Showing papers in "The Prostate in 1993"
TL;DR: The effect of the isoflavones, genistein, daidzein, and biochanin A on the growth of the LNCaP and DU‐145 human prostate cancer cell lines has been examined, and the mechanism of action does not depend on inhibition of EGF receptors tyrosine autophosphorylation, but on a more distal event in the EGF receptor‐mediated signal transduction cascade.
Abstract: The effect of the isoflavones, genistein, daidzein, and biochanin A on the growth of the LNCaP and DU-145 human prostate cancer cell lines has been examined. Genistein and biochanin A, but not daidzein, inhibit both serum and EGF-stimulated growth of LNCaP and DU-145 cells (IC50 values from 8.0 to 27 micrograms/ml for serum and 4.3 to 15 micrograms/ml for EGF), but have no significant effect of the EGF receptor tyrosine autophosphorylation. In contrast, tyrphostin 25, a specific EGF receptor tyrosine kinase inhibitor, inhibits EGF-stimulated growth and EGF receptor tyrosine autophosphorylation in these whole cells, but does not inhibit serum-stimulated growth. These data suggest that the mechanism of action of genistein and biochanin A does not depend on inhibition of EGF receptor tyrosine autophosphorylation, but on a more distal event in the EGF receptor-mediated signal transduction cascade.
438 citations
TL;DR: In vitro and in vivo growth analysis and Immunohistochemical staining for P53 protein in the cell lines indicated that protein overexpression in LNCaP was heterogeneous, even in clonal isolates derived from L NCaP‐GW that contained the codon 273 mutation in every cell.
Abstract: p53 gene structure and chromosome 17p alleles were studied in the three human prostate cancer cell lines, LNCaP, DU-145, and PC-3. Our laboratory has two separate culture lines of the LNCaP human prostate cancer cells. One strain, LNCaP-GW, had a mutation in one of two alleles at position 273 (arg > his). This mutation could not be detected in a second strain of LNCaP, LNCaP-ATCC. Immunohistochemical staining for P53 protein in the cell lines indicated that protein overexpression in LNCaP was heterogeneous, even in clonal isolates derived from LNCaP-GW that contained the codon 273 mutation in every cell. We also performed in vitro and in vivo growth analysis to compare the LNCaP-GW and LNCaP-ATCC cells. LNCaP-GW grew more rapidly than LNCaP-ATCC in vitro. However, LNCaP-ATCC formed tumors efficiently when inoculated into nude mice, whereas LNCaP-GW formed tumors much less efficiently. Consideration must be given to the notion that some of these p53 mutations arose during in vitro passage. We also confirmed published findings with two other human prostate cancer cell lines. In DU-145, two mutations were found in the p53 gene. A mutation at codon 274 (pro > leu) and a second mutation at codon 223 (val > phe) were present. PC-3 cells were hemizygous for chromosome 17p. The single copy of the p53 gene had a base pair deletion at codon 138 that generated a frame shift and a new in-frame stop codon at position 169.
300 citations
TL;DR: In this article, an isolated mammalian nucleic acid molecule encoding a mammalian prostate-specific membrane antigen was used for detecting hematogenous micrometastic tumor cells of a subject performing the polymerase chain reaction (PCR) on samples of the subjet using primers of said antigen.
Abstract: This invention provides for an isolated mammalian nucleic acid molecule encoding a mammalian prostate-specific membrane antigen. This invention provides for nucleic acid probes which specifically hybridize with the nucleic acid molecule encoding said antigen. This invention provides for a method of detecting hematogenous micrometastic tumor cells of a subject performing the polymerase chain reaction (PCR) on samples of the subjet using primers of said antigen. This invention provides for methods to identify ligands which bind to said antigen. This invention provides for the prevention and/or treatment of prostate tumor growth.
266 citations
TL;DR: The results suggest that IGF‐I may play an important role in stimulating the growth and progression of prostate cancer.
Abstract: The role of insulin-like growth factor I (IGF-I) in the growth and development of prostate cancer was studied using established human prostate cancer cell lines. Under steroid and growth factor-free culture conditions, IGF-I significantly stimulated the androgen-independent cell lines PC-3 and DU-145 to incorporate [3H]thymidine into DNA, while the androgen-dependent cell line, LNCaP, was not affected. However, in the presence of dihydrotestosterone (DHT), DNA synthesis of LNCaP cells was stimulated by IGF-I in a dose-dependent manner. None of the cell lines tested secreted an immunoreactive level of IGF-I into their conditioned medium. Characterization of receptors by ligand binding assays revealed that all prostate cancer cell lines tested express specific binding sites for IGF-I with similar dissociation constants (0.23-0.39 nM). Crosslinking studies supported the suggestion that 125I-IGF-I was bound to a receptor on these cells. The IGF-I receptor concentrations of androgen-independent cell lines were significantly higher than those of the androgen-dependent cell line. Androgen appeared to affect neither the expression of IGF-I receptors nor the secretion of IGF-I. The results suggest that IGF-I may play an important role in stimulating the growth and progression of prostate cancer.
216 citations
TL;DR: Testosterone undecanoate or placebo was given orally in a double‐blind fashion for 8 months to 23 middle‐aged men without urinary tract symptoms and found to increase the mean prostate volume by 12% (P < .012).
Abstract: Testosterone undecanoate (160 mg/day) or placebo was given orally in a double-blind fashion for 8 months to 23 middle-aged men without urinary tract symptoms. Testosterone was found to increase the mean prostate volume by 12% (P < .012). The treatment suppressed the serum concentrations of sex-hormone-binding globulin and follicle stimulating hormone. The observed decrease in the mean serum concentration of luteinizing hormone was not statistically significant. The serum concentrations of prostate-specific antigen did not change as measured by two different well-validated immunometric assays. No changes in micturition habits or urine flow charts were reported.
128 citations
TL;DR: Limited experience with finasteride in men with prostate cancer suggests that the reduction in PSA of malignant origin appears to be no greater than the percentage reduction in BPH patients with PSA levels of 2.0 ng/ml after 12 months of treatment.
Abstract: Finasteride is a specific 5-alpha-reductase inhibitor that has been shown to reduce prostate size and decrease serum levels of prostate specific antigen (PSA). Among men who received finasteride (5 mg/day) for 12 months in North American clinical trials and in whom prostate cancer was not diagnosed the median percentage change in PSA was -50% (5-95% range: -81% to +20%). At baseline 72% had PSA < or = 4.0 ng/ml and 93% had PSA < or = 10.0 ng/ml. After 12 months on finasteride, 75% had PSA < or = 2.0 ng/ml and 95% had PSA < or = 5.0 ng/ml. Thus, the proportion of BPH patients with PSA levels of 2.0 ng/ml and 5.0 ng/ml after 12 months of treatment was comparable to the proportion with pretreatment PSA levels of 4.0 ng/ml and 10.0 ng/ml. Among the 10 men in these trials subsequently diagnosed with prostate cancer while on long-term finasteride therapy (5 mg/day), the median percentage change in PSA was -26% (range: -48% to +12%). Limited experience with finasteride in men with prostate cancer suggests that the reduction in PSA of malignant origin appears to be no greater than the percentage reduction in PSA of benign origin. These effects on PSA have not been shown to confer any therapeutic benefit. Physicians using finasteride should be aware of its effect on PSA levels.
126 citations
TL;DR: This study test for structural changes of the androgen receptor in prostatic tumor cell lines and primary tumors to find out the effects of androgen ablation therapy on the hormone‐and DNA‐binding domains.
Abstract: Essentially all prostatic carcinomas relapse to an androgen-independent stage during androgen ablation therapy. The underlying genetic changes are still unclear. Such changes are suspected to affect the androgen-signalling pathway as well as growth promoting and inhibiting factors. This study was undertaken to test for structural changes of the androgen receptor in prostatic tumor cell lines and primary tumors. Complementary DNA (cDNA) fragments of the androgen receptor (AR) were isolated from the cell lines LNCaP, PC-3, and DU 145, ten tissue specimens obtained by radical prostatectomy, and five fine-needle biopsies by means of the polymerase chain reaction (PCR) technique. Fragments encoding the hormone- and DNA-binding domains were analyzed by DNA sequencing. The PCR technique is highly sensitive and especially recommended for the analysis of small tissue samples, such as those obtained by fine-needle aspiration. No alterations were detected in the tissue specimens and the five fine-needle aspirates. In the three tumor cell lines that represent late stages of prostatic tumor, different findings were obtained. The androgen-independent DU 145 cells did not express androgen receptors, whereas the PC-3 cells, which are also androgen-independent, expressed very low levels of normal AR. In contrast to this, the androgen-dependent LNCaP cells expressed high levels of structurally abnormal androgen receptors. These results suggest that androgen receptor mutations are probably uncommon molecular events in the early stages of prostatic cancer. Qualitative and quantitative changes, however, seem to occur in advanced prostatic cancer.
121 citations
TL;DR: In castrate rats stimulated with testosterone (T) or dihydrotestosterone (DHT), finasteride, but not Permixon or Bazoton, inhibited T stimulated prostate growth, while none of the three compounds inhibited DHT stimulated growth.
Abstract: Human prostate was used as a source of 5α reductase. Compounds were incubated with an enzyme preparation and [3H]testosterone. [3H]-dihydrotestosterone production was measured to calculate 5a reductase activity. IC50 values (ng/ml) were finasteride = 1; Permixon = 5,600; Talso = 7,000; Strogen Forte = 31,000; Prostagutt = 40,000; and Tadenan = 63,000. Bazoton and Harzol had no activity at concentrations up to 500,000 ng/ml. In castrate rats stimulated with testosterone (T) or dihydrotestosterone (DHT), finasteride, but not Permixon or Bazoton, inhibited T stimulated prostate growth, while none of the three compounds inhibited DHT stimulated growth. These results demonstrate that finasteride inhibits 5α reductase, while Permixon and Bazoton have neither anti-androgen nor 5α reductase inhibitory activity. In addition, in a 7 day human clinical trial, finasteride, but not Permixon or placebo, decreased serum DHT in men, further confirming the lack of 5α reductase inhibition by Permixon. Finasteride and the plant extracts listed above do not inhibit the binding of DHT to the rat prostatic androgen receptor (concentrations to 100 μg/ml). Based on these results, it is unlikely that these plant extracts would shrink the prostate by inhibiting androgen action or 5α reductase. © 1993 Wiley-Liss, Inc.
114 citations
TL;DR: It is suggested that efforts should be made to confirm the identity of the α1‐receptor subtype expressed by prostate smooth muscle, in order to develop subtype‐selective α1 antagonists, and to evaluate their safety and efficacy in benign prostatic hyperplasia (BPH).
Abstract: We have characterized the alpha 1 adrenoceptor subtypes in the human prostate using radioligand receptor binding studies. The objective of the present study was to determine the alpha 1 subtype mediating the tension of prostatic smooth muscle. Fresh human tissue was obtained from 9 males between 50 and 80 years of age undergoing prostatectomy for BPH. The incubation of prostatic tissue with the irreversible antagonist chlorethyclonidine (CEC) resulted in an 80% reduction of the maximal contractile response produced by phenylephrine. However, the alpha 1A-selective antagonists WB-4101 and 5-methylurapidil (5-MU) competitively inhibited the contractile response induced by phenylephrine, with KB = 2.64 and 4.46 nM, respectively, consistent with their affinity at the alpha 1A receptor subtype. The pharmacological profile of the alpha 1-receptor-mediated contractile response of prostate smooth muscle is inconsistent with their classification as either an alpha 1A or alpha 1B subtype. Alternatively, when compared with the properties of the cloned alpha 1 receptors, our results suggest that the alpha 1 receptors involved in the contraction of prostate smooth muscle have some pharmacological properties similar to those encoded by the gene of the bovine alpha 1C receptor subtype. The findings of the present study suggest that efforts should be made to confirm the identity of the alpha 1-receptor subtype expressed by prostate smooth muscle, in order to develop subtype-selective alpha 1 antagonists, and to evaluate their safety and efficacy in benign prostatic hyperplasia (BPH).
105 citations
TL;DR: This in vivo model of hormone‐sensitive human prostate cancer cell line will serve as a model for the study of prostate tumor biology and treatment and can be manipulated by castration, leading to involution of tumor and stabilization of serum PSA level.
Abstract: This study was undertaken to establish an androgen-sensitive model of human prostatic carcinoma in nude mice. The androgen-sensitive prostatic carcinoma cell line, LNCaP, was suspended in reconstituted basement membrane (Matrigel) and injected subcutaneously into nude mice. The LNCaP cell line was chosen for the study, because the cell line is androgen-sensitive and secretes prostate specific antigen (PSA) into culture media. Following injection of 1 × 106 LNCaP cells with 0.25 ml of Matrigel, 88. of mice exhibited palpable tumor burdens after 12 weeks of observation. In addition, significant levels of PSA were observed in the serum of LNCaP-bearing mice. Bilateral orchiectomy of mice resulted in tumor regression and stabilization of serum PSA levels, compared to testis-intact controls. A significant correlation of PSA to tumor volume and weight was observed. The castrate level of testosterone was confirmed by radioimmunoassay and was similar to testosterone levels in female nude mice. Matrigel allows for a conducive environment to propagate LNCaP cells in nude mice. Furthermore, the growth can be manipulated by castration, leading to involution of tumor and stabilization of serum PSA level. This in vivo model of hormone-sensitive human prostate cancer cell line will serve as a model for the study of prostate tumor biology and treatment. © 1993 Wiley-Liss, Inc.
95 citations
TL;DR: Twenty men with a history of documented bacterial prostatitis, that had become resistant to appropriate antibiotic therapy, were studied in an attempt to determine where the bacteria had become localized, and possibly explain their survival in a relative bactericidal environment.
Abstract: Chronic bacterial prostatitis, that has become resistant to antibiotic therapy, remains a frustrating clinical entity for both clinicians and patients Twenty men with a history of documented bacterial prostatitis, that had become resistant to appropriate antibiotic therapy, were studied in an attempt to determine where the bacteria had become localized, and possibly explain their survival in a relative bactericidal environment The antibiotics were discontinued for 4 weeks, and cultures of the expressed prostatic secretions, tissue biopsies, histology, and ultrastructure were correlated Twelve (60%) of the tissue biopsies cultured presumed pathogens In six of the tissue-positive cases, the expressed prostatic secretion was negative Specific electron micrographs demonstrate exopolysaccharide coated microcolonies of bacteria firmly attached to the ductal and acinar walls This mode of growth helps explain some of our difficulties in the diagnosis and treatment of chronic bacterial prostatitis
TL;DR: Three weeks after removal of the excess of androgen, the passage 70 cells regained a biphasic growth response to androgens, and prostate specific antigen (PSA) secretion did not show this biphaic response pattern.
Abstract: Several effects of androgens on LNCaP-FGC prostate tumor cells showed a biphasic pattern. Stimulation of growth and inhibition of secretion of prostatic acid phosphatase (PAP) was observed at low androgen concentrations (below 1 nM of the synthetic androgen R1881), and inhibition of growth and stimulation of PAP secretion was observed at higher concentrations. In contrast, prostate specific antigen (PSA) secretion did not show this biphasic response pattern. Comparable effects were found for two sublines of the LNCaPFGC cells: an early (passage 20, androgen-dependent) and relatively late (passage 70, androgen-sensitive) passage of the cells. Culturing of both sublines in the presence of a high concentration of androgens (10 nM R1881) resulted initially in a decrease in growth rate, but the cells started to proliferate within 3 weeks. These cells became less sensitive to androgens, lost their biphasic response pattern, and showed reduced androgen receptor levels. Three weeks after removal of the excess of androgens, the passage 70 cells regained a biphasic growth response to androgens. Culture in medium without steroids but with EGF resulted in a decrease of both androgen sensitivity and androgen receptor level. In conclusion, rapid changes of the androgen sensitivity and receptor level of the LNCaP cells occurred under the influence of culture conditions. These changes were partly reversible and, therefore, were most likely due to adaptation of the cells.
TL;DR: It is indicated for the first time that androgen deprivation induces a significant decrease in the size of the periurethral zone of the prostate in men with established BPH.
Abstract: To determine the influence of androgen deprivation induced by the potent 5 alpha-reductase inhibitor finasteride on the volume of the zones of the prostate, 20 symptomatic men with established BPH were randomized to one of three groups: placebo, finasteride 1 mg, and finasteride 5 mg/day. The volume of the entire prostate gland, periurethral zone, and peripheral zone and the seminal vesicles were determined by three dimensional reconstructions of magnetic resonance contoured images of the prostate. There was no significant difference between the results achieved with 1 and 5 mg of finasteride per day; thus the results in these two groups were combined. In the placebo group there was no significant change in the volume of any structure. Following treatment for 1 year with finasteride there was a significant (P < 0.02) 17% decrease in total gland size (11.5 +/- 3.2 cc). Similarly, there was a significant (P < 0.02) 17% decrease in total gland size (11.5 +/- 3.2 cc). Similarly, there was a significant (P < 0.03) decrease in the size of the periurethral zone of the prostate (6.2 +/- 3 cc). Although there was also a decrease in the size of the peripheral zone of the prostate (2.8 +/- 1.2 cc) this did not reach statistical significance. There was no significant change in the volume of the seminal vesicles. These findings indicate for the first time that androgen deprivation induces a significant decrease in the size of the periurethral zone of the prostate in men with established BPH.
TL;DR: A role for vitamin A as a modulator of the growth and differentiation of prostatic epithelial cells is indicated, and in post‐confluent cultures, retinoic acid prevented the appearance of keratin 1, which accompanied the development of a squamous phenotype by cells maintained under these conditions.
Abstract: The response of cultured human prostatic epithelial cells to vitamin A was measured by clonal growth assay in serum-free medium. Retinoic acid at 3 nM or higher inhibited the proliferation of cell strains derived from normal, benign hyperplastic and malignant tissues, while lower levels (0.03 nM) were stimulatory. Reduced proliferation induced by retinoic acid was accompanied by a marked change in morphology, as intercellular adhesion decreased. In conjunction, the expression of keratins 8 and 18, associated with the differentiated luminal phenotype of prostatic epithelia, was increased. In post-confluent cultures, retinoic acid prevented the appearance of keratin 1, which accompanied the development of a squamous phenotype by cells maintained under these conditions. The findings of this study indicate a role for vitamin A as a modulator of the growth and differentiation of prostatic epithelial cells.
TL;DR: It is concluded that, in prostate carcinoma, the least differentiated tumors more often expressed greater amounts of immunoreactive TGFα; however, no relationship between TGF α expression and cellular proliferation markers was found.
Abstract: Transforming growth factor alpha (TGF alpha) expression was analyzed immunocytochemically on formalin-fixed wax-embedded sections obtained from 24 benign prostatic hyperplasia (BPH) specimens and 76 prostatic carcinoma tissues, 3 human prostatic tumor xenografts, normal kidney, and salivary gland. Low amounts of TGF alpha immunopositivity were encountered in the epithelium of BPH glandular tissues, whereas in the prostatic adenocarcinoma samples, a greater heterogeneity and intensity of TGF alpha immunostaining was observed. The most intense staining was exhibited by the least differentiated tumors, although a few of these were weakly stained. Statistical analysis of the relationship of histopathological grade of tumor with TGF alpha expression in the carcinomas showed a significant correlation of these parameters, 0.01 > P > 0.001. The expression of the proliferation markers Ki-67 and PCNA was also analyzed in the carcinoma specimens, and the relationship of these to TGF alpha expression indicated that there was no significant correlation in this series of tumors between increased growth activity and TGF alpha expression (p approximately 0.25 with both markers). The prostatic carcinoma xenografts TEN12 and TEN15 contained low levels of immunoreactive TGF alpha, which was uniformly distributed, whilst heterogeneous immunostaining was observed in the uroepithelial xenograft TEN16. In the normal human kidney, TGF alpha was concentrated in the epithelium of the distal convoluted tubules (DCT) and the collecting tubules (CT), and lower amounts were identified in the proximal convoluted tubules (PCT). As in the prostatic carcinomas, the immunostaining was eliminated by prior absorption of the antibody with pure TGF alpha and not with human or mouse EGF. No crossreactivity of the TGF alpha antibody with salivary EGF was demonstrated. This study concludes that, in prostate carcinoma, the least differentiated tumors more often expressed greater amounts immunoreactive TGF alpha; however, no relationship between TGF alpha expression and cellular proliferation markers was found.
TL;DR: Observations suggest that PF proliferation is controlled by the interaction of two different growth factors, and that bFGF/TGF‐β imbalance in favor of cell proliferation promotes prostatic stromal hyperplasia.
Abstract: Basic fibroblast growth factor (bFGF) has been identified in the human prostate. The level of bFGF has been reported to be elevated in benign prostatic hyperplasia (BPH), compared with normal prostate, suggesting that the growth factor may play a role in this disease of the prostate. Basic FGF is a mitogen for cultured human prostate-derived fibroblasts (PF). PF also synthesize bFGF, suggesting that growth regulation of these cells may be under autocrine control. The current study was undertaken to identify factors that affect PF proliferation and bFGF expression. Transforming growth factor beta 1 (TGF-beta 1) inhibited PF proliferation. The inhibition by TGF-beta 1 was partially overcome by bFGF but not by epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor type 1 (IGF-1), or insulin. Incubation of PF with TGF-beta 1 increased bFGF mRNA and immunoreactive bFGF levels in a dose- and time-dependent fashion. None of the other growth factor studies affected bFGF levels. PF were also found to express TGF-beta 1 mRNA, the level of which was increased two- to fivefold by TGF-beta 1. These observations suggest that PF proliferation is controlled by the interaction of two different growth factors. It is possible that bFGF/TGF-beta imbalance in favor of cell proliferation promotes prostatic stromal hyperplasia.
TL;DR: Men with BPH had a higher level of bothersomeness attributed to urinary symptoms, and more interference in selected daily living activities caused by urinary dysfunction, and patients' feelings of well‐being should be taken into account in the clinical management of BPH.
Abstract: Little is known about the impact of benign prostatic hyperplasia (BPH) on the general well-being of men with this condition. All men aged 40-79 years registered with a group general practice were enumerated. BPH was defined as enlargement of the prostate gland of equivalent weight > 20 g in the presence of symptoms of urinary dysfunction and/or a urinary peak flow rate < 15 ml/s, without evidence of malignancy. Four hundred and ten men (20% of those who participated) satisfied these criteria. The proportion of men with a negative feeling of well-being was higher in men with BPH than in men who did not have BPH. The difference was consistent for all aspects of well-being (anxiety, depression, self-control, vitality, being worried or being bothered by illness). Men with BPH had a higher level of bothersomeness attributed to urinary symptoms, and more interference in selected daily living activities caused by urinary dysfunction. These were related to worry or concern over urinary function and prostate cancer, together with a higher level of embarrassment caused by urinary dysfunction, compared with men who did not have BPH. Patients' feelings of well-being should be taken into account in the clinical management of BPH.
TL;DR: Alcohol, diet, and other lifestyle factors were investigated in a cohort of 6581 Japanese‐American men, examined and interviewed from 1971 to 1975 in Hawaii, finding each associated with increased risk of obstructive uropathy, but no association was found with education, number of marriages, or cigarette smoking.
Abstract: 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.
TL;DR: The expression of the mutant p53 tumor suppressor gene was evaluated in 33 human prostate carcinomas using an immunohistochemical method with monoclonal antibodies PAb 1801 and PAb 240, demonstrating that abnormal p53 expression is a frequent event in prostate cancer.
Abstract: The expression of the mutant p53 tumor suppressor gene was evaluated in 33 human prostate carcinomas. Using an immunohistochemical method with monoclonal antibodies PAb 1801 and PAb 240, 26 (79%) tumors demonstrated positive immunostaining for mutant p53. Only areas of glandular tumor were positive, with adjacent stromal elements and areas of glandular hyperplasia being negative. The predominant staining pattern was cytoplasmic. This pattern may be related to p53 binding to certain heat shock proteins (HSP 72/73), as a monoclonal antibody to these proteins demonstrated a cytoplasmic location as well. These results demonstrate that abnormal p53 expression is a frequent event in prostate cancer.
TL;DR: A new human prostate tumor cell line (ALVA-31) has been established from a biopsy specimen of primary tumor obtained during prostatectomy as mentioned in this paper, which has been maintained for more than 48 months in stable growth.
Abstract: A new human prostate tumor cell line (ALVA-31) has been established from a biopsy specimen of primary tumor obtained during prostatectomy. The cell line has been maintained for more than 48 months in stable growth. The in vitro doubling time was determined to be approximately 26 hr. The chromosome number ranged from 24–112, with a modal number of 59 tested over several time points throughout continuous culture. Karyotypic analysis of late-passaged cells demonstrated approximately 70 human chromosomes, 8–14 markers, and two × chromosomes without a Y chromosome. Prostatic origin was confirmed by the expression of both prostate specific antigen and prostatic acid phosphatase, using specific antisera and immunoradiolabelling techniques. Prostate tumor xenografts were grown in intact male, castrate male, and female athymic mice; however, the rate of tumor growth was clearly dependent upon serum testosterone levels. © 1993 Wiley-Liss, Inc.
TL;DR: There are conflicting data on the effect of cigarette smoking on serum levels of the various sex hormones, but some studies suggest that cigarette smoke produces an antiestrogenic effect.
Abstract: There are conflicting data on the effect of cigarette smoking on serum levels of the various sex hormones Some studies suggest that cigarette smoke produces an antiestrogenic effect Smoking may also affect the metabolism of other sex steroids such as testosterone and adrenal hormones, and thereby influence the incidence of benign and malignant growth of the prostate Epidemiologic studies analyzing a possible association between cigarette smoking and prostate cancer are not conclusive, although some show a positive relationship The etiology of BPH is undoubtedly multifactorial Estrogens as well as androgens may be involved in the pathogenesis of BPH There are several studies that indicate that cigarette smokers have a lower likelihood of requiring surgery for BPH Growth of the prostate may not correlate with serum levels of androgens and estrogens The local hormonal milieu of the target cells in the prostate are probably more critical than the more easily measured serum levels This review examines the literature dealing with cigarette smoking and both BPH and prostate cancer If there is an effect, then elucidation of the mechanism by which smoking affects the growth of the prostate may improve our understanding of BPH and prostate cancer, and may suggest preventive strategies for high risk groups
TL;DR: A multivariate analysis of six possible parameters has shown the difference in the β‐MSP immunoreactivity to be a significant, independent, prognostic indicator of prostatic carcinoma.
Abstract: Human beta-microseminoprotein (beta-MSP), isolated from seminal plasma, is one of the proteins secreted by the prostate gland. To determine whether the beta-MSP immunoreactivity can be a prognostic indicator of prostatic carcinoma, the beta-MSP immunohistochemical distribution has been examined in needle biopsy specimens taken from 96 patients with prostatic carcinoma. Although no significant correlation was found between the beta-MSP immunoreactivity and the histological grade (Gleason score), patients with a positive beta-MSP expression had a significantly better prognosis than those with a negative beta-MSP expression (P = 0.01). Further, a multivariate analysis of six possible parameters (age, clinical stage, histological grade, serum prostatic acid phosphatase, beta-MSP immunoreactivity, and the type of initial treatment) has shown the difference in the beta-MSP immunoreactivity to be a significant, independent, prognostic indicator of prostatic carcinoma (P = 0.04).
TL;DR: It is demonstrated that an immortal, but nontumorigenic, human epithelial cell line (267B1) established from fetal prostate tissue can be malignantly transformed by a biological carcinogen, and can serve as a useful model for investigations of the progression of carcinogenesis.
Abstract: Investigations of mechanisms of human prostate carcinogenesis are limited by the unavailability of a suitable in vitro model system. We have demonstrated that an immortal, but nontumorigenic, human epithelial cell line (267B1) established from fetal prostate tissue can be malignantly transformed by a biological carcinogen, and can serve as a useful model for investigations of the progression steps of carcinogenesis. Activated Ki-ras was introduced into 267B1 cells by infection with the Kirsten murine sarcoma virus. Morphological alterations and anchorage-independent growth were observed; when cells were injected into nude mice, poorly differentiated adenocarcinomas developed. These findings represent the first evidence of malignant transformation of human prostate epithelial cells in culture, and support a role for Ki-ras activation in a multistep process for prostate neoplastic transformation. © 1993 Wiley-Liss, Inc.
TL;DR: Silver staining for nucleolar organizer regions (AgNORs) is reported to be helpful for assessing tumor proliferation, and these counts were investigated in formalin fixed, paraffin embedded human prostate tissues in three microscopic fields of 330X using an image analysis system.
Abstract: Tumor differentiation and proliferative activity are important predictors of biological behavior. While routine histological evaluation is fairly adequate to assess differentiation, tumor proliferative activity is difficult to measure. Silver staining for nucleolar organizer regions (AgNORs) is reported to be helpful for assessing tumor proliferation. We investigated the AgNOR counts in 20 formalin fixed, paraffin embedded human prostate tissues in three microscopic fields of 330X, using an image analysis system. A total of 200–700 nuclei were evaluated on histologically controlled areas of nonneoplastic prostate tissue, prostatic intraepithelial neoplasia (PIN), and invasive carcinoma. The values were compared to flow cytometrically obtained synthesis phase fractions (SPF) and immunohis-tochemically semi-quantitated, proliferative cell nuclear antigen (PCNA) patterns. AgNOR counts were also compared to tumor stage and Gleason's score.
The pattern of PCNA staining in formalin fixed specimens was widely variable, probably due to differences in preservation of antigen. The positive counts varied from 0 to 55%, with a mean value of 8.55 ± 15.9. The SPF values ranged from 5 to 13% with a mean value of 8.50 ± 2.37. Two of 20 tumors were aneuploid and 18 were of diploid range. The mean AgNOR values in nonneoplastic nuclei (1.836 ± 0.299), PIN (3.129 ± 0.295), and invasive tumor cell nuclei (4.737 ± 0.369) were highly significant (P 0.24), possibly because of the small number of samples examined. The highest AgNOR counts were found in the two aneuploid tumors. We conclude that AgNOR count may be a potential indicator of cellular proliferation, and possibly a marker of tumor differentiation. © 1993 Wiiey-Liss, Inc.
TL;DR: It is concluded that the castration‐induced inhibition of tumor growth is caused by factors other than tumor cell death.
Abstract: Rats with implanted highly differentiated Dunning R3327PAP prostatic tumors were castrated, and at 3, 7, and 14 days thereafter, the effects on tumor volume, epithelial cell numbers, and sizes were quantified using morphometrical methods. The castration response on these parameters was also examined in the normal prostate of the same rats. Castration resulted in a rapid decrease in organ volume, epithelial cell number, and size in the normal prostate, and morphological signs of epithelial cell death (apoptosis) were observed. Tumor growth and mitotic index were reduced, but there were no signs of increased apoptosis, and cell numbers remained fairly constant in the Dunning tumors during the study period. It is concluded that the castration-induced inhibition of tumor growth is caused by factors other than tumor cell death.
TL;DR: Differences in response of these tumor models to androgen depletion and repletion appear to be related to the putative involvement of different cell death pathways and the role of the stroma in these processes is unclear.
Abstract: The transplantable human prostate tumor lines PC-82 and PC-EW regress after androgen depletion. The castration-induced decline in tumor volume was faster in the PC-EW tumor (half-life 6 days) than in the PC-82 tumor (half-life 18 days), despite similar castrate androgen levels of less than 3 pmollg tissue. Androgen ablation of the PC-82 tumor induced a wave of apoptosis, whereas in the PC-EW tumor, necrotic cell death was predominantly observed. The proliferative activity (BrdU index) of PC-82 and PC-EW tumor tissue declined from 3% to less than 1% after castration. After androgen depletion, some proliferative activity remained, the major part of which was localized in the (murine) stromal compartment of the tumors. In contrast to the PC-EW tumors, regrowth of androgen-ablated PC-82 tumors was rapidly induced by androgen resubstitution. The differences in response of these tumor models to androgen depletion and repletion appear to be related to the putative involvement of different cell death pathways. The role of the stroma in these processes is unclear. © 1993 Wiley-Liss, Inc.
TL;DR: Findings support the contention that raloxifene is a pure estrogen antagonist and a physiological antagonist of androgen action in male rats and provide support for further structure‐activity and mechanistic investigations with benzothiophenes in the medical management of prostatic neoplasia.
Abstract: The benzothiophene anti-estrogen, raloxifene [LY156758; (6-hydroxy-2-(4-hydroxyphenyl) benzo(b)thien-3-yl)(4-(2-1-piperidinyl)ethoxy)phenyl methanone hydrochloride] has selective estrogen pharmacological antagonist activity in female rats. The present studies were done in the male rat to assess activity of raloxifene related to inhibition of prostatic growth and effects on the hypothalamic-pituitary-gonadal axis. Raloxifene did not compete for binding of the androgen, [3H]-methyltrienolone (R1881) in cytosolic extracts of ventral prostate. Similarly, the compound did not inhibit prostatic 5 alpha-reductase or testicular 17 alpha-hydroxy/C17,20-lyase activities. Raloxifene had no effect on the ventral prostatic uptake of [3H]-R1881 in vivo. Administration of estradiol to castrated male rats stimulated fourfold increases of in vitro ventral prostatic binding of [3H]-R1881. Raloxifene was devoid of agonist activity in castrated animals, because the compound had no stimulatory effect on prostatic androgen receptor binding activity. When raloxifene was coadministered with estradiol, the compound markedly antagonized the estrogen-induced increase of prostatic [3H]-R1881 binding, confirming its antiestrogenic properties in male rats. Serum prolactin was also elevated significantly (P < 0.05) with a single injection of raloxifene (20.0 mg/kg). In these same animals, serum FSH was significantly (P < 0.05) decreased by one dose (10.0 mg/kg) of the compound. Luteinizing hormone levels in castrated male rats were unaffected by raloxifene administration. Raloxifene treatment of castrated males significantly (P < 0.05) antagonized the stimulatory response of the ventral prostate (VP) to exogenous androgens in a dose-dependent manner. Raloxifene treatment of intact male rats for 14 and 28 days produced significant (P < 0.05) dose-dependent regression of the VP and seminal vesicles (SV). The VP regressive responses to raloxifene were associated with a decline in serum testosterone levels. Histological analysis of the VPs in raloxifene-treated rats was consistent with an androgen-deprived state. These findings support the contention that raloxifene is a pure estrogen antagonist and a physiological antagonist of androgen action in male rats. These pharmacological properties provide support for further structure-activity and mechanistic investigations with benzothiophenes in the medical management of prostatic neoplasia.
TL;DR: It appears that, in vivo, PIP may inhibit prostate cancer growth by inhibiting FSH, and may represent a novel hormonal treatment for prostate cancer.
Abstract: 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.
TL;DR: The available data indicate that prostatic tumors as well as a high percentage of prostatic hyperplasia tissues express c‐neu protein; however, its role in cellular proliferation needs further study.
Abstract: The expression of the neu oncogene product was investigated immunohistochemically in 36 cases of benign prostatic hyperplasia (BPH) and seven cases of adenocarcinoma of prostate (CaP). c-neu oncogene encodes a transmembrane growth factor receptor that has partial structural homology with EGF receptor, and is overexpressed and amplified in a number of human tumors, specially, breast cancers. Using a monoclonal antibody, AB-3, which recognizes -COOH-terminal of neu oncoprotein, we have analyzed immunohistochemically the expression of this protein in buffered formalin and Zamboni fluid-fixed surgically removed tissues. Focal patchy and/or diffused cytoplasmic staining of varying intensity was observed in 34 of 36 BPH cases. Four cases showed cell membrane staining as well (4/36 = 11%). All seven cases of adenocarcinomas had moderate to strong c-neu immunoreactivity, and two gave a distinct cell membrane-positive reaction (100%). The available data indicate that prostatic tumors as well as a high percentage of prostatic hyperplasia tissues express c-neu protein; however, its role in cellular proliferation needs further study.
TL;DR: This study was designed to determine the frequency of residual cancer in the prostate two years following definitive external beam radiotherapy designed, using a 3‐D planning system.
Abstract: The incidence of residual neoplastic cells on prostatic biopsy following conventional external beam radiotherapy is reported to range from 40–90%. As a result, it has been stated that current modalities of radiotherapy may carry an unacceptable local failure rate even in patients irradiated for low stage disease. In order to assess the potential benefits of threedimensional (3-D) treatment planning, an unselected, consecutive group of patients with localized adenocarcinoma of the prostate was evaluated. This study was designed to determine the frequency of residual cancer in the prostate two years following definitive external beam radiotherapy designed, using a 3-D planning system.
Between February 1988 and February 1989, 30 consecutive patients with localized (Stage T1 -T3NxM0) adenocarcinoma of the prostate received definitive external beam radiotherapy. All treatment fields were designed with a computed tomography (CT)-based 3-D treatment planning system, resulting in a static conformal radiotherapy plan. The minimum dose delivered to the target volume, which included the prostate, periprostatic tissues, and a 1 cm margin, was between 65 and 69 cGy. Twenty-six patients had Stage T1, T2NxM0 primary tumors and four were T3NxM0. Two years following the completion of treatment, all patients underwent digital rectal examination, transrectal ultrasound examination of the prostate with multiple biopsies, bone scan, and serum prostate specific antigen (PSA) determinations.
Residual prostate cancer was proven by biopsy in six of 30 patients (20%). Four of 26 (15%) with Stage T1 and T2 tumors had a positive biopsy. However, two of the four Stage T3 tumors had postradiation biopsies positive for cancer (50%). Only one patient with a positive biopsy had an abnormal rectal examination. Five of the eight patients with elevated serum PSA levels after two years had residual neoplasia identified on biopsy. One of six patients with an abnormal postradiation ultrasound had residual tumor. Only one of the 22 patients (5%) with a normal serum PSA at two years had a positive postradiation biopsy.
In patients with localized prostate cancer, the use of 3-D static conformal radiotherapyfollowed by multiple ultrasound guided biopsies confirmed the efficacy of external beam radiotherapy in low stage disease. We believe that the low incidence of positive biopsies in this study resulted from the benefits of 3-D treatment planning as well as the fact that all patients were evaluated, whereas past studies have been in selected patient groups when suspicion of residual disease existed prior to biopsy. However, the 50% posttreatment positive biopsy rate in Stage T3 and T4 tumors underscores the unsatisfactory local control even with 3-D conformal radiotherapy. More aggressive treatment (e.g., neoadjuvant hormones, interstitial boost, hyperthermia, or dose escalation) may improve local control in these patients. It appears that routine postradiation biopsies may not be necessary in patients with normal serum PSA levels at two years following treatment. © 1993 Wiley-Liss, Inc.