndrome (CP/CPPS), or cat. IV asymptomatic inflammatory prostatitis (AIP), according to NIH criteria. 132 intent-to-treat patients, showing levels of PSA > or =4 ng/mL, were subjected to a 6-week course of combination pharmacological therapy with 500 mg/day ciprofloxacin, 500 mg/day azithromycin (3 days/week), 10 mg/day alfuzosin and 320 mg b.i.d. Serenoa repens extract. At the end of treatment, 111 per-protocol patients belonging to all categories of prostatitis showed a total 32.5% reduction of PSA levels. In the same group, 66 patients (59.4%) showed "normalization" of PSA values under the 4 ng/mL limit. Patients affected by cat. IIIb CP/CPPS showed the highest PSA reduction and normalization rates (40% and 68.4%, respectively). Follow-up data show that, after a marked, significant reduction at completion of therapy, PSA levels, urine peak flow rates and NIH-CPSI symptom scores remained constant or decreased throughout a period of 18 months in patients showing normalization of PSA values. Prostatic biopsy was proposed to 45 patients showing persistently high PSA values (> or = 4 ng/mL) at the end of treatment. Fourteen patients rejected biopsy; of the remaining 31, 10 were diagnosed with prostate cancer. Four months after a first biopsy, a second biopsy was proposed to the 21 patients with a negative first diagnosis and persistently elevated PSA levels. Three patients rejected the procedure; of the remaining 18, four were diagnosed with prostatic carcinoma. In summary, combination pharmacological therapy decreased the number of patients undergoing prostatic biopsy from 111 to 45. Normalization of PSA values in 59.4% of patients--not subjected to biopsy--increased the prostate cancer detection rate from 12.6% (14/111) to 31.1% (14/45). The reduction of PSA after a 6-week course of therapy was calculated in patients affected by cat. II, IIIa, IIIb and IV prostatitis after stratification with respect to the concomitant presence or absence of benign prostatic hyperplasia (BPH). PSA was reduced by 41% in cat. II CBP patients without BPH, compared to a 12.7% reduction in patients affected by BPH. Cat. IIIa CP/CPPS patients without BPH showed a 58.3% reduction of PSA levels, compared to a 20.7% reduction observed in CPPS/BPH patients. These data show that the presence of BPH may prevent the reduction of PSA induced by combination pharmacological therapy, and suggest that care has to be taken in the adoption of PSA as a marker of therapeutic efficacy in the presence of confounding factors like BPH. PSA should in our opinion be used as a significant component of a strategy integrating multiple diagnostic approaches.