The Prostate. Supplement最新文献

Background: Prostate-specific antigen (PSA) is a widely-used tumor marker to aid in the early detection of prostate cancer. PSA testing has appreciable false-positive and false-negative results, particularly in the 2.5-10.0 ng/ml range. Measurements of the percentage of nonprotein-bound (free) PSA in serum, which is lower in patients with prostate cancer, has been evaluated as a method for increasing the accuracy of PSA testing.

Methods: The literature on forms of PSA in serum, as it relates to issues of clinical utility for prostate cancer screening, was reviewed and summarized through May 1996.

Results: Measurements of the percentage of free PSA in serum increase the accuracy of PSA testing for prostate cancer in men whose total PSA levels are 2.5-10.0 ng/ml. Cutoffs for screening are affected by prostate volume and total PSA levels. One study also demonstrated a correlation between percentage of free PSA and pathologic features of cancer aggressiveness.

Conclusions: Measurement of free PSA in serum has potential clinical utility for increasing the sensitivity and specificity of PSA screening. Insufficient data are available to establish cutoffs to be used in clinical practice. Cutoffs are affected by total PSA level and prostate volume. The prevalence rate of cancer in the screened population (age, race, previous biopsy history, etc.) will also influence screening cutoffs. Percentage of free PSA may also correlate with the potential aggressiveness of early-stage prostate cancer.

We evaluate the metabolic inhibitory, antiproliferative, and antisecretory effects of LY300502, a benzoquinolinone human-specific type I-selective steroid 5alpha-reductase inhibitor in LNCaP human prostatic adenocarcinoma cell cultures. Reductive metabolism of [3H-T] in the LNCaP cells was inhibited in a concentration-dependent manner by LY300502 (IC50 approximately 5.77 nM). The proliferative responses of LNCaP cells to LY300502 were examined in the presence of 0.1 NM testosterone (T), a concentration that stimulates maximal LNCaP cell numbers 40% above control levels. LY300502 significantly anatagonized T-induced stimulation of LNCaP cellular proliferation at concentrations greater that 10 nM (P<0.05), and at 1,000 nMcompletely blocked the mitogenic effects of T on LNCaP cells. In the absence of androgen, LY300502 had no effect on LNCaP cellular proliferation. In the presence of 100 nM T, an androgen concentration that maximally stimulates in vitro PSA production, LY300502 significantly antagonized T-induced PSA secretion at a concentration equal to or greater than 30 nM (P<0.05). These studies provide the basis for additional investigations into the pathophysiologic significance of type I 5alpha-reductase to prostatic cancer and the potential utility of selective inhibitors as therapeutic agents.

The etiology of prostate cancer or of benign prostatic hyperplasia (BPH) is essentially not understood. It is becoming clear, however, that major determinants of the malignant or hyperplastic phenotype are various growth-stimulatory or -inhibitory factors and their receptors, whose inappropriate expression or loss disrupts normal regulation of cell proliferation and differentiation. Cell culture has been a versatile tool for studying the expression and interaction of growth factors in prostatic cells. Immunohistochemistry and in situ hybridization have provided a view of growth factor expression coupled with histopathology. The eventual definition of autocrine, paracrine, and endocrine pathways of growth regulation in the human prostate will facilitate the design of new preventative, diagnostic, and therapeutic strategies.

Background: Serum prostate-specific antigen (PSA) exists in different molecular forms, and their respective concentration has been proposed as a useful tool to improve discrimination between benign prostatic hypertrophy (BPH) and prostate cancer (PC).

Methods: The relevance of the free to total PSA ratio was prospectively studied in a selected urology clinic population of 420 patients. Total serum PSA ranged from 2.1 to 30 ng/ml; 154 had PC and 266 had BPH.

Results: Receiver operating characteristic (ROC) curves were constructed for the total population (total-PSA range from 2.1 to 30 ng/ml) and for the diagnostic gray zone of 2.1-10 ng/ml. For the two groups, the free to total PSA ratio had a higher specificity than total-PSA for all sensitivity levels. Cut-off values were found to, vary with prostate weight.

Conclusions: Although free to total PSA ratio demonstrated better performances than total-PSA, its use in screening appears problematic, due to the low prevalence of prostate cancer.

Background: Prostate-specific antigen (PSA) is a most valuable tool for the early detection of prostate cancer; however, it has a high false-positive rate as presently used in prostate cancer screening programs. Patients with persistent PSA elevations, normal digital rectal examinations, and multiple negative biopsies present a clinical dilemma. We prospectively evaluated whether free PSA improves the specificity of PSA and can be useful as a clinical guide to avoid repeat prostate biopsies in a group of such patients.

Methods: Sixty-seven men with persistent PSA elevations (mean 9.6 ng/mL; range 4.1-24.8 ng/mL), normal digital rectal examinations, and two or more prior sextant biopsies (mean 2.8), had serum collected for measurement of total and free PSA. All patients were rebiopsied to determine the receiver-operating characteristics (ROC) of total PSA vs. percent free PSA for prostate cancer detection.

Results: This study by biopsy identified 11 new prostate cancer cases. The median percent free PSA was significantly higher at 18.1% among men without prostate cancer, compared to 6.4% in men with prostate cancer (P < 0.00005). When sensitivity was plotted against I-specificity, the area under the receiver-operating curve (ROC) for percent free PSA was 0.95, compared to 0.75 for free PSA density, 0.59 for PSA density, and 0.54 for PSA. In patients with elevated total PSA levels, normal digital rectal examinations, and two prior sets of negative sextant prostate biopsies, a cutoff of 10% free PSA would maintain sensitivity at 91% with a corresponding specificity of 86%.

Conclusions: Selective measurement of percent free PSA in cases of uncertain diagnosis can significantly improve the specificity of prostate cancer detection compared to total PSA alone. A low percent free PSA (< 10%) appears to be a significant predictor of prostate cancer even after two or more negative prostate biopsies.

The ability to induce multiple apoptotic regressions of an androgen-dependent tumor cell population by repeated cycles of androgen withdrawal and replacement may be advantageous in therapeutic strategies aimed at delaying or preventing tumor progression. With greater insight into factors that either initiate or limit apoptosis, more efficient application of intermittent therapy might be achieved, especially if methods could be devised to increase the length or number of treatment cycles. Both calreticulin and clusterin represent proteins with a potential role in the regulation of apoptosis. Calreticulin may inhibit target gene transcription by interacting with steroid hormone receptors, thereby masking their DNA-binding sites and triggering the onset of the apoptotic process. Clusterin, on the other hand, is a membrane-stabilizing protein that appears to be involved in limiting the autophagic lysis of epithelial cells during apoptosis. Also, the increasing tendency for nuclear localization of clusterin after androgen withdrawal may preserve the nuclear environment, limiting the lethal effect of treatment. Thus, tumor progression, characterized by the loss of apoptotic potential, appears to be linked in part to the inappropriate activation of TRPM-2 gene, which accounts for the constitutive expression of clusterin.

Background: Since free prostate-specific antigen (PSA) and gamma-seminoprotein (gamma-SM) recognize similar epitope(s) of PSA, the significance of serum-free PSA and gamma-SM in the early detection of prostate cancer was compared.

Methods: A prospective clinical trial was conducted on 701 male volunteers, age 50 years or older. Free PSA (Tandem-R free PSA, Hybritech) and gamma-SM (gamma-SM, Chugai) levels were determined, and biopsies were performed if the PSA (Tandem-R, Hybritech) level was > 4 ng/ml, or if digital rectal examination (DRE) was suspicious.

Results: One hundred and eighty-seven men (27%) had either a PSA level > 4 ng/ml or a suspicious DRE. Of 116 biopsies performed, cancer was detected in 13 (1.9%, 13/701). Receiver-operating characteristic analysis of free PSA to PSA ratio (free PSA ratio, %) and gamma-SM to PSA ratio (gamma-SM ratio), to differentiate normal biopsy findings from cancer, showed that the optimal values were 12% and 0.38, respectively. Positive predictive value for cancer was 24% (12 cancers/50 biopsies) for PSA alone, 42% (8/19) for the combination of PSA and DRE, 45.5% (10/22) for the combination of PSA and gamma-SM ratio, and 50% (10/20) for the combination of PSA and free PSA ratio. Regression analysis showed that gamma-SM highly correlated with free PSA, but that the analytical detection limit of gamma-SM was 1 ng/ml, significantly higher than that of free PSA.

Conclusions: Free PSA determination might effectively eliminate unnecessary biopsies in subjects with PSA > 4 ng/ml, and gamma-SM might provide a complementary index to free PSA, but its validity should be further studied in other settings, such as after radical prostatectomy or during endocrine treatment.

Androgen ablation by bilateral orchiectomy or by the administration of gonadotropin-releasing hormone (GnRH) agonists has become standard treatment for advanced prostate cancer. However, serum levels of dihydrotestosterone (DHT) remain at about 40% of the precastration levels due to the conversion of the adrenal androgens. Maximal androgen blockade (MAB) aims to block the stimulatory action of this adrenal-derived DHT by adding antiandrogens to surgical or medical castration. Some of the largest and best controlled randomized trials in Europe and the United States have shown statistically better progression-free survival, overall survival, and survival from death by prostate cancer with MAB than with monotherapy with a GnRH agonist or with bilateral orchiectomy. Trial 30853 of the European Organization for Research and Treatment of Cancer (EORTC) compared MAB using a combination of goserelin subcutaneous depot (Zoladex; Zeneca Pharmaceuticals, Macclesfield, UK) and flutamide with bilateral orchiectomy. Some other published trials did not find the differences revealed by EORTC 30853, however, and so an overview or meta-analysis of trials on the effects of MAB was organized jointly by the American Cancer Society, the Urological Group of the EORTC, and the International Prostate Health Council. Preliminary results on some of the 23 trials included in the meta-analysis showed an advantage of the GnRH agonist therapy in combination with an anti-androgen, particularly in time to progression. If time to progression is viewed as improved quality of life due to the absence of symptoms, a net result in favor of the combination therapy is noted. The MAB trials, using flutamide as the antiandrogen, also showed a small but distinct improvement in survival with the combination treatment. An emphasis on prognostic factors allows treatment decisions to be reached more easily.