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BACKGROUND: Prostate-specific membrane antigen (PSMA) is abundantly expressed in virtually 100% of prostate cancers and metastases. In addition, unlike prostate-specific antigen (PSA), PSMA is upregulated under conditions of androgen deprivation. Therefore, PSMA is an attractive therapeutic target for advanced prostate cancer. Recently, both the promoter and the enhancer driving prostate-specific expression of the PSMA gene were cloned. We describe here our analysis of the PSMA enhancer for the most active region(s) and present a way of using the enhancer in combination with the E. coli cytosine deaminase gene for suicide-driven gene therapy that converts the nontoxic prodrug 5-fluorocytosine (5-FC) into the cytotoxic drug 5-fluorouracil (5-FU) in prostate cancer cells. METHODS: Deletion constructs of the full-length PSMA enhancer were subcloned into a luciferase reporter vector containing either the PSMA or SV-40 promoter. The most active portion of the enhancer was then determined via luciferase activity in the C4-2 cell line. We then replaced the luciferase gene with the E. coli cytosine deaminase gene in the subclone that showed the most luciferase activity. The specificity of this technique was examined in vitro, using the prostate cancer cell line LNCaP, its androgen-independent derivative C4-2, and a number of nonprostatic cell lines. The toxicity of 5-FC and 5-FU on transiently transfected cell lines was then compared. RESULTS: The enhancer region originally isolated from the PSMA gene was approximately 2 kb. Deletion constructs revealed that at least two distinct regions seem to contribute to expression of the gene in prostate cancer cells, and therefore the best construct for prostate-specific expression was determined to be 1, 648 bp long. The IC(50) of 5-FC was similar in all cell lines tested (>10 mM). However, transfection with the 1648 nt PSMA enhancer and the PSMA promoter to drive the cytosine deaminase gene enhanced toxicity in a dose-dependent manner more than 50-fold, while cells that did not express the PSMA gene were not significantly sensitized by transfection. CONCLUSIONS: Suicide gene therapy using the PSMA enhancer may be of benefit to patients who have undergone androgen ablation therapy and are suffering a relapse of disease.
Radioimmunoscintigraphy using a radio-labelled antibody to prostate-specific membrane antigen (PSMA) has growing applications as a means of tissue-specific imaging based on functional characteristics and complements traditional staging investigations. Clinical applications in men with carcinoma of the prostate are being refined, and this study reports outcomes with this technique in our practice. Prostatic immunoscintigraphy scans were performed with In-111 CYT 356 in 49 men with carcinoma of the prostate, obtaining sequential images in two and three dimensions at 10 min, 24 and 48 h. Of the 49 men, 36 had clinically localized cancer, 10 had recurrent disease after radical radiotherapy or radical prostatectomy and three had rising PSA after primary endocrine treatment. Scan findings are discussed in the context of clinical management. Of the 36 men with clinically localized cancer, seven had increased uptake in regional and distant lymph nodes. Of these seven, three were treated with hormone manipulation, two by radical prostatectomy and two by radical radiotherapy. Among 10 patients who had recurrence after radical treatment of the primary tumour, scans showed local recurrence alone in four, and six had regional or distant metastases. Three patients treated with primary hormone manipulation had scans for rising PSA, and of these one had a positive regional node and two had distant soft tissue and bone metastases. In conclusion, prostatic radio-immunoscintigraphy scans highlight tissues involved by prostate cancer, including the prostate, lymph nodes, soft tissues and bone metastases as well as pelvic recurrence. Results may contribute to the clinical management of individual patients, although histological confirmation may be appropriate when considering alternative treatment. Prostate Cancer and Prostatic Diseases (2000) 3, 47-52
BACKGROUND: Zinc plays important roles in maintaining normal function of the prostate and in development of prostate malignancy. It has been demonstrated that prostate malignant epithelial cells contain much less cellular zinc than the surrounding normal epithelial cells. However, the pathway(s) which leads to lower zinc accumulation in malignant prostate epithelial cells is poorly understood. In this study, the zinc homeostatic features of two human prostate epithelial cell lines (non-tumorigenic, RWPE1, and tumorigenic, RWPE2) were investigated. Effects of over-expression of ZIP1 in RWPE2 on cell proliferation and apoptosis were also studied. RESULTS: RWPE2 accumulated less intracellular zinc than RWPE1 due to the decreased zinc uptake activity. The mRNA expression of ZIP1 and ZIP3 in RWPE1 and RWPE2 was comparable. However, the protein expression of ZIP1 in RWPE2 was lower than that in RWPE1. ZIP3 was detected in a lysosomal compartment of RWPE2 while no ZIP3 was detected in the same compartment of RWPE1. Over-expression of ZIP1 in RWPE2 resulted in an elevation of intracellular zinc concentration and suppression of cell growth of RWPE2 due to the increased apoptosis. CONCLUSION: These findings suggest that tumorigenic prostate epithelial cells accumulated less intracellular zinc than non-tumorigenic prostate epithelial cells. The reduction in capacity for accumulation of intracellular zinc in tumorigenic prostate epithelial cells may be caused by the decrease in the ZIP1 protein expression and the intracellular redistribution of ZIP3 in RWPE2. RWPE1 and RWPE2 are excellent cellular models to study the association of intracellular zinc levels with prostate cancer progression.
Procollagen (I) carboxyterminal propeptide (PICP) is a metabolite of procollagen, a precursor molecule of collagen type I, which accounts for more than 90% of the organic matrix of the bones. Serum PICP levels indicate the rate of bone collagen synthesis and therefore the osteoblastic activity. In this study we evaluate the clinical usefulness of serum PICP as an indicator of bone metastases in patients with prostate cancer in relation to bone scan and to prostate specific antigen (PSA) measurements. We found no similar study in the literature relating these three tests. Seventy-eight patients (median age 63+/-4,3 years) with prostate adenocarcinoma were examined. The diagnosis was confirmed histologically. Bone metastases were diagnosed in 42 (54%) of them assessed by bone scans (Group A), while the remaining 36 patients (46%) had no bone metastases (negative bone scans and X-rays) (Group B). We also examined 21 patients with benign prostate hyperplasia as a control group (Group C). All patients had serum PICP measurements, bone scans with (99m)Tc-MDP and PSA measurements. None of them had a history of disease or of using drugs known to affect bone metabolism. Serum levels of PICP were assayed by a radioimmunoassay (RIA) kit (Orion Cooperation, Farmos Diagnostics, Finland). Serum PSA was also tested by a RIA kit (Tandem-R, Hybritech Inc, USA). PICP levels in Group A were 265+/-89 microg/l, in Group B 128+/-39 microg/l and in Group C patients 110+/-48 microg/l. High levels of PICP above 170 microg/l, were diagnostic of bone metastases with sensitivity 54%, specificity 93% and accuracy 84%. In comparison, PSA levels above 4 ng/ml were also diagnostic with a sensitivity of 68%, specificity of 91% and accuracy 88%. Patients with low levels of PICP, lower than 90 microg/l, n=31, had no bone metastases. The positive prognostic value of bone scan was 74% with a sensitivity of 76%, specificity of 58% and accuracy 71%. Positive bone scans combined with very high levels of PICP and PSA, had positive prognostic value 97%, with sensitivity of 78%, specificity of 96% and accuracy 97%, while bone scans with levels of PICP lower than 170 microg/l, had positive prognostic value of 32%. Levels of PICP and PSA were significantly higher in patients with prostate cancer and bone metastases in comparison to patients with benign prostate hyperplasia (P<0.0001) respectively. Also, levels of PICP and PSA were higher in patients with prostate cancer without metastases as compared to prostate hyperplasia (P<0.0005 and P<0.0001 respectively) (Wilcoxon-Mann-Whitney test). When metastases were more extensive, PICP levels were higher than PSA. It is concluded that PICP as a marker of osteoblastic activity is useful for diagnosing bone metastases of prostate adenocarcinoma but when co-evaluated with PSA and the bone scan, the diagnostic accuracy of these three diagnostic procedures is much higher.
High-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor to invasive prostate cancer observed as an isolated entity in a growing subset of men undergoing prostate biopsy. The presence of HGPIN predicts an increased risk of 1) coexisting occult prostate cancer at baseline and 2) delayed progression to prostate cancer. As such, men with HGPIN represent a population at high risk for the development of prostate cancer. Because the current recommended therapy is observation and delayed-interval biopsies until cancer develops, a well-tolerated therapeutic agent capable of interrupting the progression of HGPIN to cancer is highly desirable. Given the known cancer-stimulatory effects of estrogens in the prostate, the use of selective estrogen receptor modulators (SERMs) to provide an antiestrogen effect represents a novel strategy for prostate cancer prevention. Recent phase II data from trials using toremifene in the treatment of men with HGPIN validate the use of SERMs as a rational and provocative strategy for the prevention of prostate cancer.
Recent studies and analyses have confirmed that baseline prostate volume is related to progression of benign prostatic hyperplasia (BPH) as well as to negative outcomes related to BPH, such as acute urinary retention (AUR) and need for surgery, and can also predict response to therapy. Other investigations have determined that prostate-specific antigen (PSA) level has good predictive value for assessing prostate volume. Strong evidence exists that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. Randomized placebo-controlled finasteride trials have shown that men with larger prostate volumes and higher PSA levels experience a clinically significant response to therapy compared with those with smaller prostate volumes and lower PSA levels. It has also been demonstrated that men with larger prostate glands and higher PSA levels are at increased risk for AUR and BPH-related surgery but that finasteride reduces these risks. Moreover, doxazosin and finasteride, alone and in combination, have been shown to significantly reduce BPH clinical progression.
Recent studies have indicated that the prostate-specific antigen (PSA) gene polymorphisms may be associated with the risk of prostate cancer in Caucasian populations. To verify the association, we examined the PSA polymorphisms at positions -158 and -252 in 300 prostate cancer cases, 216 benign prostatic hyperplasia (BPH) cases, and 266 controls by the PCR-restriction fragment length polymorphism analysis. Regarding the PSA polymorphism at position -158, the A allele was less common in the Japanese population (A 0.22, G 0.78) than that in other ethnic populations (A 0.37-0.52, G 0.48-0.63). No significant associations were found between the polymorphism and the risks of prostate cancer (P=0.530) and BPH (P=0.740) and between the polymorphism and the serum PSA level (P=0.626). As for the polymorphism at position -252, no significant results were also found. In conclusion, the PSA polymorphisms may not be associated with the risk of prostate cancer development and its disease progression and the risk of BPH in Japanese men, and may also be not related to the serum PSA level in Japanese men with prostate cancer.
OBJECTIVE: To determine whether prostate cells are disseminated into the circulation of patients after transurethral resection of the prostate (TURP), as assessed by a reverse transcription-polymerase chain reaction (RT-PCR) assay for prostate specific antigen (PSA) mRNA. PATIENTS AND METHODS: Fifty-one patients, comprising 34 with benign prostatic hyperplasia (BPH) and 17 with prostate cancer who were undergoing routine TURP, had blood samples taken before and 30 min after surgery. The blood mononuclear cell layer was isolated by density-gradient centrifugation and total RNA extracted. Complementary DNA was synthesized by RT of the RNA. The target PSA sequence was amplified by PCR with specific PSA primers and the product detected on agarose-gel electrophoresis with ethidium bromide staining. RESULTS: Five patients (all with prostate cancer) were positive on PSA RT-PCR before surgery and remained positive after TURP. Of the remaining 46 patients, five (11%; three with BPH and two with cancer) changed from a negative to a positive result after TURP. CONCLUSION: In a proportion of patients TURP causes the dissemination of prostate cells into the circulation which are then detectable by RT-PCR of PSA mRNA.
PURPOSE: To determine whether additional, far lateral cores improve the diagnostic performance of transrectal sextant biopsy in men with large prostate glands. METHODS: Men with prostate volumes of 50 mL or greater in transrectal ultrasonography who were suspected of prostatic adenocarcinoma were prospectively enrolled. Biopsy criteria were defined as 2.0 ng/mL or greater of serum total prostate-specific antigen and/or abnormal findings on digital rectal examination. Four cores of far lateral biopsies were added to the standard sextant technique. RESULTS: Of 104 patients enrolled in the present study and undergoing biopsy, 14 (13.5%) were diagnosed as having prostate cancer and 27 (26.0%) were diagnosed as having prostatic intraepithelial neoplasia (PIN) or an atypical gland. There were no cases where cancer was only detected in the additional cores, whereas PIN/atypical gland was uniquely detected from the additional, far lateral sites in eight of the 27 patients who were diagnosed with this condition. CONCLUSIONS: Although the number of patients diagnosed as having PIN/atypical gland might increase with the addition of far lateral cores, this additional sampling does not improve cancer detection rates in men with large prostate glands.
The effectiveness of transurethral microwave thermotherapy (TUMT) for BPH has been confirmed. To identify the characteristics of the ideal candidate, retrospective analysis and morphometric study of prostatic tissue were performed. Forty-two patients with symptomatic BPH were included in the study; these comprised 10 patients treated for more than 3 months with anti-androgen pre-TUMT (group A) and 32 fresh cases (group B). Subjective and objective responses were evaluated at 2 months post TUMT. In 12 fresh cases who underwent pre-TUMT biopsy of the prostate, the stromal-to-epithelial ratio was determined via quantitative image analysis on a computer-assisted morphometry system. No significant differences in baseline patient characteristics were found between the two groups: age, prostate volume, peak flow rate (PFR), or International Prostate Symptom Score (I-PSS). However, significant differences in treatment outcome were found between the two groups (group A vs. group B, respectively): total energy delivered to the prostate: 96 kJ vs. 125 kJ: I-PSS decrease from baseline: 5.9 vs. 11.6; PFR increase from baseline: 1.1 vs. 4.7 ml/sec. There was a positive correlation between the I-PSS change from baseline and the stromal-to-epithelial ratio of the prostatic tissue (r = 0.4857). The results suggest that microwave interacts poorly with the prostate due to the artificially created "lack" of glandular tissue. The morphometric study also supports the contention that the histological composition of the prostatic tissue plays an important role in terms of microwave thermal interactions and treatment outcome.
LNCaP lineage-derived human prostate cancer cell lines C4-2 and C4-2B4 acquire androgen independence and osseous metastatic potential in vivo. Using C4-2 and C4-2B4 the goals of the current investigation were 1) to establish an ideal bone xenograft model for prostate cancer cells in intact athymic or SCID/bg mice using an intraosseous route of tumor cell administration and 2) to compare prostate cancer metastasis by administering cells either through intravenous (i.v.) or intracardiac administration in athymic or SCID/bg mice. Subsequent to tumor cell administration, prostate cancer growth in the skeleton was assessed by radiographic bone density, serum prostate-specific antigen (PSA) levels, presence of hematogenous prostate cancer cells and histopathologic evaluation of tumor specimens in the lymph node and skeleton. Our results show that whereas LNCaP cells injected intracardially failed to develop metastasis, C4-2 cells injected similarly had the highest metastatic capability in SCID/bg mice. Retroperitoneal and mediastinal lymph node metastases were noted in 3/7 animals, whereas 2/7 animals developed osteoblastic spine metastases. Intracardiac injection of C4-2 in athymic hosts produced spinal metastases in 1/5 animals at 8-12 weeks post-injection; PC-3 injected intracardially also metastasized to the bone but yielded osteolytic responses. Intravenous injection of either LNCaP or C4-2 failed to establish tumor colonies. Intrailiac injection of C4-2 but not LNCaP nor C4-2B4 cells in athymic mice established rapidly growing tumors in 4/8 animals at 2-7 weeks after inoculation. Intrafemoral injection of C4-2 (9/16) and C4-2B4 (5/18) but not LNCaP (0/13) cells resulted in the development of osteoblastic bone lesions in athymic mice (mean: 6 weeks, range: 3-12 weeks). In SCID/bg mice, intrafemoral injection of LNCaP (6/8), C4-2 (8/8) and C4-2B4 (8/8) cells formed PSA-producing, osteoblastic tumors in the bone marrow space within 3-5 weeks after tumor cell inoculation. A stepwise increase of serum PSA was detected in all animals. Reverse transcription-polymerase chain reaction (RT-PCR) to detect hematogenously disseminated prostate cancer cells could not be correlated to either serum PSA level or histological evidence of tumor cells in the marrow space. We have thus established a PSA-producing and osteoblastic human prostate cancer xenograft model in mice.
BACKGROUND: An elucidation of the complex, morphological and molecular changes that underlie benign and malignant prostatic disease will likely lead to improved methods of diagnosis and therapy for those disorders. To identify and understand the interrelation of the phenotypic and genetic changes inherent in these important diseases requires the development and use of in vivo and in vitro models that closely mimic specific aspects of the disease process. Once the suspected molecular underpinnings of prostatic disease are uncovered, in vivo and in vitro models will be required for further testing of the functional significance of specific genetic alterations as they are identified. In addition models of prostatic disease are necessary to evaluate novel therapeutic approaches. METHODS: The mouse prostate reconstitution (MPR) model system was developed more than a decade ago with these specific needs in mind. Over the years, specific modifications of the MPR model have demonstrated its versatility and applicability for the study of benign and malignant prostatic disease, including metastatic progression. RESULTS: We discuss various modifications of the MPR model system made for its application to specific aspects of prostatic disease; the clinically relevant information that has been gleaned thus far from the use of this model system; and advances on the horizon for the expansion of its role in prostate research. CONCLUSIONS: The MPR model system has contributed substantially to the understanding and treatment of benign and malignant prostatic diseases. Additional modifications in this series of in vivo and in vitro models will likely lead to further advances.