Molecular urology最新文献

In 1997, we resolved to survey UsToo members and other men known at that time to be taking PC-SPES, a Chinese herb combination that contains eight herbs: chrysanthemum, dyers woad, licorice, reishi, san-qi ginseng, rabdosia, saw palmetto, and baikal skullcap. The survey showed positive results, with respondents experiencing a decline in serum prostate specific antigen (PSA), most to the undetectable range. Of these patients, 88% maintained a low PSA concentration, whereas 12% had a rise from nadir. These results made it obvious that we should obtain follow-up reports from the respondents. We therefore conducted a second survey, this time finding 93% of the respondents with positive results and only 7% reporting a rise in PSA after the initial lowering with PC-SPES. Even though there are some side effects, a great majority of men are realizing good PSA control while taking the capsules, and some of the respondents are now into their fourth year of PC-SPES use. Currently, several institutions are investigating the biology of this Chinese herb combination. Although there is some estrogenic effect, there are other potential mechanisms of action to enable this product to control PSA, not only in newly diagnosed cancer, but also in longer-term use.

Background: Local high-intensity focused ultrasound (HIFU) is a minimally invasive method of coagulation (85 degrees C) that ablates prostatic tissue with high precision.

Patients and methods: Over a 3-year period, 184 patients with organ-confined prostate cancer have undergone 232 sessions of transrectal HIFU therapy (mean duration 90 minutes) under spinal anesthesia at 2.25 or 3.0 MHz, 50 W, with a penetration depth of 25 mm.

Results: Follow-up sextant biopsies (mean 1.9) were cancer free in 80% of patients, and in patients with residual cancer, the tumor mass was reduced more than 90%. The nadir value of prostate specific antigen (PSA) was <4 ng/mL in 97%, including 61% who had values <0.5 ng/mL. After primary HIFU, no severe side effects (fistula, grade 2 or 3 incontinence, rectal mucosal burn) were seen. All patients had a suprapubic tube (mean 29 days), and 33% needed transurethral resection of debris (mean 7 g). Hospital discharge was within 23 hours after treatment.

Conclusion: Transrectal HIFU enables minimally invasive local prostate tissue ablation with high rates of negative biopsies, low PSA nadir, and low complication rate. Further follow-up is needed to define the efficacy of disease control.

Androgen-independent prostate cancer cells are remarkably resistant to therapeutic agents that work by triggering apoptosis via the caspase cascade. The recent sequencing of the entire genome of one of the most radiation-resistant organisms known, Deinococcus radiodurans, yields some insight into how prostate cancer cells might mount such resistance to apoptosis. Rather than being attributable to any one mechanism, the extreme radiation resistance of D. radiodurans appears to reflect the expression of a large number of different systems capable of preventing, repairing, or tolerating DNA damage and a very high degree of redundancy in these systems. Many molecular alterations that may influence the threshold for apoptosis have already been described in advanced prostate cancer; changes in bcl-2, p53, and the androgen receptor have been the most extensively studied. Current information is consistent with the concept that individual prostate cancer cells express multiple antiapoptotic mechanisms. This conclusion implies that it will not be possible to enhance cellular sensitivity to therapeutics that activate apoptosis by disabling just one target in a pathway, because other proteins are likely to be available to assume its function. Likewise, even elimination of a whole pathway may have little effect on sensitivity because cellular viability is protected by so many different mechanisms. However, where molecular changes have a phenotypic consequence, they offer a window of opportunity for the development of novel therapeutic strategies. One such example is a recently identified small organic compound that can inhibit p53 function and thus protect normal tissues against radiation-induced apoptosis without impairing killing of p53-deficient tumor cells.

Purpose: In a search for alternative and preventive therapies for prostate cancer, attention was focused on the ways in which curcumin (Turmeric), used in food and medicine in India for centuries, could interfere with the growth factor signaling pathways in both androgen-dependent and androgen-independent prostate cancer cells, as exemplified by the epidermal growth factor receptor (EGF-R) signaling.

Materials and methods: The androgen-sensitive LNCaP and androgen-insensitive PC-3 cell lines were grown in 5 to 50 microM curcumin and analyzed for EGF-R protein by Western blotting and for EGF-R tyrosine kinase activity.

Results: Curcumin was a potent inhibitor of EGF-R signaling, and it accomplished this effect by three different means (1) down regulating the EGF-R protein; (2) inhibiting the intrinsic EGF-R tyrosine kinase activity; and (3) inhibiting the ligand-induced activation of the EGF-R.

Conclusions: These results, taken together with our previous results that curcumin can induce apoptosis in both androgen-dependent and androgen-independent prostate cancer cells, support our view that curcumin may be a novel modality by which one can interfere with the signal transduction pathways of the prostate cancer cell and prevent it from progressing to its hormone-refractory state.

Background and purpose: Prostate secretory epithelial cells have the unique function and capability of accumulating extremely high intracellular levels of zinc. One of the effects of this accumulation is inhibition of cell growth due, in part, to an increase in apoptosis. The present studies were conducted to determine if this zinc-induced apoptosis involves stimulation of mitochondrial apoptogenesis.

Materials and methods: The PC-3 a human malignant prostate cell line, which is zinc accumulating, was exposed to medium supplemented with physiologic levels of zinc.

Results: By 24 h, zinc treatment resulted in the translocation of cytochrome c from the mitochondria to the cytosol, the activation of caspase-9 and caspase-3, and eventually, the cleavage of nuclear poly(ADP)-ribose polymerase (PARP). Under similar conditions, exposure of freshly prepared rat ventral prostate cells (which are also zinc accumulating) resulted in increased apoptosis following translocation of cyochrome c and activation of caspases-9 and 3. The human prostate PZ-HPV-7 cells, which do not accumulate zinc, did not exhibit any apoptotic effect from zinc treatment.

Conclusion: The accumulation of high intracellular levels of zinc by prostate cells induces mitochondrial apoptogenesis. This represents a newly identified physiological effect of zinc in the regulation of prostate cell growth.

Background and purpose: The clinical utility of the percentage of positive prostate biopsies in predicting prostate specific antigen (PSA) outcome after radical prostatectomy (RP) or external-beam radiation therapy (EBRT) for men with PSA-detected or palpable prostate cancer is not established.

Methods: A Cox regression multivariable analysis was used to determine whether percent-positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men, while accounting for the previously established risk groups based on the pretreatment PSA concentration biopsy Gleason score, and the 1992 American Joint Commission on Cancer clinical T stage.

Results: In the intermediate-risk group, 80% of the patients (stage T(2b) or biopsy Gleason 7 or PSA 10-20 ng/mL) could be classified into either an 11% or an 86% 4-year PSA control cohort using the preoperative prostate biopsy data. These findings were validated using an independent surgical (N = 823) and radiation (N = 473) data set. Percent-positive prostate biopsies added clinically significant information regarding time to PSA failure after RP.

Conclusions: The percentage of positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome after RP or EBRT.

Purpose: We report the results of surgery in 520 patients with clinically localized carcinoma of the prostate (CaP) who received preoperative neoadjuvant hormonal therapy (NHT) for 3 to 11(+) months.

Methods: The results in the NHT patients were compared with those in 1,413 men having surgery without NHT at our institution during the same time period. In the group without pretreatment, the median and mean follow-up was 36 and 21 months, respectively. In the patients receiving NHT, the median follow-up was 33 months and the mean 41 months.

Results: The overall disease-free survival (DFS) rate (serum prostate specific antigen [PSA] concentration < or = 0.2 ng/mL) was 75% at 5 years and 50% at 10 years. There was no statistically significant difference in overall DFS rate between men who had NHT and those who did not. No DFS advantage could be demonstrated for those patients with a presenting PSA >20 ng/mL who received NHT compared with patients with the same PSA concentration who did not receive NHT. Despite our previous experience indicating improved survival with NHT in men with a presenting PSA of > 10 ng/mL, we could find no advantage to NHT in enhancing DFS. At a median survival of 35 months (mean 41 months) in 201 men with an initial PSA > or = 10 ng/mL, 70% had an undetectable PSA concentration at 5 years compared with 72% at the same time point in men presenting with PSA <10 ng/mL. In the group expected to have the best surgical result; i.e. those men whose preoperative PSA was < or = 7 ng/mL, there was no DFS difference in men given NHT compared with those having no hormonal manipulation. Patients presenting with stage T(1) disease had a significantly better DFS than those with either T(2) or T(3) CaP. However, within each stage, the addition of NHT to surgery did not result in a higher DFS rate. The 5- and 10-year DFS rates for stage T(1) were 80% and 64%, for T2 disease 78% and 50%, and for T3 disease 67% and 50%. There was a statistically significant difference (P < or = 0.003) in survival between stage T(1) and stage T(2) disease, but no significant difference in DFS was noted in patients presenting with stage T(2) compared with T3 cancer (P = 0.431). Gleason score was not a significant predictor of durable DFS, and the addition of NHT did not improve the DFS within groups of patients with similar Gleason scores. Men with only one or two positive biopsy cores did significantly better than those with more than three positive cores (P = 0.06). There was a significant difference in DFS between men who had organ-confined disease and those with disease outside the gland (P = 0.0003). However, NHT did not improve DFS. The presence of positive surgical margins was a negative prognostic factor (P = 0. 001). Men who received NHT had a statistically lower positive margin rate (P = 0.001), but NHT did not increase the likelihood of a durable DFS (P = 0.175). The duration of NHT did

Background and purpose: Neoadjuvant hormonal therapy (NHT) has been used for more than a decade for prostate cancer, but the results of clinical trials are only now becoming available, and the value of the treatment is not yet clear. The authors reviewed the results of the European randomized trials to increase our understanding of the role of this treatment.

Patients and methods: We report the results of 402 patients with prostate cancer (220 clinical stage T(2) and 182 clinical T(3) tumor), of whom 192 were randomly assigned to NHT using an LHRH analog (goserelin) plus flutamide for a period of 3 months (NHT) and 210 underwent radical prostatectomy only (RP).

Results: "Pathologic downstaging" occurred in 15% and 7% of the NHT and the RP group, respectively (P < 0.01). Fifty of the 189 patients in the NHT group (26%) and 68 of the 209 patients in the RP group (33%) developed disease progression, as determined by rising serum prostate specific antigen (PSA) concentration. Regarding local disease progression, the advantage for the use of NHT approached but did not reach statistical significance:18 of 189 patients (10%) in the NHT group and 33 of 209 patients (16%) in the RP group (P = 0. 07).

Conclusions: Although there was a trend in favor of the NHT group with respect to the number of patients with PSA progression and the number with local disease progression, it did not reach statistical significance. These results may be attributable to a true lack of benefit of adjuvant hormonal ablation or to a lack of statistical power to demonstrate a difference in a subset of patients who might benefit from this therapy.