bluuebunny/crossref_metadata_2025 huggingface dataset:
Homozygous deletions but no sequence mutations in coding regions of p15 or p16 in human primary bladder tumors
Authors: Packenham Joan P. , Taylor Jack A. , Anna Colleen H. , White Catherine M. , Devereux Theodora R.
Published: February 2007

Chromosome 9p21 appears to harbor a tumor suppressor gene, as evidenced by deletions in this region in a variety of human primary tumors and cell lines. To map the deletion at 9p21 in bladder tumors, we analyzed DNA from 28 tumor and normal pairs at five microsatellite markers that flank the region occupied by the putative tumor suppressor genes p16 and p15. Loss of heterozygosity (a) at the markers human interferon (a) α and D9S171, which are adjacent to the p15 and p16 loci, was detected in 41% and 33%, respectively, of informative cases of bladder tumors. No sequence mutations were detected in exons 1 or 2 of either p15 or p16 in any of the bladder tumors. Three sequence‐tagged site markers in the region bordered by HIFNα and D9S171 were used to further map the deleted region by multiplex polymerase chain reaction with the HIFNγ marker (on chromosome 12) as a control for amplification. Six of 11 tumors with LOH at surrounding markers had homozygous deletions of the marker c5.1, which is located within the p16 gene; and two tumors appeared to have homozygous deletions within p15(RN1.1) but not p16 (c5.1). A recently identified microsatellite marker, p16‐CA‐1, located 16 kb distal to p16, proved valuable in defining the minimal deletion involved in these bladder tumors. Five tumors exhibited homozygous deletions of this marker but not HIFNα and two tumors showed LOH at this marker and homozygous deletion of p16. Although these data could not be used to identify p16 or p15 as the definitive tumor suppressor gene in this region that is involved in bladder carcinogenesis, they suggest that homozygous deletion is a common mechanism of loss of tumor suppressor gene function in this region. © 1995 Wiley‐ Liss, Inc.
The effect of the JE (MCP‐1) gene, which encodes monocyte chemoattractant protein‐1, on the growth of hela cells and derived somatic‐cell hybrids in nude mice
Authors: Kleine Kerstin , König Gerd , Kreuzer JÖRg , Komitowski Dymitr , Hausen Harald Zur , Rösl Frank
Published: February 2007

To investigate the effect of tumor‐associated macrophages on the in vivo growth properties of cervical carcinoma cells, tumorigenic human papilloma virus (a) 18–positive HeLa cells were transfected with an expression vector harboring the cDNA for the macrophage chemoattractant protein‐1 JE (MCP‐1). Although the endogenous gene is present and not structurally rearranged, its expression seems to be negatively affected by a still unknown mechanism. Inoculation of JE (MCP‐1)‐negative HeLa cells into nude mice led to rapidly growing tumors, where macrophage infiltration into the inner tumor mass was not detectable immunohistochemically. The activity that attracted mononuclear cells under both in vitro and in vivo conditions was reconstituted in HeLa cells after transfection with the JE (MCP‐1) expression vector. Heterotransplantation of those cells into immunocompromised animals resulted in significant growth retardation that was accompanied by a strong infiltration of macrophages. On the other hand, in vivo selection of nonmalignant hybrids made between wild‐type HeLa cells and normal human fibroblasts in nude mice resulted in tumorigenic segregants 4 mo after inoculation into the animals. Monitoring JE (MCP‐1) expression directly within those nodules, we found that transcription was either absent or only weakly detectable. Recultivation of JE (MCP‐1)‐positive tissue grafts under in vitro conditions revealed that the gene was only marginally inducible by tumor necrosis factor‐α, a cytokine that normally induces a very strong activation of transcription in nontumorigenic cells. These findings suggest that functional JE (MCP‐1) expression and in turn activated macrophages may play a pivotal role in controlling the proliferation rate of HPV‐positive cells in vivo. © 1995 Wiley‐ Liss, Inc.
Strand bias of ultraviolet light‐induced mutations in a transcriptionally active gene in human cells
Authors: Basic‐Zaninovic Tamara , Meschini Roberta , Calcagnile Angelo Salvatore , Palombo Fabio , D'errico Mariarosaria , Sanctis Lorenzo Proietti‐De , Dogliotti Eugenia
Published: February 2007

Ultraviolet (a) ‐induced repair and mutational spectra were analyzed in an inducible marker gene, the metallothionein‐l/guamine‐xanthine phosphoribosyl transferase (a) fusion gene, carried by an Epstein‐Barr virus‐derived shuttle vector episomically maintained in human cells. The repair rate of UV photodimers from the shuttle‐vector molecules was typical of transcriptionally active sequences, 70% of the dimers being removed within 8 h after irradiation. The spectrum obtained under basal gene transcription was compared with that obtained under induced transcription. In both cases, base substitutions at dipyrimidine sequences predominated. Multiple mutations and deletions probably due to recombinational events induced by UV damage were also observed. Most of the UV‐mutated dipyrimidine sites were located in the transcribed strand and were independent of the transcriptional activity of the target gene. In contrast, the distribution of mutations throughout the coding region of the gpt gene was affected by transcription, with a preferential clustering of mutations occurring in the 3′ half of the gene after transcription induction. The strand bias observed in the UV spectra most likely reflects selection for nonfunctional gpt protein. © 1995 Wiley‐ Liss, Inc.
Characterization of a promoter for γ‐glutamyl transpeptidase activated in rat liver in response to aflatoxin B1 and ethoxyquin1
Authors: Griffiths Susan A. , Good Valerie M. , Gordon Linda A. , Hudson E. Ann , Barrett Mandy C. , Munks Rebecca J. L. , Manson Margaret M.
Published: February 2007

γ‐Glutamyl transpeptidase (a) is normally absent from adult rat hepatocytes but is induced by a range of xenobiotics, including carcinogens and chemoprotective agents. As many as six mRNA species for this enzyme have been described in both rat and mouse, with various degrees of tissue specificity. These originate from one gene and have separate promoters within alternative 5′ untranslated sequences. By using a cDNA‐derived sequence specific for GGT mRNA III to screen a rat genomic library, a clone that contains the promoter region for this mRNA was isolated and characterized. The transcriptional start site lay some 3.5 kb upstream from that already characterized for mRNA II in rat kidney. Luciferase activity was obtained after transfection of rat hepatoma‐derived cell lines with constructs containing the putative promoter III fused to a luc reporter. Although this promoter lacks a TATA box, a sequence close to the start site that binds the transcription factor TFIID in vitro was identified. By using PCR techniques, mRNA III (homologous to both mouse III and IV) and an mRNA (a) with homology to VI in mouse were found in ethoxyquin‐ and aflatoxin B1‐treated rat liver and kidney as well as in a hepatoma‐derived cell line. No evidence was found for a product homologous to mRNA from promoter V described in the mouse. © 1995 Wiley‐ Liss, Inc.
Inhibition of gap junctional intercellular communication and enhancement of growth in BALB/c 3t3 cells treated with connexin43 antisense oligonucleotides
Authors: Ruch Randall J. , Guan Xiaojun , Sigler Kristi
Published: February 2007

Many studies have correlated reductions in gap junctional intercellular communication (a) with altered cellular growth, tumor promotion, and neoplastic transformation. To test directly whether reduced GJIC affects cellular growth, GJIC was inhibited in murine BALB/c 3T3 fibroblasts by treatment with a phosphorothioatemodified antisense oligonucleotide targeted against the connexin43 translation start codon, and in vitro cell growth was monitored. The cells were incubated with the oligonucleotide (0.1‐0.5 μM) in liposomes in serumless culture medium for 16 h; washed and refed with serum‐containing medium; and analyzed for dye‐coupling, connexin43 protein and mRNA levels, and cell growth over the next 5 d. The antisense oligonucleotide inhibited dye‐coupling and reduced connexin43 protein levels in a concentration‐dependent manner but had no effect on connexin43 mRNA levels. Cell growth rate was not affected, but saturation density was increased approximately threefold by the oligonucleotide. These data support a role for GJIC in the establishment of contact inhibition of in vitro cell growth. © 1995 Wiley‐ Liss, Inc.
Bed‐wetting in Chinese children: Epidemiology and predictive factors
Authors: Wang Qing Wei , Wen Jian Guo , Song Dong Kui , Su Jing , Zhu Qing Hua , Liu Kui , Che Ying Yu , Du Ai Min , Wei Jin Xing
Published: February 2007

Aims

To estimate the prevalence and severity of bed‐wetting in 1–18‐year‐old Chinese children.

Materials and Methods

A cross‐sectional study of bed‐wetting was performed by using 13,515 self‐administered questionnaires distributed to the parents of 1–18‐year‐old Chinese children in Henan province. The prevalence of bed‐wetting was determined. The relationship of wetting to age, gender, community characteristics (rural or urban), arousal dysfunction, associated day‐time symptoms (frequency, urgency, and incontinence), and family history were analyzed.

Results

There was a response rate of 87% (5,978 boys and 5,786 girls). The overall prevalence of bed‐wetting was 23.03% in those aged 1–4, 5.66% in those 5–12, and 1.37% in those 13–18. When a logistic regression analysis was applied to determine risk factors for the bed‐wetting, a positive relationship was seen with male gender and living in rural areas. Further, living in rural areas, arousal dysfunction, and associated day symptoms were significantly related to more severe bed‐wetting. Only 3.64% of the children had undergone professional evaluation.

Conclusion

The prevalence of bed‐wetting is significant in Chinese children, but lower than in most western countries, which is likely due to cultural differences. Living in rural areas, having arousal dysfunction, and having associated day‐time symptoms may be predicative factors for marked bed‐wetting. Neurourol. Urodynam. 26:512–517, 2007. © 2007 Wiley‐Liss, Inc.
Synthesis of graft and block copolymers from 2‐dimethylaminoethyl methacrylate and caprolactone
Authors: Motala‐Timol Shaheen , Jhurry Dhanjay
Published: February 2007

This paper outlines the synthesis of a range of graft and block copolymers containing 2‐dimethylaminoethyl methacrylate and caprolactone sequences by means of two distinct strategies. In the first place, common to both pathways, low‐molar‐mass hydroxyl end‐capped polycaprolactone (PCL‐OH) was prepared by the ring‐opening polymerization of caprolactone in the presence of an aluminium alkoxide Schiff's base (HAPENAlOiPr) as initiator followed by hydrolysis of the AlO bond. For the synthesis of copolymers with a main vinyl carbon–carbon backbone and PCL grafts, PCL‐OH was initially converted into ω‐methacryl‐PCL using methacryloyl chloride. This macromonomer was then copolymerized with 2‐dimethylaminoethyl methacrylate (DMAEMA) by atom transfer radical polymerization (ATRP). For the synthesis of block copolymers, PCL‐OH was first transformed into a bromine end‐capped PCL (PCL‐Br) with 2‐bromoisobutyryl bromide. PCL‐Br was then used as macroinitiator in various concentrations for the ATRP of 2‐dimethylaminoethyl methacrylate, thus leading to PCL and poly(DMAEMA) blocks of varying lengths. The formation of both graft and block copolymers was thoroughly checked using NMR and size exclusion chromatography. Copyright © 2007 Society of Chemical Industry
Preparation of a topologically linked branch polymer containing cyclodextrin
Authors: Tamura Kiyoshi , Hatanaka Kenichi , Yoshie Naoko
Published: February 2007

Macromolecules containing topological linkages made of α‐cyclodextrin (αCD) and poly(ethylene glycol) (PEG) were prepared by condensation of mono‐6‐O‐deoxy‐mono‐6‐amino‐α‐cyclodextrin (NH2‐αCD) with PEG dicarboxylic acid (PEG‐diCOOH) having one carboxyl group at both chain ends. The analysis of 1H NMR and 13C NMR spectra of the condensation products showed completion of the condensation reaction between NH2 and COOH groups, and the absence of ester linkages, thus indicating that all of the PEG chains carried one αCD molecule at both chain ends through amide linkages. Gel permeation chromatography analysis of these condensation products showed that NH2‐αCD formed inclusion complexes with PEG‐diCOOH prior to condensation, resulting in macromolecules having topological linkages. In addition, the amount of the topological linkages increased with the increase of molecular weight of PEG‐diCOOH. This result shows that the complexation equilibrium of NH2‐αCD with PEG‐diCOOH depends on the concentration of ethylene glycol units. Copyright © 2007 Society of Chemical Industry
Evaluation of histological grading (Gleason) in carcinoma of the prostate: Adverse influence of highest grade
Authors: McGowan David G. , Bain Gordon O. , Hanson John
Published: February 2007

The value of the Gleason system of histological grading in carcinoma of the prostate is a subject of considerable controversy. The value of this system is demonstrated in a group of 488 patients treated radically with radiation therapy.

Analysis, utilizing the Gleason system in these patients, indicates that the worst histological grade identified is most important in determining the prognosis. Since nearly 18%of our patients have more than two grades identified, simple identification of primary and secondary grades, ie, the two predominating grades, is inadequate and may underestimate the aggressiveness of the tumor. This finding has implications in the analysis of the results of treatment and in determining the method of treatment in individual patients.
Human benign prostatic hyperplasia in organ culture: Studies on iododeoxyuridine uptake
Authors: Masters J. R. W. , O'Donoghue E. P. N.
Published: February 2007

Prostate tissue architecture and function may be retained in vitro using organ culture. However, the application of the technique is limited due to the lack of simple means for measuring tissue response, for instance to factors controlling cell growth. It is confirmed in this study that measuring the uptake of the radioactive precursor of DNA, 5‐[125I]‐iodo‐2′‐deoxyuridine, is simple, rapid, and reproducible provided the heterogeneity of benign prostatic hyperplasia (BPH) is taken into account. Factors affecting the reproducibility (numbers of replicate explants and dishes), specificity (removal of unbound radioactivity and uptake into killed tissue), and sensitivity (radioactive concentration and exposure period) of this technique were investigated. A particular advantage of this approach is that histological assessments are made on the same tissue used for biochemical measurements. Furthermore, the method is sufficiently simple to permit serial investigations chronologically concerning factors, such as hormones, controlling BPH cell growth.
Morphologic and endocrine aspects of prostatic function
Authors: Aumüller Gerhard
Published: February 2007

Current topics on the normal anatomy and functional organization of the human prostate are presented and related to endocrine principles studied experimentally in dogs and rats. While detailed internal organization and gross anatomical structure of the human gland are still debated by some, there is considerable unanimity on the functional interdependence and relationship between the stroma and the epithelium, as has been concluded from experimental, embryological, and pathological observations. This review also focuses on prostatic secretion, its normal postnatal development, and its functional and possible regulatory significance. Secretion is closely related to both hormonal and neurovascular regulatory mechanisms, and any changes in their balance evoke characteristic, and in some instances species‐specific, morphological and functional reactions in the prostate. An hypothesis is presented on the interdependence of secretion and cell proliferation in the prostate.
Elimination of stored material from the seminal vesicles of the guinea pig following castration
Authors: Shepherd Benjamin A. , Martan Jan
Published: February 2007

Experiments were carried out to determine what factors are involved in the disappearance of stored secretion from the seminal vesicles of the giunea pig and in the concurrent decline in weight of these glands following castration. Seminal vesicles of sexually mature males were unilaterally ligated, and the males were either castrated or left testes intact for a 14‐day period. At necropsy, the seminal vesicles were removed and weighed, and biopsies were collected for histological inspection.

The weight of nonligated vesicles from castrated males declined to less than half that of ligated sides. In testes‐intact males, the weight of ligated vesicles was nearly double that of nonligated vesicles. Epithelial cell heights remained unchanged during the study. The rapid decline in weight of the guinea pig seminal vesicles following castration was attributed to the elimination of stored secretion by way of the urethra rather than by absorption.
Combined external radiotherapy and hormonal therapy for localized carcinoma of the prostate
Authors: Mukamel Eliahu , Servadio Ciro , Lurie Hedwig
Published: February 2007

Forty‐nine patients with localized carcinoma of the prostate were treated by external radiotherapy together with hormonal manipulation and were followed up to six years. Hormonal manipulation included bilateral orchiectomy and diethylstilbestrol, 3 mg/day. The cumulative five‐year survival for the 49 patients was 87.6%, with 11 % progression rate to stage D during that period. In 40 patients (81.6%), a decrease in the size of the prostate was noted. In none of the patients was there local recurrence of the tumor during the period of follow‐up. Transient gastrointestinal and/or urinary symptoms occurred following radiotherapy in 11 patients (22.4%), and in four patients severe cystitis or proctitis appeared. Complications related to hormonal therapy occurred in 11 patients (22.4%).

The high survival rates reported herein, together with the low progression rate to stage D during six years of follow‐up, may justify the early institution of radiotherapy in combination with hormonal manipulation for patients with localized carcinoma of the prostate. A randomized study with an extended number of patients is underway to further evaluate this mode of therapy.
Organ culture studies of human prostatic adenocarcinomas
Authors: Mistry Damienti , Riches Andrew , Patrick Weaver J.
Published: February 2007

The proliferative responses of human prostatic carcinoma have been evaluated in organ culture using [125I]‐iododeoxyuridine ([125I]UdR) to monitor DNA synthesis. The morphological preservation was not influenced by the addition of fetal calf serum or insulin (5 μgm/ml), transfemn (10 μgm/ml), and thyrotropin releasing hormone (10−9 M) to the active medium. Testosterone (4 ± 10−6 M) stimulated [125I]UdR uptake, whereas diethylstilboestrol (4 ± 10−6 M) had no direct effect on uptake. Both estramustine phosphate (4 ± 10−6 M) and oestradiol‐17β (4 ± 10 −6 M) inhibited uptake in a similar manner. Thus while explants of human prostatic carcinoma derived from transurethrally resected specimens can be well maintained in organ culture for a few days, proliferative responses are small and difficult to measure for individual patients.
Autoradiographic localization of androgen binding in the developing mouse prostate
Authors: Shannon John M. , Cunha Gerald R.
Published: February 2007

The ontogeny of expression of [3H]dihydrotestosterone (3H‐DHT) binding in the developing mouse prostate was studied using steroid autoradiography. At all prenatal stages examined, 3H‐DHT binding in the urogenital sinus was restricted to the stromal tissue compartment. This pattern of binding continued until approximately day 4 of postnatal life, when some epithelial cells began to exhibit nuclear localization of 3H‐DHT. The pattern of binding was asynchronous within the prostate, with the onset of nuclear labeling seemingly correlated with canalization of prostatic ducts. By 3 weeks of age, virtually all prostatic epithelial cells exhibited nuclear labeling with 3H‐DHT. The significance of these results, with respect to the role of epithelial‐mesenchymal interactions in hormone‐induced development, are discussed.
Inhibition of prostate tumors by agonistic and antagonistic analogs of LH‐RH
Authors: Schally Andrew V. , Redding Tommie W. , Comaru‐Schally Ana Maria
Published: February 2007

We have compared the effects of chronic administration of D‐Trp6‐LH‐RH, a superactive agonist of LH‐RH, and a potent antagonist, (NAc‐p‐CI‐D‐Phe1,2, D‐Trp3, D‐Arg6, D‐Ala10)LH‐RH, on male Copenhagen F‐1 rats bearing the Dunning R‐3327H prostate adenocarcinoma. Treatment with 25 μg of D‐Trp6‐LH‐RH bid for 21 days decreased the weights of the ventral prostate, testes, and adrenals, but had no effect on the weight of the anterior pituitary gland. Administration of similar doses of the antagonist reduced the weight of the ventral prostate, anterior pituitary gland, and adrenals, but did not change the weight of the testes. Both the agonist and antagonist greatly and significantly reduced tumor weight and volume as compared to controls. Serum LH, prolactin, and testosterone levels in Copenhagen F‐1 rats bearing Dunning tumors were significantly decreased after treatment with D‐Trp6‐LH‐RH as well as the antagonist. The inhibition of rat prostate tumors achieved with D‐Trp6‐LH‐RH and the antagonistic analog raised the possibility that these compounds could be used clinically in the treatment of prostate carcinoma and other endocrine‐dependent neoplasias. The antagonistic analogs have not yet been tried clinically on a chronic basis. However, the data accumulated so far from clinical trials in men with prostate carcinoma suggest that D‐Trp6‐LH‐RH and other LH‐RH agonists can be used for an effective therapy which avoids the side effects of estrogen and the pyschological impact of castration.
The use of multiparameter flow cytometry to assess tumor cell heterogeneity and grade prostate cancer
Authors: Benson Mitchell C. , McDougal Denise C. , Coffey Donald S.
Published: February 2007

Multiparametric flow cytometry has permitted the quantitative assessment of tumor cell heterogeneity within a single tumor. This technique was applied to four tumor lines with biological activity similar to the variety observed in human prostate cancer. These tumors were derived from the Dunning R3327 transplantable rat prostatic adenocarcinoma and have permitted the development of an index to assess, quantitate, and discriminate variation in the aggressive nature of these tumors. The index is based upon measurements of the mean and the variance for perpendicular light scatter and forward light scatter. Perpendicular light scatter has been shown to correlate with nuclear shape, volume, and roundness as measured by digitized image analysis. Forward light scatter increases in quantity and range as the tumors become more undifferentiated. This technique is rapid, reproducible, and applicable to the quantitative measurement of cytometric parameters on large numbers of individual tumor cells.
Metabolic epidemiology of prostatic cancer
Authors: Wynder E. L. , Laakso K. , Sotarauta M. , Rose D. P.
Published: February 2007

A review of the epidemiological evidence indicates that dietary fat very likely has an etiologic role in the development of prostatic carcinoma. While this effect may be mediated by way of altered hormonal action on the prostate, there is little supporting evidence from assays of plasma or urinary hormones in case‐control studies or the investigation of high‐risk and low‐risk groups. The application of metabolic epidemiology to this problem is most likely to succeed by direct studies of the prostate gland, and the performance of relevant assays on prostatic fluid. Estradiol and estrone levels were found to be higher in prostatic fluid than in serum, whereas for prolactin the reverse was true. Testosterone concentrations were very low in prostatic fluid, perhaps because of the high degree of plasma protein binding. Preliminary data indicated that prostatic fluid estradiol and prolactin levels are elevated in some prostate cancer patients; estrone levels appear to be normal.
Estramustine‐induced mitotic arrest in two human prostatic carcinoma cell lines du 145 and PC‐3
Authors: Hartley‐Asp Beryl
Published: February 2007

In growth proliferation experiments on two human prostatic carcinoma cell lines, DU 145 cells were found to be more sensitive to the cytotoxic effect of estramustine and nor‐nitrogen mustard than PC‐3 cells. Estramustine was, however, much more cytotoxic in both cell lines than nor‐nitrogen mustard.

Cytogenetic experiments revealed that estramustine produced a drastic increase of the mitotic index in both these cell lines. This increase could be accounted for by the arrest of cells in their first treatment‐metaphase. The arrested metaphases exhibited all the characteristics commonly found for stathmokinetic agents such as colchicine and vinca‐analogues. No mitotic arrest was found for nor‐nitrogen mustard but chromosomal aberrations were found at toxic concentrations. Estradiol exhibited minimal toxicity and caused no mitotic arrest in these cell lines. The mitotic arrest induced by estramustine was found to be reversible on removal of the drug.
Androgen receptor binding characteristics in the cytosol of the rat dorsolateral prostate gland and the dunning R‐3327 prostatic adenocarcinoma
Authors: Rowley David R. , Thompson Sue Ann , Lubaroff David M. , Heidger Paul M.
Published: February 2007

The incidence of prostatic cancer is highly correlated with advanced age, and it has been suggested that changes in androgen binding may be important in age‐associated alterations in growth regulatory mechanisms of prostatic epithelial cells. In this study the effects of age on androgen binding characteristics in the dorsolateral prostate glands of young and aged Copenhagen rats were determined and the binding properties in the Dunning R3327/130 subline of rat prostatic adenocarcinoma were characterized. Tritium‐labeled and nonlabeled methyltrienolone analogs (R1881) were used to study the binding properties of 5α‐dihydrotestosterone receptor in the cytosol of tumors and prostate glands. Binding of R1881 was low but specific for the androgen receptor as shown by competition studies in which nonlabeled R1881, 5α‐dihydrostestosterone, and testosterone competed successfully with 3H‐R1881 for binding sites, but 17β‐estradiol and low levels of progesterone did not. In Copenhagen dorsolateral prostate, Scatchard analysis suggested a single class of binding sites. In young animals (three to five months) the average binding capacity was 10.36 fmol/mg cytosol protein with a dissociation constant (Kd) of 2.28 nmol/L. The dorsolateral prostate of aged rats (11–16 months) showed no significant difference in specific binding characteristics as compared to the younger age group. Specific binding of 3H‐R1881 in R3327/130 tumor was saturable with a single class of high‐affinity binding sites having an average binding capacity of 64.77 fmol/mg cytosol protein and a Kd of 2.76 nmol/L. These data show that the tumor had approximately 6.5 times the number of binding sites as did the normal Copenhagen rat dorsolateral prostate gland. However, no age‐related changes were detected through 11–16 months of age in the androgen binding characteristics of normal rat dorsolateral prostate gland that could be correlated with the higher concentration of androgen binding sites in the R3327/130 tumor subline.
Acid phosphatase‐producing androgen‐independent subline of rat prostatic adenocarcinoma (dunning r3327 tumor) in cell culture
Authors: Igarashi Tatsuo , Isaka Shigeo , Miyauchi Taisei , Hayata Isamu , Shimazaki Jun
Published: February 2007

Establishment of a cell line derived from the androgen‐independent subline of rat prostatic adenocarcinoma (Dunning R3327 tumor) is reported. Cells of this line produced acid phosphatase. When the cultured cells were transplanted to Copenhagen rats, solid tumors were formed. Histologically, the tumor consisted of spindle‐shaped, large and bizarre polygonal cells; this feature was almost identical to that of the original tumor. Chromosomes were in the triploid range with seven frequently appearing marker chromosomes.
Characteristics of separated epithelial and stromal subfractions of prostate: II. Human prostate
Authors: Robel Paul , Eychenne Bernard , Blondeau Jean‐Paul , Picard‐Groyer Marie‐Therese , Baulieu Etienne‐Emile , Bruner‐Lorand Joyce , Hechter Oscar
Published: February 2007

Surgical samples of human benign prostatic hyperplasia tissue (BPH) were fractionated into epithelial clumps and stromal fractions, using the “optimal” tissue dissociation procedure developed for rat prostate described in the preceding report. The separated cellular fractions were compared to control unfractionated tissue (wherein extracellular secretory products had been removed) with respect to the concentrations of androgen receptor and enzyme markers on a DNA basis; cell damage was also evaluated by light and electron microscopy (EM). EM revealed extensive cell damage in epithelial clumps and stromal fractions, which had appeared normal when examined by light microscopy. Damage to the ultrastructure of individual epithelial cells present in clump fractions was very variable, involving vacuolization of the cytoplasm and condensation of nuclear chromatin in some cells, vacuolization of just the cytoplasm in other cells; only a small fraction of the cells in clumps had normal ultrastructure. Ultrastructural damage to stromal cells was much greater in fibroblasts than in muscle fibers. The cell damage observed in both subfractions of human prostate was associated with a marked degree of receptor loss. The mean decreases in the number of androgen receptors per unit DNA relative to control unfractionated tissue was 68.5 and 62.5% recovered in epithelial and stromal fractions, respectively. Measurement of various enzymes as “markers” revealed that acid phosphatase activity (per unit DNA) was associated exclusively with the epithelial clump fraction. Prolyl hydroxylase and myosin ATPase activities (per unit DNA) were restricted to the stromal fraction. The limitations of using mechanically separated subfractions of human prostate tissue for evaluation of the cellular distribution or the initial concentration of steroid receptors in human prostate tissue are discussed.
The pure antiandrogen ru 23908 (anandron®), a candidate of choice for the combined antihormonal treatment of prostatic cancer: A review
Authors: Raynaud J. P. , Bonne C. , Moguilewsky M. , Lefebvre F. A. , Bélanger A. , Labrie F.
Published: February 2007

The nonsteroidal antiandrogen RU 23908 (AnandronR) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth‐promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight. This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals. In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles. In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7‐ and 17‐fold, respectively, after 14 days of similar daily treatment. Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion. Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.
Carcinoma of the prostate in israel: Some epidemiological and therapeutic considerations
Authors: Servadio C. , Mukamel E. , Kahan E.
Published: February 2007

Analysis of the different rate of prostatic cancer in Israel among Jews from various countries of origin reveals some very interesting and marked varieties in incidence, which are studied more closely now. Aggressive, combined treatment for the invasive cases of prostatic cancer has been used since 1975. This was based on orchiectomy, DES, and chemotherapy for the stage D2 disease, and on radiotherapy and hormonal therapy for the stage C, and possibly also the stage D1 disease. Results so far have been very encouraging indeed, and with considerably better results than obtained with the individual, more conventional forms of therapy. Five‐year survival in the stage D2 disease has been 63.5%, and 87.6% in the stage C (+D1?) disease. It appears that this approach is more justified, certainly in the advanced stages of this disease.
Fluorescent androgen derivatives do not discriminate between androgen receptor‐positive and ‐negative human tumor cell lines
Authors: Berns Els M. J. J. , Mulder Eppo , Rommerts Focko F. G. , Van Der Molen Henk J. , Blankenstein Rien A. , Vries Joan Bolt‐De , De Goeij Ton F. P. M.
Published: February 2007

For the evaluation of histochemical procedures for detection of androgen receptors, three human tumor cell lines have been used: PC‐93 and NHIK‐3025, both biochemically characterized as androgen receptor‐positive, and EB‐33, biochemically characterized as androgen receptor‐negative. The binding of three fluorescent ligands, testosterone‐17β‐hemisuccinate‐bovine serum albumin‐fluorescein isothiocyanate, testosterone‐17β‐hemisuccinate‐fluoresceinamine, and 5α‐dihydrotestosterone‐17β‐hemisuccinate‐fluoresceinamine, to the cells was evaluated. The relative binding affinities of the ligands for the androgen receptors were low (less than 5% when compared to methyltrienolone). Treatment of the cells with the androgen‐fluoresceinamine derivatives resulted in a fluorescent labeling of the cytoplasm in both intact and “freeze‐damaged” cells of the three cell lines. This staining was independent of the presence of receptors. Nuclei were not stained.

Incubation of intact cells with the protein‐linked conjugate did not result in significant cellular fluorescence. Only cells with damaged membranes showed a positive histochemical reaction, both in nucleus and cytoplasm, irrespective of the receptor content of the cells. The fluorescence intensity was not suppressed with excess 5α‐dihydrotestosterone or methyltrienolone, which are known to prevent binding of low affinity ligands to androgen receptors.

From these results it is concluded that androgen receptors cannot be detected by these fluorescent ligands with low affinity for the receptor. The observed fluorescence of the cells is therefore due to binding of the ligands to other binding sites. The visualization/histochemical demonstration of these binding sites does not appear to be related to the presence of androgen receptors.
Percutaneous lymph node aspiration biopsy and tumor grade in staging of prostatic carcinoma
Authors: Piscioli Francesco , Leonardi Elena , Reich Alessandro , Luciani Lucio
Published: February 2007

Percutaneous fluoroscopy‐guided fine‐needle aspiration biopsy was performed for staging procedures in 31 patients with clinically localized carcinoma of the prostate and showed overall accuracy of 93.54%, with a false‐negative rate of 6.46%. The Gleason grading system was found to be highly accurate in predicting the absence or presence of nodal metastases in low‐and high‐grade tumors (Gleason's sums 2, 3, or 4, and 8, 9, or 10). The combination of pelvic node biopsy aspiration and tumor grade can result in a very accurate prediction of nodal involvement, and may spare patients a staging lymphadenectomy or even an unnecessary radical operation.
Cytotoxic chemotherapeutic agents under development with a possible future role in prostate cancer
Authors: Creaven Patrick J.
Published: February 2007

New cytotoxic chemotherapeutic compounds under development or in early clinical trial which might be considered for clinical evaluation in prostatic carcinoma are discussed. The following classes of agents are considered: lipid‐soluble antifolates, anthracyclines, nitro‐soureas, and platinum analogues. A group of miscellaneous compounds is also discussed.
Endogenous phosphorylation in dunning prostate tumors of rats treated with LH‐RH analogues
Authors: Cehovic Georges , Redding Tommie W. , Hierowski Marion T. , Schally Andrew V.
Published: February 2007

We investigated phosphorylation in Dunning R‐3327H prostate tumor tissue of untreated rats, and rats treated with the agonist D‐Trp6‐LH‐RH and antagonist N‐Ac‐D‐p‐Cl‐Phe1,2, D‐Trp3, D‐Arg6, D‐Ala10‐LH‐RH. The total phosphorylation was significantly higher in Dunning tumors than in normal ventral and dorsal prostate. Incorporation of 32P into tumor tissue of rats treated with D‐Trp6‐LH‐RH was significantly lower than in tumors from untreated animals. The tumor regression produced by LH‐RH agonist appeared to be linked with changes in the pattern of tumor protein phosphorylation. Although inhibition of tumor growth also occurred after administration of the LH‐RH antagonist, no significant changes in phosphorylation were observed. The dissimilarity of effects of the agonists and the antagonists on protein phosphorylation in rat prostate tumors may be related to the differences in the mechanisms of action of these two types of LH‐RH analogues.
Review: Prostate cancer epidemiology
Authors: Flanders W. Dana
Published: February 2007

Prostate cancer is common among men in the United States. Factors of possible importance in the etiology of prostate cancer include diet, primarily implicated by ecologic studies of national, regional, and ethnic variation in rates; endocrine function, implicated by the importance of endocrine function in normal prostatic growth and in the treatment of prostate cancer; genetic susceptibility, supported by familial aggregation; some aspect of sexual behavior, suggested by case‐control differences in sexual behavior; and occupational exposure, particularly cadmium exposure. Despite the public health importance of prostate cancer, it has received only moderate epidemiologic study; thus the etiologic importance of these and other possible determinants of prostrate cancer risk is uncertain [55].
The use of steroid‐containing silastic implants in male nude mice: Plasma hormone levels and the effect of implantation on the weights of the ventral prostate and seminal vesicles
Authors: Van Steenbrugge G. J. , Groen M. , De Jong F. H. , Schroeder F. H.
Published: February 2007

The effects of implantation of steroid‐containing capsules into male nude mice on steroid concentrations in plasma and weight of accessory sex organs were studied. Intact male nude mice had plasma levels of testosterone (T) of 8.0 ± 2.4 ng/ml, while T implantation (length 1.0 cm) of a group with castrated male mice resulted in a mean level of 8.1 ± 0.3 ng/ml. This level was reached within 2 days after implantation and lasted for at least 40 days. After longer periods of application (up to 75 days) physiological levels could still be attained. Treatment of intact male nude mice with estradiol (E2)‐containing implants (length 0.5 cm) resulted in constant levels of plasma‐E2 (250 pg/ml) also lasting for at least 32 days. This treatment resulted in a mean plasma‐T level of 1.0 ± 0.2 ng/ml, which was still significantly higher than that obtained after castration (0.14 ± 0.03 ng/ml). Up to 16 days after implantation E2 did not cause a decrease of the weights of the accessory sex glands in intact male mice, while after 32 days a significant reduction (50% of the control animals) of the organ weights was observed. The present data obtained with T and E2 implantation show that this route of administration of hormones is also very applicable in the nude mouse model.
Metabolic action of prolactin in regressing prostate: Independent of androgen action
Authors: Smith Cornelius , Assimos Dean , Lee Chung , Grayhack John T.
Published: February 2007

The mechanism of the observed synergistic effect of prolactin and androgen on the lateral lobe of the rat prostate is not established. The observation that prolactin alone delayed the rate of loss of weight, protein, and DNA of the lateral lobe in castrated rats has led us to question the assumption that the effect of prolactin is produced by a modification of recognized androgen‐induced intracellular changes. The present study was conducted to explore whether or not the sites of prolactin action in the rat prostate coincided with those recognized as the androgen effect. Two anterior pituitaries from female donors were grafted under the right renal capsule of adult male Sprague‐Dawley rats. Seven days later, bilateral orchiectomy and unilateral nephrectomy were performed in these rats. In one half of the animals, the kidney bearing the pituitary grafts was removed. In the other half, the contralateral kidney was removed. Seven days following the orchiectomy‐nephrectomy, animals bearing the pituitary grafts had a higher level of serum prolactin (93 ± 7 ng/ml, mean ± SE) than in those without the graft (26 ± 3 ng/ml). This condition of hyperprolactinemia was associated with the delay of castration‐induced regression in the lateral prostate. The rate of protein degradation, as judged by the amount of radioactivity remaining in the tissue following a single i.v. pulse of 3H‐leucine 24 hr before orchiectomy‐nephrectomy, was significantly slower in the lateral prostate in graft‐bearing animals than in those without grafts. However, the rate of protein synthesis, as judged by both in vitro and in vivo incorporation of 3H‐leucine into the protein fractions of the prostate, was not significantly different between the two groups. Nor was the total activity of cathepsin D in the lateral prostate different. These results were not consistent with parameters known as the effect mediated through androgen‐controlled mechanisms. We therefore conclude that the action of prolactin in the regressing rat prostate is probably not mediated through the action of androgen.
Amifloxacin distribution in the dog prostate
Authors: Frimodt‐Møller P. C. , Dørflinger T. , Madsen P. O.
Published: February 2007

Constant infusion experiments with amifloxacin, a quinoline carboxylic acid derivative, were performed in five anesthetized dogs to determine the drug concentrations in prostatic secretion (PS), prostatic interstitial fluid (PIF), prostatic tissue, and plasma (P). The experiments were carried out under steady‐state conditions. Amifloxacin concentrations in PS and PIF were lower than the corresponding P concentrations, as might be expected for an acid compound. There was no significant difference between the PS/P and PIF/P concentration ratios of the drug, and none exceeded 1.0. The concentrations of amifloxacin in PS, PIF, and prostatic tissue were above the minimal inhibitory concentration values of most gram‐positive bacteria causing chronic bacterial prostatitis. Clinical trials of amifloxacin seem justified.
Fluctuations in prostatic glycosaminoglycans during fetal and pubertal growth
Authors: De Klerk D. P. , Human H. J.
Published: February 2007

Mesenchymal glycosaminoglycans have been shown to fluctuate during the development of various organs. Prostatic development is an interesting example of organogenesis as it is only at puberty, under androgen influence, that differentiation is completed. We have extracted and quantitated the glycosaminoglycans of human prostates obtained from fetuses, prepubertal, and adult males to determine the changes that occur during prostatic differentiation.

The total glycosaminoglycan content per prostate followed the wet weight growth curve. The percentages of heparan sulfate and heparan sulfate sulfation seemed to correlate with prostatic epithelial differentiation. After 25 years of age prostatic glycosaminoglycan concentrations tend toward the glycosaminoglycan ratios typical of benign prostatic hyperplasia.
Investigation of the combination of the agonist D‐Trp‐6‐LH‐RH and the antiandrogen flutamide in the treatment of dunning R‐3327H prostate cancer model
Authors: Redding Tommie W. , Schally Andrew V.
Published: February 2007

The therapy for the treatment of prostate cancer and other sex‐steroid‐dependent tumors based on agonists of LH‐RH has been made more practical and efficacious by the development of a long‐acting formulation of microcapsules of D‐Trp‐6‐LH‐RH for controlled release. Antiandrogens, which neutralize the effect of endogenous androgens, have been used also in the management of prostate cancer in man. The effects of a simultaneous administration of the antiandrogen flutamide and microcapsules of the agonist D‐Trp‐6‐LH‐RH were studied in the Dunning R‐3327H rat prostate adenocarcinoma model to determine whether the combination of these two drugs might inhibit tumor growth more effectively than single agents. Microcapsules of D‐Trp‐6‐LH‐RH, calculated to release a controlled dose of 25 μg/day for a period of 30 days were injected intramuscularly once a month. Flutamide was administered SC at a daily dose of 25 mg/kg. The therapy was started 100 days after the tumor transplantation and continued for 60 days. Tumor weights and volumes were significantly reduced in rats treated with microcapsules or flutamide alone, but the former drug inhibited tumor growth more than the latter. The combined treatment of flutamide and microcapsules significantly decreased tumor weight and volume, but did not exert a synergistic effect on tumor growth, the reduction being smaller for the combination than for the microcapsules alone. There was a significant elevation of serum testosterone, LH, and prolactin in rats treated with flutamide. On the other hand, in rats given microcapsules of D‐Trp‐6‐LH‐RH, testosterone fell to castration levels within 7 days and remained at nondetectable values, serum LH and prolactin levels being also suppressed in this group. The combined administration of microcapsules and flutamide also significantly decreased serum testosterone to nondetectable levels by day 7 and suppressed serum LH and prolactin. Our findings raise doubts of whether the daily administration of the combination of LH‐RH agonist with an antiandrogen offers an advantage over the use of microcapsules of an agonist like D‐Trp‐6‐LH‐RH alone in the treatment of prostatic carcinoma.