A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy.

Pomegranates slow prostate cancer xenograft growth and prolong prostate-specific antigen (PSA) doubling times in single-arm human studies. Pomegranates' effects on human prostate tissue are understudied. We hypothesized that orally administered pomegranate extract (POMx; Pom Wonderful) would lower tissue 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress biomarker. Seventy men were randomized to two tablets, POMx or placebo, daily up to four weeks before radical prostatectomy. Tissue was analyzed for intraprostatic urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NF-κB, and Ki67. Primary endpoint was differences in 8-OHdG, and the study was powered to detect 35% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (P = 0.095), which was not statistically significant. POMx was well tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21 of the 33 patients in the POMx group versus 12 of the 35 in the placebo group (P = 0.031). Cancer pS6 kinase, NF-κB, Ki67, and serum PSA changes were similar between arms. POMx before surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary endpoint in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitively test whether POMx reduces prostate oxidative stress, as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology.

Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis.

The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines. Recently, potent anti-tumorigenic effects of pomegranate juice and extracts have been reported. Consequently, pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer, including prostate. In this study, we investigated the relationship between pomegranate-induced apoptosis in human prostate cancer cells and the IGF/IGFBP system. Treatment of LAPC4 prostate cancer cells with 10microg/ml POMx, a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content (37% punicalagins by HPLC), resulted in inhibition of cell proliferation and induction of apoptosis. Interestingly, co-treatment with POMx and IGFBP-3 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth. Western blot analysis revealed that treatment with POMx or POMx/IGFBP-3 combination resulted in increased JNK phosphorylation, and decreased Akt and mTOR activation, consistent with a growth inhibitory, pro-apoptotic function. We also investigated the relationship between IGF-1 and pomegranate-induced apoptosis in 22RV1 prostate cancer cells. Co-treatment with 100ng/ml IGF-1 completely blocked apoptosis induction by POMx. In contrast, IGF-I failed to inhibit POMx-induced apoptosis in R(-) cells, suggesting the importance of IGF-IR. POMx-treatment decreased Igf1 mRNA expression in a dose-dependent manner indicating that its actions also involve tumor-specific suppression of IGF-1. These studies revealed novel interactions between the IGF system and pomegranate-induced apoptosis.

Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm.

OBJECTIVE: To evaluate our early experience with neoadjuvant therapy (sunitinib or sorafenib) in advanced renal cell carcinoma (RCC), to explore the effect on both tumour biology and potential for downstaging advanced tumours, as systemic therapy for RCC has historically resulted in little if any primary tumour response, but recent experience with targeted therapy suggests otherwise. PATIENTS AND METHODS: The preliminary experience with neoadjuvant therapy for the surgical management of RCC was reviewed at two large referral centres. Several unique patients were identified who had a novel response to systemic therapy that altered the surgical strategy. RESULTS: Four patients who had targeted therapy before surgery are described and in whom there were effects on tumour biology not seen previously with chemotherapy and cytokine therapy. The selected patients who had neoadjuvant targeted therapy had shrinkage of a tumour thrombus in the inferior vena cava, nodal involvement, renal fossa recurrence and tumour within a solitary kidney. CONCLUSIONS: The introduction of new molecular agents has revolutionized the treatment of patients with metastatic RCC. Responses to targeted therapy within the primary tumour, tumour thrombus, renal fossa recurrence, and lymph node metastases are novel findings not seen during treatment with immunotherapeutic-based strategies. This might be a signal for urological surgeons to re-evaluate the paradigm for the surgical management of advanced RCC. Potential applications are presented to encourage further investigations with targeted therapy in the neoadjuvant setting.

Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo.

Angiogenesis is critical to tumor growth and is stimulated by tissue hypoxia due to poor oxygen delivery. In turn, cellular hypoxia leads to angiogenesis via the induction of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at a cellular level. Pomegranate juice and extracts, which are rich sources of ellagitannins, have been shown to have chemopreventive potential against prostate cancer, but there have been no studies on the effects of an ellagitannin-rich pomegranate extract on angiogenesis. Human prostate cancer cells (LNCaP) and human umbilical vein endothelial cells (HUVEC) were incubated with a pomegranate extract standardized to ellagitannin content (POMx), under normoxic and hypoxic conditions in vitro. Human prostate cancer cells (LAPC4) were injected subcutaneously into severe combined immunodeficient (SCID) mice and the effects of oral administration of POMx on tumor growth, microvessel density, and HIF-1alpha and VEGF expression were determined after 4 weeks of treatment. POMx inhibited the proliferation of LNCaP and HUVEC cells significantly under both normoxic and hypoxic conditions. HIF-1alpha and VEGF protein levels were also reduced by POMx under hypoxic conditions. POMx decreased prostate cancer xenograft size, tumor vessel density, VEGF peptide levels and HIF-1alpha expression after 4 weeks of treatment in SCID mice. These results demonstrate that an ellagitannin-rich pomegranate extract can inhibit tumor-associated angiogenesis as one of several potential mechanisms for slowing the growth of prostate cancer in chemopreventive applications. Further studies in humans are needed to confirm that angiogenesis can be inhibited by an ellagitannin-rich pomegranate extract administered orally as a dietary supplement.

A novel resectoscope for transurethral resection of bladder tumors and the prostate.

PURPOSE: Transurethral bladder tumor resection is associated with imperfect clinical staging and incomplete tumor removal. Transurethral prostate resection may be complicated by inadvertent damage to the urinary sphincter, bladder neck and trigone. We performed a multicenter pilot and feasibility study of a novel working element for resectoscopes designed to improve the efficacy and safety of transurethral endoscopic surgery. MATERIALS AND METHODS: An innovative working element for resectoscopes was developed to convert the standard in/out linear/axial movement at the handgrip into a side-to-side, bidirectional, lateral rotating motion. The device is compatible with current optical technology and conventional electrocautery generators, and it has been granted marketing approval. It consists of variably sized cutting loops designed for transurethral resection of bladder tumors and the prostate. To date 80 patients with bladder cancer (38) or benign prostatic hyperplasia (42) have undergone surgery with this instrument at our 3 clinical sites. RESULTS: No safety concerns were evident. When used during transurethral bladder tumor resection, lateral resection at the base of the tumor enabled accurate depth of penetration into the bladder wall, which may decrease the risk of bladder perforation and improve pathological assessment of tumor invasion. During transurethral prostate resection this novel tool facilitated dissection of adenoma adjacent to the verumontanum and prostatovesical junction, which may decrease the risk of sphincteric damage and bladder neck injury. CONCLUSIONS: A novel resectoscope is currently under prospective clinical investigation to establish its surgical and pathological efficacy, ease of use and side effect profile. Current data suggest that the learning curve is mild, its use is safe and it provides distinct advantages when used for transurethral resection of bladder tumors and the prostate.

Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland.

Our group has shown in a phase II clinical trial that pomegranate juice (PJ) increases prostate specific antigen (PSA) doubling time in prostate cancer (CaP) patients with a rising PSA. Ellagitannins (ETs) are the most abundant polyphenols present in PJ and contribute greatly towards its reported biological properties. On consumption, ETs hydrolyze to release ellagic acid (EA), which is then converted by gut microflora to 3,8-dihydroxy-6H-dibenzo[b, d]pyran-6-one (urolithin A, UA) derivatives. Despite the accumulating knowledge of ET metabolism in animals and humans, there is no available data on the pharmacokinetics and tissue disposition of urolithins. Using a standardized ET-enriched pomegranate extract (PE), we sought to further define the metabolism and tissue distribution of ET metabolites. PE and UA (synthesized in our laboratory) were administered to C57BL/6 wild-type male mice, and metabolite levels in plasma and tissues were determined over 24 h. ET metabolites were concentrated at higher levels in mouse prostate, colon, and intestinal tissues as compared to other tissues after administration of PE or UA. We also evaluated the effects of PE on CaP growth in severe combined immunodeficient (SCID) mice injected subcutaneously with human CaP cells (LAPC-4). PE significantly inhibited LAPC-4 xenograft growth in SCID mice as compared to vehicle control. Finally, EA and several synthesized urolithins were shown to inhibit the growth of human CaP cells in vitro. The chemopreventive potential of pomegranate ETs and localization of their bioactive metabolites in mouse prostate tissue suggest that pomegranate may play a role in CaP treatment and chemoprevention. This warrants future human tissue bioavailability studies and further clinical studies in men with CaP.

Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer.

PURPOSE: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. EXPERIMENTAL DESIGN: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. RESULTS: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. CONCLUSIONS: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.

Prevention of bladder cancer: a review.

INTRODUCTION: Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention. MATERIALS AND METHODS: A literature review of peer-reviewed articles which address bladder cancer prevention was performed. RESULTS: Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects. CONCLUSIONS: While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.

Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma.

PURPOSE: To create a comprehensive algorithm that can predict postoperative renal cell carcinoma (RCC) patient outcomes and response to therapy. PATIENTS AND METHODS: A prospective cohort study was performed with outcome assessment on the basis of chart review of 814 patients who underwent nephrectomy between 1989 and 2000. At diagnosis, M1 or N1/N2M0 metastatic disease (M) was present in 346 patients (43%), whereas 468 patients had no metastatic disease (NM) (N0M0). On the basis of UCLA Integrated Staging System category and the presence of metastases, patients were divided into low-risk (LR), intermediate-risk (IR), and high-risk (HR) groups. Decision boxes integrating tumor-node-metastasis staging, tumor grade, and performance status were compiled for determining a patient's risk group. RESULTS: NM-LR patients had 91% disease-specific survival at 5 years, lower recurrence rate, and better disease-free survival compared with NM-IR and HR patients. Disease progressed in 50% of NM-HR patients. Disease-specific survival of NM-HR patients who received immunotherapy (IMT) for recurrent disease was similar to that of M-LR patients treated with cytoreductive nephrectomy and adjuvant IMT. Time from recurrence to death for NM-HR patients was inferior to that for M-LR patients. After IMT, approximately 25% of M-LR and 12% of M-IR patients had long-term progression-free survival. M-HR patients did poorly despite IMT. CONCLUSION: Stratifying RCC patients into high-, intermediate-, and low-risk subgroups provides a clinically useful system for predicting outcome and provides a unique tool for risk assignment and outcome analysis. Subclassifying RCC into well-defined risk groups should allow better patient counseling and identification of both NM-HR subgroups that need adjuvant treatment and nonresponders who need alternative therapies.

PC-SPES: herbal formulation for prostate cancer.

PC-SPES is a potent eight-herb formulation sold directly to consumers; it has promising efficacy in the treatment of prostate cancer (CaP). The product induces a castrate status in most, if not all, men, resulting in a 50% or greater prostate-specific antigen reduction in the great majority of men with androgen-dependent CaP and in more than one half of the men with androgen-independent CaP. The duration of response is not yet clear. The efficacy of PC-SPES appears to exceed that of androgen ablation alone, but is not necessarily separate from an estrogenic effect. Common side effects include gynecomastia, nipple tenderness, loss of libido, and impotency; uncommon side effects include a 4% incidence of thromboembolic phenomena, but also two reports of bleeding diatheses. The mechanisms of action may involve downregulation of the androgen receptor, induction of apoptosis by way of inhibition of the bcl-2 gene, and increased expression of p53. Two marker compounds in PC-SPES are baicalin and oridonin, both of which exhibit antiproliferative effects in CaP cell lines. Thousands of men are currently obtaining this nonprescription medicine, and physicians should ask patients specifically about its use. PC-SPES is of great interest in men with androgen-independent CaP, an area in which future research should be primarily directed.