bluuebunny/crossref_metadata_2025 huggingface dataset:
The in vivo effect of regional hyperthermia on dunning R3327 prostatic tumor
Authors: Tucker Robert D. , Loening Stefan A. , Landas Steve , Mardan Ali H. , Zong‐Ying Ren , Lubaroff David M.
Published: February 2007

This report describes the in vivo effect of regional hyperthermia on male Copenhagen rats implanted with Dunning R3327 prostatic carcinoma. In six rats, a 22‐gauge 1.5‐cm needle was inserted into the tumor and heated to 46.5%C for 2 hr. Two hyperthermia treatments were administered 48 hr apart. In a separate group of six rats, the needle was inserted into the tumor, but not heated. After treatment, serial measurements of tumor volume and body weight were made twice a week for 4 weeks. From the first day of measurement to day 22, the tumor size in the treated group compared to control was significantly smaller, P = 0.02. In the first 12 days following treatment, the mean value of body weight in the treated and control groups decreased 7% and 3%, respectively. Following this, body weights increased to baseline levels by the end of the study. No other side effects related to hyperthermia were observed and no immediate mortality occurred. In the control group, two rats died from lung metastasis of the prostatic carcinoma after day 22. In the treated group, no lung metastases were found and no rats died before being sacrificed on day 29. Our experiments show that local elevation of the temperature of the Dunning tumor results in the deam of tumor cells; at 46.5°C for 2 hr there is marked tumor damage while the rats tolerated the hyperthermia well.
Differential antiproliferative activities of alpha‐ and gamma‐interferon and tumor necrosis factor alone or in combinations against two prostate cancer xenografts transplanted in nude mice
Authors: Van Moorselaar Reindert J. A. , Van Stratum Peter , Borm George , Debruyne Frans M. J. , Schalken Jack A.
Published: February 2007

We have investigated the antiproliferative effects of recombinant human alpha‐ and gamma‐Interferon (IFN) and recombinant human Tumor Necrosis Factor alpha (TNF) against the hormone‐independently growing PC3 and DU145 prostatic tumor lines. Subcutaneous, peritumoral administration of the drugs was started 24 hours after subcutaneous implantation of 1–2 mm3 tumor pieces. IFN was given three times per week and TNF five times per week. IFN‐alpha (dose‐range 0.5–5 ng/gram bodyweight) had significant growth‐inhibiting effects against the PC3 tumor, but showed no significant antitumor effects against the DU145 tumor. IFN‐gamma monotherapy (dose‐range 8–80 ng/gram bodyweight) was less effective than IFN‐alpha. 500 ng/gram TNF produced growth inhibition of both tumors, whereas the lower dose (50 ng/g) was only effective against the PC3 tumor. IFN‐alpha and ‐gamma combination treatment had significant antiproliferative effects against the PC3 tumor, but not against the DU145 tumor. Combinations of IFN‐alpha and TNF were very effective against both xenografts; some combinations resulted in complete growth inhibition. IFN‐gamma and TNF combinations also showed significant antitumor effects against both tumor lines. We therefore conclude that cytokine combination treatment may provide a new approach in the treatment of hormone‐escaped prostatic tumors.
Investigation on serum neurone‐specific enolase in prostate cancer diagnosis and monitoring: Comparative study of a multiple tumor marker assay
Authors: Tarle Marko , Radoś Nikola
Published: February 2007

A quadruple tumor marker serotest assay (neurone‐specific enolase, NSE, prostate‐specific antigen, PSA, prostatic acid phosphatase, PAP, and carcino‐embryonic antigen, CEA) was performed on sera from both 63 patients with untreated prostate cancer and 135 patients treated with orchiectomy, flutamide, diethylstilbestrol (DES), cyproterone acetate (CPA), and Estracyt. In untreated patients with local tumor elevated blood NSE concentrations were found more frequently (10/35, 28,6%) than in untreated subjects with disseminated disease (3/28, 10.7%). Elevated NSE values were measured more frequently in nonre‐sponders to therapy 10/46 (21.7%), than in responders during prostate cancer partial remission (2/89, 2.2%). In none of NSE‐positive neoplasms a small cell prostate cancer has been histologically detected. Many of NSE‐positive tumors are also closely associated with elevated blood CEA values. The applied anticancer drugs were inefficient in the normalization of neither one from the pair of elevated NSE and CEA concentrations (regardless of the numerical values of the other two markers, PSA and PAP), but their values were found to decline occasionally only after surgical treatment. In patients with raised PSA, PAP, and CEA levels but with a normal NSE value, the application of the same treatment strategies was in the most of subjects sufficient to provoke either temporary or even lasting tumor response to therapy. Hence, it appears that the assessment of the NSE serotest, despite its minimal value in the overall tumor staging and monitoring, might furnish the decision‐making step related to the treatment of aggressive prostate cancer with an additional and powerful tool.
Immunohistochemical study of metallothionein in normal and benign prostatic hyperplasia of human prostate
Authors: Suzuki Takanori , Umeyama Tomokazu , Ohma Chikako , Yamanaka Hidetoshi , Suzuki Keiji , Nakajima Katsuyuki , Kimura Masami
Published: February 2007

Metallothionein (MT) in the human prostate gland was examined. Prostatic tissues were obtained from patients of urinary bladder cancer who had received radical cystoprostatectomy. MT content was 99.3 μg/g wet tissue (w.t.) in the peripheral zone (PZ), 12.0 μg/g w.t. in the preprostatic region (PR), 7.3 μg/g w.t. in the central zone (CZ), 6.8 μg/g w.t. in the anterior fibromuscular stroma, and 29.5 μg/g w.t. in benign nodular hyperplasia (adenoma) by radioimmunoassay. Immunohistochemical study demonstrated that MT was localized in the cytoplasm, nuclei of glandular epithelia, and secretory products. In general, a positive immunoreaction was strong in PZ and weak in CZ. It is considered that glandular epithelial cells in PZ, PR, CZ, and adenoma may react differently to heavy metals, e.g., zinc and cadmium.
Effect of etidronate disodium on the development of bone lesions in an animal model of bone metastasis using the human prostate cancer cell line PC‐3
Authors: Shevrin Daniel H. , Gorny Kathleen I. , Rosol Thomas J. , Kukreja Subhash C.
Published: February 2007

We have established an animal model of bone metastasis using the PC‐3 human prostate tumor cell line. In order to assess whether inhibition of bone resorption would prevent the development of bone metastasis, the diphosphonate etidronate (EHDP) was administered to 20 mice at a dose of 30 mg/kg subcutaneously daily starting 2 days prior to injection of tumor cells. Control mice received daily injections of the saline vehicle. In the EHDP‐treated mice, there was no significant reduction in the incidence of bone metastasis, the size of the lesions, or the number of bone lesions per mouse. Approximately 50% of the mice developed bone metastasis, which was similar to the control group and similar to what was observed in earlier studies with this animal model. Histomorphometric analysis of bones showed marked inhibition of mineralization in EHDP‐treated mice, thus indicating biological effect on the bone. Therefore, the use of EHDP in biologically effective doses failed to reduce the incidence, size, or number of bone metastases in this animal model.
Reconstituted basement membrane promotes morphological and functional differentiation of primary human prostatic epithelial cells
Authors: Fong Chau‐Jye , Sherwood Edward R. , Sutkowski Debra M. , Abu‐Jawdeh Graziella M. , Yokoo Hidejiro , Bauer Kenneth D. , Kozlowski James M. , Lee Chung
Published: February 2007

Prostatic epithelial cells undergo rapid proliferation and lose their ability to synthesize and secrete prostate‐specific antigen (PSA) and prostatic acid phosphatase (PAP) under standard tissue culture conditions. Herein, we compared the morphology, growth, secretory activity, and intermediate filament expression of human prostatic epithelial cells cultured on either standard tissue culture plastic or reconstituted basement membrane. Epithelial cells grown on plastic exhibited a 10‐fold increase in proliferation and a higher percentage of cells in the S‐phase of the cell cycle compared to cells cultured on basement membrane. However, cells grown on basement membrane secreted markedly higher levels of PSA and PAP. The basement membrane‐induced enhancement of secretory activity was potentiated by dihydrotestosterone (DHT) and prostate stromal cell conditioned medium. Morphological studies showed that cells plated on basement membrane formed organoid‐like clusters and maintained several aspects of differentiated epithelium including abundant secretory vesicles, microvilli, and desmosomes with associated cytoskeletal elements. Cultivation of epithelial cells on basement membrane components also suppressed the expression of vimentin, a mesenchymal intermediate filament polypeptide. However, cytokeratin expression was abnormal in cells grown on either surface. These results indicate that the differentiated properties of prostatic epithelial cells are promoted by cultivation on reconstituted basement membrane in the presence of DHT and stromal cell conditioned medium.
Endogenous protein substrates for prostatic acid phosphatase in human prostate
Authors: Lee Hansoo , Ming Chu T. , Lee Ching‐Li
Published: February 2007

In order to identify the endogenous phosphoprotein substrates for human prostatic acid phosphatase (PAP), cellular proteins of human normal, benign, and malignant prostatic tissues as well as carcinoma cell lines were phosphorylated by the cellular kinases in the presence of (γ‐32P)‐ATP and then were subjected to dephosphorylation reaction by PAP. Of several endogenous phosphoproteins, PAP preferentially dephosphorylated a cytosolic protein of Mr 83 kDa. The dephosphorylation of the 83 kDa phosphoprotein (designated pp83) by PAP was uniformly observed in all cells/tissues of prostate origin, and was completely inhibited by L(+)‐tartrate, the classic inhibitor of PAP. Phosphoamino acid analysis revealed that pp83 was a tyrosine‐poor phosphoprotein and was mostly dephosphorylated by PAP at serine/threonine residues rather than tyrosine residues. Further comparison of dephosphorylation rate with that of an endogenous phosphotyrosine‐containing phosphoprotein (pp53) revealed that PAP possessed both phosphoserine/threonine protein phosphatase and phosphotyrosine protein phosphatase activity. These results demonstrate that pp83 apparently is an endogenous substrate of PAP in human prostate, and that, instead of a phosphotyrosine protein specific phosphatase, PAP is a universal protein phosphatase hydrolyzing equally well the phosphotyrosine, serine, and threonine residues.
Growth hormone receptor expression in the dunning R 3327 prostatic carcinoma of the rat
Authors: Sinowatz F. , Breipohl W. , Waters M. I. , Lincoln D. , Lobie P. E. , Amselgruber W.
Published: February 2007

The Dunning R3327 rat carcinoma is an important model for human prostate adenocarcinoma. In the present study this tumor was further characterized by immunohistochemical demonstration of receptors for growth hormone (GH‐R). Weak GH‐R immunoreactivity was present in the secretory epithelial cells of the tumor acini. Large epithelial cells which were localized at the periphery of the acini and large cells in the stroma, which are probably derived from the epithelium (“Large neoplastic epithelial cells”), displayed a strong staining with one of the monoclonal antibodies (Mab 263) to GH‐R. The presence of GH‐R receptors in proliferating prostatic tumor cells supports the concept that GH reacts directly on prostate target tissue to facilitate tumor cell growth.
Evidence for a non‐estrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in vivo
Authors: Eklöv S. , Nilsson S. , Larson A. , Björk P. , Hartley‐Asp B.
Published: February 2007

Estramustine is one of the main metabolites of estramustine phosphate (EstracytR), a drug used in the treatment of advanced prostatic cancer. In the present study the hormone independent human prostatic carcinoma cell line DU 145 implanted subcutaneously in nude mice (NMRI) was used to investigate the mode of action of estramustine in vivo. Metaphase arrest was found in mice treated with estramustine intraperitoneally, 200 and 400 μg daily for 2 weeks, 5 days a week. A significant dose dependent decrease in the number of anaphase figures was found. A 7 to 8 fold increase in the number of abnormal metaphases, i.e., highly contracted and unaligned chromosomes, was found. Uptake and retention of 3H‐estramustine was found in tumour tissue. No increase in the mitotic index or the number of abnormal metaphases was found in animals treated with polyestradiol phosphate (EstradurinR). This is the first time evidence has been presented demonstrating the anti‐mitotic effect of estramustine in vivo.
A local direct effect of pituitary graft on growth of the lateral prostate in rats
Authors: Schacht M. J. , Niederberger C. S. , Garnett J. E. , Sensibar J. A. , Lee C. , Grayhack J. T.
Published: February 2007

Prolactin and testosterone are synergistic in stimulating growth of the rat prostate. The lateral lobe is more sensitive to this synergism than the ventral and dorsal lobes. To investigate whether prolactin acts directly in the rat prostate or indirectly through another systemic mediator, anterior pituitary grafts (1 mm3) were implanted in the lateral prostate of castrated Sprague‐Dawley rats in whom a 0.5 cm or 1.0 cm testosterone‐filled silastic tubing was implanted subcutaneously at the same time. Rats were randomly assigned to receive either the pituitary or a muscle chip of similar size grafted beneath the fascia lateral to the lateral prostate. Twenty‐one days later, serum prolactin levels were not elevated in pituitary‐grafted animals and were not significantly different from those in muscle‐grafted rats. The mean lateral prostate weight on the grafted side in pituitary‐implanted rats with 1.0 cm testosterone tubing was 43% heavier than either that of the contralateral side or the corresponding weights in muscle‐implanted rats. In pituitary‐implanted rats with 0.5 cm testosterone tubing, the mean lateral prostate weight on the grafted side was 60% heavier than either that of the contralateral side or that of the corresponding weights in muscle‐implanted rats. The weight of the ventral and dorsal lobes of the prostate was not significantly affected by the presence of pituitary grafts in one of the lateral lobes. The local effect of prolactin on the lateral prostate was further demonstrated by an overall decline in tissue concentrations of dihydrotestosterone in the grafted side. These results provided evidence to indicate that there was a direct effect of prolactin on growth of the lateral prostate in rats.
Phase II evaluation of coumarin (1,2‐benzopyrone) in metastatic prostatic carcinoma
Authors: Mohler James L. , Gomella Leonard G. , Crawford E. David , Glode L. Michael , Zippe Craig D. , Fair William R. , Marshall M. Ernest
Published: February 2007

The unavailability of effective treatment of metastatic hormone refractory prostatic carcinoma warrants trials of new and promising treatments. Coumarin is an investigational new drug that has produced objective tumor regression in some patients with metastatic renal cell carcinoma and malignant melanoma. Coumarin has shown activity against prostatic carcinoma in the Dunning R‐3327 rat prostatic adenocarcinoma model. Forty‐eight patients with metastatic hormone naive (5 stage D1 and 10 stage D2) or hormone refractory (33 stage D3) prostatic carcinoma of average age 67.6 years (range 46–86) and ECOG performance status of 2 or better were given 3 grams coumarin daily by mouth and evaluated monthly for toxicity and response by rigid criteria in a multicenter trial. Toxicity was limited to asymptomatic SGOT elevations in 3 patients and nausea and vomiting in 4 patients that required cessation of therapy in 2. Eligibility and protocol violations removed 6 additional patients from response evaluation. There were no complete responses. Partial responses (3 of 40 patients, 8%) occurred in 2 patients with bidimentionally measurable disease and 1 patient with disease evaluable by bone scan and elevated prostate specific antigen and prostatic acid phosphatase. The remaining patients progressed after 1 to 12 (average 4.4) months. Coumarin is a relatively nontoxic drug that may warrant further trials in a subset of patients with prostatic carcinoma.
Osteocalcin: Is it a useful marker of bone metastasis and response to treatment in advanced prostate cancer?
Authors: Arai Yoichi , Takeuchi Hideo , Oishi Kenji , Yoshida Osamu
Published: February 2007

Serum osteocalcin (OC) is derived largely from new cellular synthesis. It is a marker for bone formation and a noninvasive specific marker of osteoblastic activity. The clinical significance of OC in monitoring prostatic cancer bone metastases was evaluated. Pretreatment serum OC levels were determined with a radioimmunoassay kit in a total of 63 patients with prostate cancer (8 with stage B, 12 with stage C, 12 with stage D1, and 31 with metastatic bone disease). The OC levels in patients with skeletal metastasis were significantly higher than those in patients without bony lesions (P<0.01). The pattern of the initial changes in OC levels were analyzed in patients with skeletal metastasis who received endocrine treatment. The pretreatment OC value is of little use in predicting the response to treatment. The patients whose OC level initially increased and remained high tended to have a shorter interval to disease progression. On the other hand, the pattern of initial changes in OC varied according to the regimen of endocrine treatment. Our study suggests that OC seem to reflect the response to treatment and might lead to the improvement in follow‐up procedures. However, the clinical significance of OC as a marker of the response of bone metastasis should be carefully discussed with regard to the direct hormonal effect on bone metabolism.
Lack of effects of post‐initiation cholesterol on 3,2′‐dimethyl‐4‐aminobiphenyl‐induced prostate carcinogenesis
Authors: Tagawa Yoshiaki , Ozaki Keisuke , Takahashi Satoru , Ogawa Kumiko , Shirai Tomoyuki
Published: February 2007

The effects of cholesterol on 3,2′‐dimethyl‐4‐aminobiphenyl (DMAB)‐induced rat prostate carcinogenesis were investigated in male F344 rats. Animals were given 10 subcutaneous (s.c.) injections of 50 mg/kg body weight of DMAB at 2‐week intervals, each time 2 days after transfer from 1 week on 0.75 ppm of an ethinyl estradiol (EE)‐supplemented diet to a basal diet. From week 20, the animals received treatment with cholesterol (2 or 1%, in the diet), saponin (1 or 0.2 mg/rat/week, s.c.), or clofibrate (0.3%, in the diet) for 40 weeks. Although serum cholesterol levels were significantly increased by administration of cholesterol itself, and were decreased by clofibrate, the incidences of atypical hyperplasias and carcinomas of the ventral prostate were very similar with all treatments. Thus, under the present conditions, high or low cholesteremia did not affect rat prostate lesion development.
Anti‐desmin vs. anti‐actin for quantifying the area density of prostate smooth muscle
Authors: Shapiro Ellen , Hartanto Victor , Lepor Herbert
Published: February 2007

Anti‐desmin and anti‐actin are commercially available antibodies that bind to smooth muscle. The present study was designed to compare the staining properties of anti‐desmin and anti‐actin in the human prostate in order to determine the optimal antibody for quantifying the smooth muscle content of the human prostate. Nineteen male subjects with symptomatic BPH underwent needle biopsy of the prostate. Double‐immunoenzymatic staining was performed with peroxidase‐anti‐peroxidase (PAP) and alkaline phosphatase‐anti‐alkaline phosphatase (APAAP) techniques. Rabbit anti‐desmin:mouse anti‐human prostatic acid phosphatase and mouse anti‐actin:rabbit anti‐human prostatic acid phosphatase were utilized. Computer assisted color image analysis was performed using the Bioquant image analysis system. The percent area density of stroma and epihtelium was independent of the antibodies used. The percent area density of smooth muscle in the anti‐actin stained tissue sections was twofold greater than the anti‐desmin stained tissue sections. A direct relationship was observed for the area density of smooth muscle (r = 0.71; P = 0.0006) and the area density of connective tissue (r = 0.82; P < 0.001) determined from anti‐desmin and anti‐actin stained tissue sections. Anti‐actin represents the optimal antibody for quantifying the area density of prostate smooth muscle. The reproducibility of the immunoenzymatic staining technique is inferred from the direct relationship observed for area density of epithelium between the different staining techniques.
Inhibition of growth of PC‐82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC‐3095 or combination of agonist [D‐Trp6]‐luteinizing hormone‐releasing hormone and somatostatin analog RC‐160
Authors: Milovanovic Slobodan R. , Radulovic Sinisa , Groot Kate , Schally Andrew V.
Published: February 2007

The effects of treatment with a bombesin receptor antagonist [D‐Tpi6, Leu13Ψ(CH2NH) Leu14]BN(6–14)(RC‐3095) and the combination of an agonist of luteinizing hormone‐releasing hormone [D‐Trp6]‐LH‐RH and somatostatin analog D‐Phe‐Cys‐Tyr‐D‐Trp‐Lys‐Val‐Cys‐Trp‐NH2 (RC‐160) were studied in nude mice bearing xenografts of the hormone‐dependent human prostate tumor PC‐82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC‐3095 and the combination of [D‐Trp6]‐LH‐RH and RC‐160 caused a greater inhibition of tumor growth than [D‐Trp6]‐LH‐RH or RC‐160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC‐160 and [D‐Trp6]‐LH‐RH. Serum prostatic‐specific antigen levels were greatly decreased, and insulin‐like growth factor I (IGF‐I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D‐Trp6]‐LH‐RH, epidermal growth factor (EGF), IGF‐I, and somatostatin (SS‐14) were found in the tumor membranes. Receptors for EGF were significantly down‐regulated by treatment with the bombesin antagonist or RC‐160. Combination of LH‐RH agonists with somatostatin analog RC‐160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC‐3095 inhibits the growth of PC‐82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.
Effect of microcapsules of luteinizing hormone‐releasing hormone antagonist SB‐75 and somatostatin analog RC‐160 on endocrine status and tumor growth in the dunning R‐3327H rat prostate cancer model
Authors: Yano Tetsu , Pinski Jacek , Szepeshazi Karoly , Milovanovic Slobodan R. , Groot Kate , Schally Andrew V.
Published: February 2007

Inhibitory effects of sustained delivery systems (microcapsules) of the modern antagonist of luteinizing hormone‐releasing hormone [Ac‐D‐Nal(2)1, D‐Phe(4Cl)2, D‐Pal(3)3, D‐Cit6, D‐Ala10]LH‐RH (SB‐75) or the potent somatostatin analog D‐Phe‐Cys‐Tyr‐D‐Trp‐Lys‐Val‐Cys‐Trp‐NH2 (RC‐160) were investigated in the Dunning R‐3327H rat prostate cancer model. In the first experiment, the treatment was started 4 months after tumor transplantation, when the tumors measured approximately 2 cm3. Tumor volumes and weights were significantly reduced by SB‐75 microcapsules releasing 48 μg/day or RC‐160 microcapsules releasing 38 μg/day given alone, as compared with the control. The combination of these two analogs showed a synergistic effect. In the second experiment, the treatment was started 7 months after tumor transplantation, when the tumors were well developed and measured about 16 cm3. In addition to a significant reduction in volume, weight, and growth rate of tumors, histological signs of tumor regression were found in the groups treated with SB‐75 microcapsules releasing 72 μg/day given alone or in combination with RC‐160 microcapsules releasing 76 μg/day, but not with RC‐160 alone. No synergistic effect of the combination therapy was found in the second experiment. Serum testosterone levels decreased to undetectable levels and LH levels were also diminished within 2 weeks by administration of SB‐75 alone or in combination with RC‐160. In both experiments, the weights of testes, ventral prostate, and seminal vesicles were greatly reduced by administration of SB‐75 alone or in combination with RC‐160. Our results suggest that the combined therapy with microcapsules of SB‐75 and RC‐160, started soon after the diagnosis of prostate cancer is made, could improve therapeutic response.
Response of rat and human prostatic cancers to the novel 5α‐reductase inhibitor, SK&F 105657
Authors: Lamb John C. , Isaacs John T. , Levy Mark A. , Johnson Randall K.
Published: February 2007

The response of two androgen‐responsive rat prostatic cancers (i.e., Dunning R‐3327 H and G sublines) and one androgen‐responsive human prostatic cancer (i.e., PC‐82) to the 5α‐reductase inhibitor, SK&F 105657, was tested in vivo. SK&F 105657 was administered orally twice a day at a dose of 25 or 50 mg/kg/dose. The rat R‐3327 G tumor and the human PC‐82 tumor have a low to undetectable level of tissue 5α‐reductase activity and both responded to SK&F 105657 treatment with a reproducible inhibition of tumor growth. Associated with this antitumor effect was a major decrease (i.e., >70%) in tissue dihydrotestosterone (DHT) content in both tumors.

By contrast, the rat R‐3327 H prostatic cancer has a much higher level of tissue 5α‐reductase activity, and neither tumor DHT content nor growth of the tumor was inhibited by treatment with SK&F 105657. Drug treatment of rats bearing R‐3227 H tumors resulted in a similar reduction in the DHT content, wet weight, and DNA content of the ventral prostate as that produced in R‐3327 G tumor‐bearing rats which experienced an antitumor response. These results suggest that SK&F 105657 can produce antitumor effects if a substantial reduction in tissue DHT is achieved. Such reduction in tissue DHT, secondary to inhibition of the tissue 5α‐reductase enzyme, appears to be more difficult to achieve in tumors than in the normal prostate. In order to achieve such a DHT reduction in tumor tissue, prostatic cancers with low 5α‐reductase activity could be treated with SK&F 105657 on a dose regimen that lowers serum DHT to surgical castration levels, while concomitantly inhibiting the already low tumor tissue 5α‐reductase activity.
Pathological and clinical associations of Ki‐67 defined growth fractions in human prostatic carcinoma
Authors: Harper M. E. , Goddard L. , Wilson D. W. , Griffiths K. , Conn I. G. , Matanhelia S. S. , Peeling W. B.
Published: February 2007

Estimation of the growth fraction of 153 prostatic carcinoma specimens employing Ki‐67 immunostaining was undertaken and its relationship to various clinical parameters investigated. In prostate specimens, the percentage of tumour nuclei expressing Ki‐67 antigen was measured and assigned a Ki‐67 score. It was observed that high Ki‐67 scores were associated with the poorly differentiated tumours, the correlation of this proliferation marker with histological grade was found to be significant (P<0.001). No relationship was observed between the Ki‐67 score of the primary tumour with either the patient's age or with the primary tumor stage (T category). The metastatic status of the patient at diagnosis and the Ki‐67 score of the tumour were correlated (P<0.05), higher Ki‐67 scores being associated with M1 disease. Life‐table analysis of 86 patients who subsequently received androgen withdrawal therapy, was undertaken with reference to the various Ki‐67 scores of their primary tumors. A statistically significant difference in survival times was observed in patients whose Ki‐67 values were less than 1% (P<0.0001) when compared to those patients whose tumours expressed 1% and over Ki‐67 positivity, the former having longer survival times. When patients were subdivided according to their metastatic status and similar life‐table analyses were carried out, no statistical difference was found between survival times and Ki‐67 scores in M0 staged patients. In the M1 population of patients, however, those patients whose tumours were negative for Ki‐67 expression had significantly longer survival times than those patients whose tumours exhibited positive Ki‐67 staining (P<0.01). Comparing M1 staged patients whose prostate tumor cells exhibited less than 1% Ki‐67 positive nuclei with M1 staged patients whose prostate tumour cells contained 1% and higher Ki‐67 stained nuclei, a significantly longer survival time was found in the former group of patients (P˜0.0001).
Prostate‐specific antigen: Establishment of the reference range for the clinically normal prostate gland and the effect of digital rectal examination, ejaculation, and time on serum concentrations
Authors: Glenski William J. , Oesterling Joseph E. , Klee George G. , Bergstralh Erik J.
Published: February 2007

This study investigated the serum prostate‐specific antigen concentration in 100 healthy men (mean age, 26.3 years; range, 20–29 years) with a clinically normal prostate gland. The effect of digital rectal examination and ejaculation on the serum concentration, and the variability of the serum concentration over 1‐week and 1‐month periods were examined.

In the 100 subjects, the serum prostate‐specific antigen concentration ranged from less than 0.1–2.6 ng/ml. The mean, median, and mode were 0.68 ng/ml, 0.6 ng/ml, and 0.4 ng/ml, respectively. The 97.5th percentile value was 2.1 ng/ml. The mean and median changes in the serum concentration after digital rectal examination were −0.013 ±0.11 ng/ml and 0.0 ng/ml, respectively (P = 0.59 compared with control group). The mean change after ejaculation was 0.05 ±0.12 ng/ml, and the median change was 0.0 ng/ml (P = 0.14 compared with control group). Diurnal variation showed minimal change in 16 patients over a 1‐week period. The mean change (p.m. value ‐ a.m. value) was 0.003 ng/ml (range, −0.2–0.06 ng/ml). In addition, the serum concentration showed minimal intrapatient variability in 20 patients throughout a 1‐month period; the average coefficient of variation (standard deviation/mean) in these subjects was 16.5% (range, 6.4–45.2%).

These results indicate that the range in the serum concentration of prostate‐specific antigen for healthy men with a clinically normal prostate gland is significantly lower (0.0–2.6 ng/ml) than the currently employed range (0.0–4.0 ng/ml; Tandem‐R PSA assay); in addition, digital rectal examination and ejaculation have no significant effect on the serum concentration. Finally, the time of day has little effect, and the variability in the serum concentration of prostate‐specific antigen over a 1‐week and 1‐month interval is minimal.
The distribution of PSA, cathepsin‐D, and pS2 in BPH and cancer of the prostate
Authors: Yang Yong , Chisholm Geoffrey D. , Habib Fouad K.
Published: February 2007

In view of the limitations associated with the present tumor markers for prostate cancer, we have examined the potential expression of two further markers, Cathepsin‐D and pS2, in human prostate and attempted to link their concentrations with the histopathology of the tissue, the PSA levels and the androgenic status of the gland. Cathepsin‐D and pS2 were measured in cytosol fractions obtained from 22 patients with benign prostatic hyperplasia (BPH) and 20 patients with prostate cancer (CaP) employing itnmunoassays specific for these markers. The concentrations of Cathepsin‐D (BPH: mean ±SEM = 18.50 ±1.88 nmol/g protein; CaP = 19.75 ±2.49 nmol/g protein) and pS2 (BPH = 1,024.7 ±348.06 ng/g protein; CaP = 1,513.88 ±268.60 ng/g protein) were not different in the two tissue types, whereas PSA in BPH tissue (1,952.27 ±249.93 μg/g protein) was significantly higher than the measurements in CaP (583.75 ±104.33 μg/g protein). However, none of the tumor marker concentrations correlated with the degree of differentiation of the tumors, and we were unable to establish any correlation with the levels of testosterone and dihydrotestosterone in the tissue. In conclusion, although Cathepsin‐D and pS2 are expressed in prostate tissue, it is doubtful whether they will have an active role in the management of prostate cancer.
Dose‐dependent induction of ornithine decarboxylase and s‐adenosyl‐methionine decarboxylase activity by testosterone in the accessory sex organs of male rats
Authors: Fjösne Hans E. , Strand Harald , Sunde Arne
Published: February 2007

The dose‐dependent induction of ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase (AMDC) activity in the different lobes of the prostate and the seminal vesicles (SV), 24 hours after administration of testosterone to castrated Wistar rats, has been studied. ODC and AMDC activities were low in all lobes 10 days after castration. A dose of approximately 300 μg testosterone/100 g body weight (B. W.) gave an ODC activity of 50 percent of maximum response, and at 600 μg/100 g B.W. maximum activity was reached in all the prostatic lobes and the SV. In the lateral and dorsal prostate, and the coagulating gland, the dose of testosterone giving 50% of maximum AMDC activity was reached after administration of between 450 and 600 μg/100 g B.W. In the ventral prostate and SV, the dose giving a 50% response was approximately 700 μg/100 g B.W. In conclusion, all prostatic lobes showed a clear dose‐response relationship concerning the activity of ODC and AMDC following administration of different doses of testosterone. We have found minor differences in androgen responsiveness between the lobes when looking at the dose requirements for induction of AMDC activity. The dose‐response curves could possibly be useful as a rapid in vivo bioassay for compounds with anti‐androgenic properties in the prostate.
Validation of a symptoms questionnaire for benign prostatic hyperplasia
Authors: Bolognese James A. , Grino Placido B. , Stoner Elizabeth , Kozloff Rene C. , Kunitz Selma C. , Patrick Donald L.
Published: February 2007

We developed a questionnaire to assess the effect of finasteride on symptoms of benign prostatic hyperplasia (BPH) by modifying that of Boyarsky (1977). To validate the questionnaire, a cohort study was conducted in 2 groups of patients with BPH and 3 control groups without BPH. The BPH groups were: (1) 34 patients before TURP (transurethral resection of the prostate), average age 68 years; (2) 65 patients after TURP, average age 68 years; (3) 40 patients after other nonserious nonurological surgery, average age 50 years; (4) 14 healthy non‐BPH volunteers, average age 58 years; and (5) 73 healthy non‐BPH volunteers, average age 37 years. The questionnaire was administered once to all subjects, and a subset responded to a second administration. Mean total symptoms scores (TSS) from the initial questioning were 6.4, 3.2, 2.9, 2.6, and 1.6 for the 5 groups, respectively (pooled SD = 3.3); mean total troublesome symptom scores (TTSS) were 4.8, 2.1, 1.4, 1.1, and 0.6, respectively (pooled SD = 2.2). All other groups were significantly less symptomatic and troubled than the pre‐TURP group, and all surgical groups were significantly more so than the younger volunteer group. These data demonstrate the discriminant validity of the questionnaire. Corroborating prior data [Gregg et al., 1990], responsiveness was shown by the 3.7‐point mean TSS improvement in response to TURP, which was significantly different from the near‐zero changes in the other groups. Reproducibility was shown by kappa statistics being nearly all greater than 0.75 and an intraclass correlation coefficient of 0.64; construct validity and reliability were demonstrated by correlation (r = 0.7) with a general urination problems question; and internal consistency was documented by Cronbach's alpha values of approximately 0.6. We conclude that this questionnaire is a useful and validated tool for assessing BPH symptoms.
Inhibition of 3α‐hydroxysteroid oxidoreductase and 5α‐reductase activity by antiandrogens and indomethacin in the rat prostate
Authors: Fukabori Yoshitatsu , Takezawa Yutaka , Yamanaka Hidetoshi , Honma Seijiro
Published: February 2007

We studied the effects of antiandrogens in vitro on inhibition of 3α‐hydroxysteroid oxidoreductase (3α‐HSOR) and 5α‐reductase activities in the rat prostate. Kinetic and inhibition experiments were analyzed by thin layer chromatography, Cyproterone acetate (CA), chlormadinone acetate (CMA), and TZP‐4238 (TZP), which is more potent than other antiandrogens, were used as inhibitors and were compared with indomethacin (IND), which is a recognized 3α‐HSOR inhibitor. The IC50s of CA, CMA, IND, and TZP for 3α‐HSOR reductase in cytosol were about 5, 10, 10, and 100 μM, respectively, and inhibition was competitive. The IC50 of IND for 3α‐HSOR reductase in microsomes was 20 μM. The IC50s of other inhibitors were >100 μM, and inhibition was noncompetitive. The IC50s of CA, CMA, IND, and TZP for 3α‐HSOR oxidase in cytosol were > 100 μM, and inhibition was competitive or noncompetitive. Inhibition of 3α‐HSOR oxidation was not observed in microsomes. The difference between these inhibition patterns suggests that there may be 4 isoenzymes in rat prostatic tissue. The IC50s of MK‐906, CMA, and TZP for 5α‐reductase in prostate homogenate were about 0.01, 200, and 200 μM, respectively.
Measurement of androgen sensitivity in the human prostate in in vitro three‐dimensional histoculture
Authors: Geller Jack , Sionit Lida R. , Connors Kenneth , Hoffman Robert M.
Published: February 2007

We have adopted an in vitro three‐dimensional histoculture technique for assay of androgen sensitivity in explants of human benign prostatic tissue. The assay is based on the uptake of 3H‐thymidine/μg protein in explants of prostate incubated in parallel with dihydrotes‐tosterone (DHT) and hydroxyflutamide (HF) controls. The ratio of 3H‐thymidine/μg protein in DHT treated samples per 3H‐thymidine/μg protein in HF treated samples provides an index of androgen sensitivity. The DHT/HF index measured in 24 BPH specimens averaged 3.6. To determine the specificity of the HF effect, we measured the DHT/HF index in a single prostate at different concentrations of HF in the presence of fixed concentrations of DHT (2 × 10−8 M) and noted a dose‐response relationship. In addition we noted no effects of HF on 3H‐thymidine incorporation over a range of 2 × 10−4 M compared to 2 × 10−7 M, except at the highest concentration. Of surprise was the finding of an average DHT/HF index in 5 different nonprostate tissues, including breast, uterus, colon, kidney, and thyroid, that was similar to the index found in prostates. We plan to adapt this androgen sensitivity assay to measure the DHT/HF index in biopsy‐size samples of prostate, since such an assay could then be utilized to determine androgen sensitivity in individual patients with prostate cancer.
Effects of the new steroidal antiandrogen TZP‐4238 on hormone‐induced canine prostatic hyperplasia
Authors: Takezawa Yutaka , Fukabori Yoshitatsu , Yamanaka Hidetoshi , Mieda Mamoru , Honma Seijiro , Kushitani Masanori , Hamataki Nobuyuki
Published: February 2007

The effects of the new steroidal antiandrogen TZP‐4238 on hormone‐induced canine prostatic hyperplasia (BPH) were studied in comparison with those of chlormadinone acetate (CMA), a steroidal antiandrogen used in Japan. One‐ to 2‐year‐old beagle dogs were castrated and administered 75 mg/week of androstanediol (A‐diol) plus 0.75 mg/week of estradiol (E2) for 25 weeks. These dogs were treated orally with placebo, 0.5 mg/kg/day of TZP‐4238, 0.1 mg/kg/day of TZP‐4238, and 2.5 mg/kg/day of CMA, respectively, for 21 weeks after 4 weeks treatment with A‐diol plus E2. Treatment with 0.5 mg/kg/day of TZP‐4238 or 2.5 mg/kg/day of CMA suppressed prostatic growth, and treatment with 0.1 mg/kg/day of TZP‐4238 suppressed prostatic growth slightly. Treatment with 0.5 mg/ kg/day of TZP‐4238 decreased 5α‐reductase activity, DHT content, and nuclear androgen receptor (AR) content in the prostate, and treatment with 0.1 mg/kg/day of TZP‐4238 or 2.5 mg/kg/day of CMA also decreased or tended to decrease these parameters. In conclusion, TZP‐4238 and CMA were effective in inhibiting the growth of hormone‐induced canine BPH, and TZP‐4238 was at least 5 times more potent than CMA. TZP‐4238 inhibited prostatic growth by decreasing prostatic androgen content and the androgen‐AR complex. TZP‐4238 decreased 5α‐reductase activity by prevention of the androgen action described above.
A coaxial microwave applicator for transurethral hyperthermia of the prostate
Authors: Wong Terence Z. , Jonsson Eirikur , Hoopes P. Jack , Trembly B. Stuart , Heaney John A. , Douple Evan B. , Coughlin Christopher T.
Published: February 2007

Benign prostatic hyperplasia (BPH) is a common disease of elderly men. The current definitive treatment for urinary obstruction caused by this disease is surgery (transurethral resection of the prostate, or TURP). Recent evidence suggests that hyperthermia may be a useful nonsurgical alternative for treatment of symptomatic BPH. A transurethral microwave applicator has been designed around a Foley catheter for delivery of local hyperthermia to the prostate. The Foley balloon is used to maintain the antenna position within the prostatic urethra. The Foley catheter also features an antenna choke to confine power deposition to the intended region. The antenna is a coaxial dipole designed to operate at 915 MHz. Qualitative and quantitative specific absorption rate (SAR) patterns are shown for this antenna. In vivo experiments in dog prostate demonstrate that temperatures >42°C can be obtained > 1 cm away from the catheter, while maintaining a maximum urethral temperature of 47°C to 48°C. Histology obtained acutely after the hyperthermia treatments showed minimal damage to the periurethral tissues. We conclude from these studies that this microwave applicator is capable of providing local hyperthermia to the prostatic tissues with a predictable and well‐circumscribed thermal distribution. © 1993 Wiley‐Liss, Inc.
DNA quantitation of intraepithelial neoplasia and invasive carcinoma of the prostate
Authors: Crissman John D. , Sakr Wael A. , Hussein Mohamed E. , Pontes J. Edson
Published: February 2007

The relation of prostatic intraepithelial neoplasia (PIN) or ductal dysplasia and the development of invasive prostate cancer is not clear. PIN, especially high grade, is usually associated with coexisting invasive cancer. Although some investigators have identified micro foci of invasive cancer evolving from PIN, the two are usually anatomically separated. Because of these distinct anatomic patterns, many investigators have concluded that PIN represents a “field effect” or marker of potential cancer progression, and is not directly involved in or leads to the development of invasive prostate cancer.

We measured the DNA content in 49 foci of invasive cancer and 87 foci of PIN identified in 34 radical prostatectomies containing both PIN and invasive cancer. In addition, we examined 13 prostatectomies and 5 TUR specimens containing only PIN. We found that the majority of low grade PIN had normal or diploid range DNA and that approximately half of the high grade PIN were abnormal or aneuploid. Prostates with coexisting diploid range PIN and invasive cancer had an approximately equal number of diploid range and aneuploid invasive cancers. Conversely, almost all of the aneuploid PIN (usually high grade) had coexisting aneuploid invasive cancers. This would support the hypothesis that events in the progression of prostate cancer may be operative in both the development of PIN and invasive cancer. © 1993 Wiley‐Liss. Inc.
Effect of prostatic inhibin peptide (PIP) on prostate cancer cell growth in vitro and in vivo
Authors: Garde Seema , Sheth Anil , Porter Arthur T. , Pienta Kenneth J.
Published: February 2007

Prostatic inhibin peptide (PIP), is a 94 amino acid protein which is secreted by the prostate gland in an androgen‐independent manner. Previously, it has been demonstrated that PIP appears to inhibit follicle‐stimulating‐hormone (FSH) secretion by the pituitary and prostate glands. In vitro, the Dunning R3327 rat prostate cancer cell line MAT‐LyLu (MLL) cells and the human prostate cancer cell line PC‐3, are stimulated to grow in response to exogenous FSH and these effects are blocked by PIP. In vivo, PIP inhibits the growth of the highly metastatic MLL prostate cancer cell line. A comparison of hormone levels in control and PIP‐treated rats demonstrates a significant inhibition of FSH in treated animals. It appears that, in vivo, PIP may inhibit prostate cancer growth by inhibiting FSH. PIP may represent a novel hormonal treatment for prostate cancer. © 1993 Wiley‐Liss, Inc.
A prospective study of alcohol, diet, and other lifestyle factors in relation to obstructive uropathy
Authors: Chyou Po‐Huang , Nomura Abraham M. Y. , Stemmermann Grant N. , Hankin Jean H.
Published: February 2007

The association of alcohol, diet, and other lifestyle factors with obstructive uropathy was investigated in a cohort of 6581 Japanese‐American men, examined and interviewed from 1971 to 1975 in Hawaii. By studying this migrant population with its heterogeneous exposures, it increases the probabilities of identifying potential risk factors of this prostate disorder. After 17 years of follow‐up, 846 incident cases of surgically treated obstructive uropathy were diagnosed with benign prostatic hyperplasia. Total alcohol intake was inversely associated with obstructive uropathy (P< 0.0001). The relative risk was 0.64(95% confidence interval: 0.52–0.78) for men drinking at least 25 ounces of alcohol per month compared with nondrinkers. Among the 4 sources of alcohol, a significant inverse association was present for beer, wine, and sake, but not for spirits. Buddhist (vs. other) religion, rural (vs. urban) birthplace, and the presence of prostate symptoms were each associated with increased risk of obstructive uropathy, but no association was found with education, number of marriages, or cigarette smoking. Increased beef intake was weakly related to an increased risk (P= 0.047), while no association was found with the consumption of 32 other food items in the study. © 1993 Wiley‐Liss. Inc.
Immunohistochemical study of phospholipase A2 in boyine prostate
Authors: Rönkkö Seppo
Published: February 2007

Approximately 1,100‐fold purified phospholipase A2 (PLA2) from bovine prostate was injected into rabbit to prepare polyclonal antibodies. Antibodies produced showed specific immunoprecipitation only with the purified enzyme, as well as with homogenate of bovine prostatic tissue. By Western blot analysis or by immunodiffusion test, no cross‐reactivity with PLA2 purified from human seminal plasma, bovine pancreas, Crotalus adamanteus venom, or with partially purified PLA2 from bovine seminal vesicle fluid or Cowper's glands was observed. Using the indirect peroxidase technique, PLA2 was localized in the cytoplasm of bovine prostatic epithelial cells. By immunogold microscopy, this enzyme was directly visualized inside the lysosomes, as well as in the endoplasmic reticulum of the glandular epithelial cells. Enzyme activity was localized in two principal subcellular sites: the mitochondria and lysosome‐enriched fraction, and in the microsomal fraction. © 1993 Wiley‐Liss, Inc.