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Seven commercial 3- to 7-ring (R) polycyclic aromatic hydrocarbons (PAH) as well as PAH derived from lignite tar were spiked into 3 soils (0.8 to 9.7% of organic carbon). The disappearance of the original PAH was determined for the freshly spiked soils, for soils incubated for up to 287 d with their indigenous microflora, and for autoclaved, unsterile and pasteurized soils inoculated with basidiomycetous and ascomycetous fungi. Three to 12 d after spiking, 22 to 38% of the PAH could no longer be recovered from the soils. At 287 d, 88.5 to 92.7%, 83.4 to 87.4%, and 22.0 to 42.1% of the 3-, 4-, and 5- to 7-R PAH, respectively, had disappeared from the unsterile, uninoculated soils. In 2 organic-rich sterile soils, the groups of wood- and straw-degrading, terricolous, and ectomycorrhizal fungi reduced the concentration of 5 PAH by 12.6, 37.9, and 9.4% in 287 d. Five- to 7-R PAH were degraded as efficiently as most of the 3- to 4-R PAH. In organic-rich unsterile soils inoculated with wood- and straw-degrading fungi, the degradation of 3- to 4-R PAH was not accelerated by the presence of fungi. The 5- to 7-R PAH, which were not attacked by bacteria, were degraded by fungi to 29 to 42% in optimum combinations of fungal species and soil type. In organic-poor unsterile soil, these same fungi delayed the net degradation of PAH possibly for 2 reasons. Mycelia of Pleurotus killed most of the indigenous soil bacteria expected to take part in the degradation of PAH, whereas those of Hypholoma and Stropharia promoted the development of opportunistic bacteria in the soil, which must not necessarily be PAH degraders. Contemporarily, the contribution of the fungi themselves to PAH degradation may be negligible in the absence of soil organic matter due to the lower production of ligninolytic enzymes. It is concluded that fungi degrade PAH irrespective of their molecular size in organic-rich and wood chip-amended soils which promote fungal oxidative enzyme production.

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We have previously shown that a transforming factor-beta species (TGF beta) is a hormonally regulated negative growth factor in estrogen responsive MCF-7 human breast cancer cells. We now demonstrate that androgen withdrawal leads to a significant stimulation of TGF beta-2 mRNA in the androgen-responsive human prostate carcinoma cell line LNCaP. These data indicate that TGF beta-2 is a marker of (anti)androgen action in human prostate cancer in vitro. Based on these results we addressed the question of whether TGF beta-2 represented a marker of (anti)androgen action in prostate cancer in vivo: expression of TGF beta mRNA was determined by RNAase protection analysis in normal and malignant prostate tissue obtained from 9 prostate carcinoma patients without endocrine therapy. In parallel, the nuclear dihydrotestosterone (DHT) concentration was measured as an indicator of androgen stimulation in the same tissues. The following results were obtained. Both normal and cancerous tissues show nuclear accumulation of DHT indicating a functional androgen receptor system. TGF beta-2 is equally expressed in both normal and cancerous tissue. Expression of TGF beta-2 and nuclear DHT concentrations are correlated in both benign and malignant tissue. We conclude that TGF beta-2 is a marker of (anti)hormonal action in androgen-dependent tissue.

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Previous studies have shown that part of steroid hormone action on hormone dependent carcinoma cells is mediated through secreted autocrine and paracrine growth factors. Coculture experiments using the androgen receptor positive human prostate carcinoma cell line LNCaP as feeder cells and the androgen receptor negative prostate cell line DU 145 as indicator cells, such as experiments with conditioned medium suggest that androgens might regulate proliferation of prostate carcinoma through a similar mechanism. LNCaP and DU 145 cells express high affinity EGF-receptors and show an increased growth rate under treatment with EGF, TGF alpha and FGF. The growth stimulating potential of LNCaP-conditioned medium can be enhanced by androgens. The polyanionic compounds suramin and dextran sulfates which have been shown to inactivate a variety of growth factors e.g. EGF/TGF alpha inhibit growth of LNCaP cells and DU 145 cells in a dose dependent and reversible fashion. Growth stimulation of LNCaP cells by EGF/TGF alpha can be completely reversed by simultaneous addition of polyanions but they inhibit androgen stimulation only partially. These data suggest the existence of at least two different mechanisms of growth regulation by androgens which can be distinguished by their different sensitivity of prostatic carcinoma cells to growth factor inhibitory agents. In order to investigate the therapeutic potential of these substances in complex, heterogeneous cell systems of solid tumors we treated 8 representative human prostate cancer lines in the nude mouse model. Systemic applications of polyanions revealed significant growth inhibition in hormone dependent as well as hormone independent xenografts. In androgen responsive lines growth inhibition was intensified by additional androgen withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

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During successful and uncomplicated angioplasty (PTCA), we studied the effect of a short lasting myocardial ischemia on plasma creatine kinase, creatine kinase MB-activity, and creatine kinase MM-isoforms (MM1, MM2, MM3) in 23 patients. Eleven patients, in whom diagnostic coronary angiography was performed, served as the control group. Blood was sampled after PTCA and every 2 h for the next 12 h, and after 24 h. CK- and CK-MB activities were determined enzymatically, the MM-isoforms by isoelectric focussing. After PTCA total CK and CK-MM3 increased significantly from 23 +/- 10 to 40 +/- 31 U/I (p less than 0.01) and from 18 +/- 5 to 32 +/- 10% (p less than 0.0005), respectively. The ratio MM3:MM1 also increased significantly from 0.4 +/- 0.1 to 1.2 +/- 0.7 (p less than 0.0005). Enzyme maxima for CK-MM3 and the ratio MM3:MM1 were reached 6 h after PTCA, for total CK 10 h after PTCA. This increase was independent of changes in the ECG, of symptoms during PTCA, as well as of the number and duration of balloon inflations. In the control group no changes in enzyme activity were found. Thus, after uncomplicated PTCA a significant increase of total CK and CK-MM-isoforms can be found, which may be due to the short-lasting myocardial ischemia following coronary occlusion.

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To evaluate the role of MM creatine kinase isoforms in detecting infarct vessel patency in 84 patients with acute myocardial infarction, total creatine kinase, MB creatine kinase, and MM isoforms were determined at the start of thrombolytic therapy and 30, 60, and 120 minutes later. Enzyme data were related to the reperfusion grade of the infarct artery, which was assessed by angiography 60 and 90 minutes after the start of thrombolysis. In 50 patients the infarct vessel was found patent at 60 and at 90 minutes after thrombolysis; in 19 patients it was occluded at both time points. In contrast to the patients with a persistently occluded infarct artery, in the patient group with a patent infarct vessel total creatine kinase and MB creatine kinase increased significantly at 60 minutes after the start of thrombolysis and MM3 creatine kinase activity and the ratio MM3:MM1 had already increased at 30 minutes after the start of thrombolytic therapy. The increases from baseline of creatine kinase and creatine kinase MB activity were significantly higher 120 minutes after the start of thrombolysis; increases of creatine kinase MM3 and the ratio of MM3:MM1, however, by 60 minutes after the start of thrombolysis were already increased compared with the increases in enzyme activity in patients with an occluded artery. Thus the rise in MM3 creatine kinase and the ratio of MM3:MM1 can be used for early detection of reperfusion after intravenous thrombolytic therapy in acute myocardial infarction.

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Growth of the normal and malignant prostate is known to be regulated by androgens. Part of their effect has been suggested to be mediated through coordinated regulation of secreted growth factors with autocrine function. We now examine the biological role of preferentially paracrine acting factors in growth control of prostate cancer, i.e. fibroblast growth factor(s) (FGF). Coculture experiments using the androgen-responsive human prostate carcinoma cell line LNCaP as feeder cells and the FGF-dependent human adrenal carcinoma SW-13 cell line as target cells show that (i) LNCaP cells induce growth of SW-13 cells, (ii) even higher stimulation of SW-13 cells is seen in the presence of androgen treated LNCaP cells and (iii) a specific anti-bFGF antibody inhibits growth of SW-13 cells induced by androgen treated LNCaP cells; no proliferation of SW-13 cells occurs in the absence of LNCaP cells. Partial purification of the secretory products of LNCaP cells was performed by affinity chromatography using a heparin sepharose column. Fractions were tested for biological activity in a soft agar assay with SW-13 cells. Several activities could be detected, the main activity was eluted with about 1.5 M NaCl. These data suggest that androgen treatment of LNCaP cells leads to enhanced secretion of proteins which belong to the FGF-family.

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It has been previously shown that estrogens may exert their action on human breast cancer cells through coordinated control of secreted growth factors which act in an autocrine and paracrine fashion. Growth stimulation of the androgen receptor negative prostate carcinoma cell line DU-145 by dihydrotestosterone in the presence of the androgen-responsive human prostate carcinoma cell line LNCaP now indicates that androgens may regulate growth of prostate carcinoma cells through related mechanisms. A variety of androgen-regulated growth modulatory activities with autocrine and paracrine potential can be detected in conditioned media from LNCaP cells partially purified by ion exchange chromatography. Androgen-induced growth of LNCaP cells is partially inhibited by the polyanions suramin and dextran sulfates which antagonize growth factor action. These data suggest the existence of at least two different mechanisms of growth regulation by androgen which can be distinguished by their different sensitivity to growth factor inhibitory agents. We conclude that the combination of antipeptidergic substances and androgen withdrawal would represent a new and promising strategy for treatment of human prostate cancer.

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CK MM isoforms (MM 3 having the highest isoelectric point, followed by MM 2, MM 1, and MM X) were measured in 35 patients with acute myocardial infarction (AMI) by isoelectric focusing on agarose gel. Blood samples were analysed every 2 h for the first 12 h, then every 4-8 h until 72 h after AMI. In the first sample, obtained 2.1 h after the onset of chest pain, the ratio of the isoforms MM 3:1 was 0.7 (range 0.2-1.8), equivalent to a normal value. Before the total CK exceeded normal, in 86% of the patients the ratio MM 3:1 rose to 2.2 (range 0.3-3.3). The maximal individual ratio MM 3:1 was 4 (range 0.9-12) after 7 h. It fell below 1 again after 27 h. Thus, the ratio MM 3:1 was useful in the early diagnosis of AMI by enzymatic methods and to estimate the time elapsed since the onset of infarction. Twenty patients with an open infarct vessel (angiographic data after thrombolytic therapy) showed similar peak enzyme activities as ten non-reperfused patients. They differed significantly in the time to the peak activity, mostly for CK MM 3 and CK MB (p less than 0.0005). A higher ratio CK MM 3:1 and a shorter time to the maximum CK MM 3 activity in reperfused patients helps to assess the success of thrombolytic therapy.

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In vitro perfusion of human placenta was evaluated for characterization of aromatase inhibitors. The results were compared with those in kinetic experiments in cell-free system. Inhibition constants (Ki) were determined by measuring the release of tritiated water during coincubation of human placenta microsomes with varying amounts of [1 beta,2 beta 3H]androstenedione and inhibitor in the presence of NADPH-generating system. Irreversible inactivation constants (Kinact) were determined in a similar manner following preincubation of the microsomes with different amounts of inhibitor for varying times. Lineweaver-Burk plots indicated a competitive type of inhibition with Ki values of 37 nM for 4-hydroxy-androstenedione, 3,700 nM for testolactone, 15 nM for 1-methyl-androsta-1,4-diene-3,17-dione, and 7.5 nM for 19-azido-androstenedione. Additionally, irreversible enzyme inactivation by all four substances could be demonstrated with Kinact values of 3.64 x 10(-3), 0.57 x 10(-3), 0.34 x 10(-3), and 0.69 x 10(-3)sec-1, respectively. Perfusion of a single cotyledon of human term placenta was performed by infusing medium through catheters placed in a fetal artery and in the maternal intervillous space. Perfused medium was collected from a cannulated fetal vein and from the maternal basal plate. The medium was supplemented with [3H]androstenedione (4.2 nM) and inhibitor. The perfusates were analyzed for their [3H]estrone and estradiol content following phenolic partition and Sephadex-LH 20 chromatography. The main results were, (1) the recovery of labelled steroids increased rapidly after perfusion started and reached a plateau within 60 min, when 55 and 30% (mean values) of the infused radioactivity were recovered in the fetal and maternal perfusates, respectively, (2) similar amounts of estrone and estradiol were found in both effluates, whereas androgens (mainly androstenedione and lower amounts of 5 alpha-androstane-3,17-dione) were found nearly exclusively in the fetal perfusate, (3) formation of estrogens (estrone + estradiol) reached a plateau within 20 min of perfusion. (4) The percentage of estrogens formed was not changed by increasing androstenedione concentration in the perfusion medium unless this concentration exceeded 3.5 microM indicating limited capacity of aromatase. (5) The four aromatase inhibitors reduced estrogen formation by 50% at concentrations about 100-fold of their Ki determined in the cell-free system, (6) irreversible aromatase inhibition could not be demonstrated in the perfusion model. It was concluded that the human placenta perfusion model can be successfully used to evaluate aromatase inhibitors.

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Total tissue content and subcellular distribution of DHEA sulfate, DHEA, androst-5-ene-3 beta,17 beta-diol, androst-4-ene-3,17-dione, testosterone, 5 alpha-DHT, and 5 alpha-androstane-3 alpha,17 beta-diol as well as the activities of steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, 3 alpha/beta-hydroxysteroid dehydrogenase, and creatine kinase were quantified in 12 untreated primary tumors of prostatic cancer. Samples were obtained by radical prostatectomy and serial sections, and were alternately used for either biochemical or morphological evaluation. The results were compared with values determined in benign parts of the same prostates. Qualitatively, all enzymes and steroids found in the benign tissues could also be demonstrated in the cancers. Steroid patterns showed individual quantitative variation but no general differences between the carcinomas and the benign tissues. Enzymes showed a tendency to lower activities in the cancers, particularly when expressed per DNA. Substantial diminutions of creatine kinase and 5 alpha-reductase activity, the latter being often accompanied by an increased testosterone/DHT ratio, were the most striking differences seen in most of the cases between malignant and nonmalignant tissues. Some interesting individual parallels of morphological and biochemical aspects were seen, but there was no obvious general parallelism between the histological picture and endocrinological characteristics.

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Activities of several steroid metabolizing enzymes (steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, and 3 alpha beta-hydroxysteroid dehydrogenase) as well as total tissue content and subcellular distribution (nuclear-extranuclear) of several androgen precursors, active androgens, and androgen deactivation products (DHEA sulfate, DHEA, 5-androstenediol, 4-androstenedione, testosterone, DHT, and 3 alpha-androstanediol) were quantified in primary tumors and lymph node metastases of human prostatic cancer obtained from patients without previous endocrine manipulation. Primary tumors were compared to benign parts of the same prostates, and the metastases were compared to their primary tumors. All enzymes and steroids found in benign prostatic tissues could also be detected in the malignant tissues. Even the capacity to accumulate active androgens in the nuclei was found to be unchanged in nearly all of the samples. Lower activities of hormone-dependent enzymes were observed in the cancers, suggesting a less efficient utilization of hormonal stimuli. Most striking changes found in the malignant tissues were a subtotal loss of 5 alpha-reductase activity and a metabolic shift to testosterone, which was more pronounced in samples from metastatic disease as compared to samples from non-metastatic disease. In conclusion, primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue. Consequently, they should be able to use at least androstenedione for production of active androgens directly in the target tissue.

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This paper presents a large body of data relating to benign prostatic hyperplasia, which have been derived from fundamental endocrinological research. For the urologist, the data open up interesting aspects of the pathomorphology of prostatic hyperplasia. The most interesting findings can be summed up as follows: 1. Testosterone is the circulating androgenic prohormone that mediates the intracellular message leading to androgen secretion, though by way of its metabolite dihydrotestosterone, which is really the active substance. 2. This metabolic conversion is catalyzed by 5 alpha-reductase, which is predominantly a stromal enzyme. 3. The estrogen metabolism in the stromal cells of the prostate may be associated with the abnormal growth of the prostate. 4. In the presence of benign prostatic hyperplasia dihydrotestosterone and 17 beta-estradiol accumulate in the nuclei of the stromal cells. 5. Adrenal androgens are also metabolized in the human prostate, yielding some substances with androgenic and some with estrogenic potency. 6. Changes in sex hormone binding globulins (SHBG) are found with age whether benign prostatic hyperplasia is present or not. It is therefore questionable whether it has any influence on the development of prostatic hyperplasia. 7. Although in some cases it is not yet possible to determine whether the findings presented in this paper have any causal significance, the data can be used as a rational basis for hormonal treatment of prostatic disease.

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In order to delineate differences in the mechanism of androgen action in epithelium (E) and stroma (S) of the human prostate, we studied the 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH) in these tissues of benign prostatic hyperplasia (BPH). Tissue was obtained by suprapubic prostatectomy. E and S were separated; samples were homogenized in buffer and incubated with [3H] steroids (4-androstenedione (Ae), estrone (E1), or dehydroepiandrosterone (DHEA] and NADH (4.2 mmol/l) as cosubstrate for 60 min at 37 degrees C. Separation and quantification of the metabolites were performed by TLC and LSC, respectively. The main results were: (1) Following incubation with DHEA and E1, only the metabolites 5-androstene-3 beta,17 beta-diol and estradiol, respectively, were found. Following incubation with Ae, testosterone, 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha-(beta),17 beta-diol were detected as metabolites (the sum of these metabolites were used for calculations). (2) The Michaelis constants were identical in E and S (mean +/- SEM (n), mumol/l, Ae 6.92 +/- 1.01, E1 7.84 +/- 0.69, DHEA 3.73 +/- 0.38). (3) The maximum velocity rate for the three substrates in E was 5-10-fold that in S (P at least less than 0.01), the value in the whole tissue homogenate (WT) being intermediate (pmol/mg protein h), for Ae: E 383 +/- 56, S 40 +/- 3, WT 75 +/- 13; for E1: E 362 +/- 71, S 33 +/- 4, WT 63 +/- 8; for DHEA: E 132 +/- 21, S 26 +/- 4, WT 36 +/- 4. On the basis of these results the role of 17 beta-HSDH in forming active androgens and estrogens from less potent precursors is discussed in the stromal and epithelial compartment of the human prostate.

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As an extension of our studies on androgen metabolism in epithelium and stroma of human benign prostatic hyperplasia (BPH) tissue our attempts to demonstrate the presence of aromatase are described. Additionally, the question is raised whether the aromatase inhibitor 17 alpha-oxa-D-homoandrosta-1.4-diene-3.17-dione (testolactone) might also act by inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH). In vitro metabolism and inhibition were analyzed by TLC. The main results were: (1) Two aromatase assays (estrone formation and tritium release) were tested with placenta microsomes. Identical results were obtained (Km = 43 +/- 7 nmol/l n = 5; Vmax = 100 resulted in recovery of the aromatase activity added. (3) In BPH tissue alone, formation of estrone from androstenedione could not be detected (less than 7 x 10(-17) mol/min per mg protein, n = 8). (4) 4-Hydroxyandrostenedione inhibited placental aromatase (Ki = 37 nmol/l) distinctly better than 17 beta-HSDH from human BPH (Ki = 18 mumol/l), whereas the Ki values for testolactone (3.7 and 29 mumol/l, respectively) were more similar. It is concluded that aromatization of androgens is not an important pathway in BPH tissue. An alternative mode of action of testolactone by inhibition of 17 beta-HSDH is discussed.

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The well-known hormone dependency of the normal human prostate and of BPH and prostatic carcinoma stimulated the study of cellular events which would possibly lead to specific steroid hormone patterns under the respective prevailing condition. In extending earlier observations on a significant DHT and E2 accumulation especially in stromal nuclei of BPH recent data on the uptake and metabolism of adrenal androgens clearly underline the important differential role of either stromal or epithelial cells. Epithelium and stroma of BPH contained a quantitatively different pattern of steroid metabolizing enzymes. This dualism of enzyme activity favours the conversion of testosterone to DHT in the stroma while androgens of adrenal origin are metabolized mainly in BPH epithelium. Further to quantitative data on the intracellular distribution of the three sex steroid classes (estrogens, androgens, adrenal androgens) and to Km and Vmax values of the respective steroid metabolizing enzymes in question (5 alpha-reductase, 3 alpha/beta-HSDH, 17 beta-HSDH, sulfatase, aromatase) the impact of antihormones (cyproterone acetate) on the intratissular distribution and on the in vivo cytosolic and nuclear binding of DHT as well as on its biological implications will be discussed. The data present a complicated picture, which points to special roles of epithelial and stromal cells and allow speculations on the relative importance of testicular and adrenal androgens and estrogens for the development and maintenance of both normal and diseased human prostates. Furthermore, the determination of intratissular steroid concentrations can be an important tool to understand and to ground a rational basis for a hormonal treatment of prostatic tumors.

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Creatine kinase isoenzymes in cytosolic and mitochondrial fractions from human cardiac tissues were studied by analytical and preparative isoelectric focusing (IEF), electrophoresis and immunoinhibition. Analytical IEF on agarose gels revealed many creatine kinase variants in human cardiac cytosol prepared by extraction with a hypotonic medium. The bands located at approximately pH 5.5 were shown to contain creatine kinase-MB and minute creatine kinase-BB bands by electrophoresis. Two bands which focused closely together in IEF (pH 6.85-7.0) showed an electrophoretic migration pattern similar to creatine kinase-MM. One of them (IP 6.85) showed a complete inhibition by anti-creatine kinase-M antibodies, whereas the other showed only 50% inhibition. Increasing the salt concentration of tris-HCl (0.1 mol/l) in the extraction medium resulted in additional creatine kinase variants. They were characterized by high alkaline isoelectric points and were not inhibited by anti-creatine kinase-M antibodies. These variants corresponded to two cathodic bands in electrophoresis. The treatment of washed mitochondria with phosphate buffer resulted in a release of mitochondrial variants with different isoelectric points, as shown by analytical IEF in agarose gels. The same pattern was obtained by using preparative IEF. Variants with high alkaline isoelectric points gave rise to two cathodic bands upon electrophoresis. These two bands resembled those present in cytosol after extraction with high salt concentration. No complete inhibition with anti-creatine kinase-M was observed in any of the eluates. The mitochondrial variants exhibited different affinities towards creatine phosphate and ADP. Variants with higher alkaline isoelectric points showed lower Km-values for these substrates than those with less alkaline isoelectric points.

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Androgen metabolites with 3 beta-hydroxy configuration--ie, dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one, DHEA), 5-androstene-3 beta-17 beta-diol (A-Diol), and 5 alpha-androstane-3 beta, 17 beta-diol (3 beta-Diol)--were measured by radioimmunoassay in the homogenate, in the mechanically separated epithelium and stroma, and in the nuclear fractions of epithelium and stroma of benign hyperplastic (BPH) and normal human prostatic tissue, in muscle homogenates and in plasma. The main results were: 1) Mean prostatic DHEA, A-Diol and 3 beta-Diol were 6-7 times as high as plasma values (1 g = 1 ml). Compared to muscle, prostatic values were more than tenfold higher. 2) The values in homogenates of BPH and normal prostate were not statistically different (pmol/mg DNA, mean +/- SEM, BPH: DHEA 46.8 +/- 7.2, n = 11; A-Diol 5.7 +/- 1.2, n = 12; 3 beta-Diol 3.7 +/- 0.6, n = 13; normal prostate: DHEA 56.0 +/- 5.5, n = 2; A-Diol 7.4 +/- 2.4, n = 5; 3 beta-Diol 5.8 +/- 1.7, n = 5). 3) In the nuclear fractions of epithelium and stroma the values were low compared to the homogenates and could not be discriminated from unspecific retention. Although we could not demonstrate either a specific retention of the 3 beta-hydroxysteroids in the nuclei or conclusive differences in steroid accumulation between epithelium and stroma of BPH and normal prostate, which could explain the development of the disease, the high levels in the tissue particularly of A-Diol would be compatible with estrogenic action at the prostate level.

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In most cases, the prostatic carcinoma (PCA) is a hormone-dependent malignant tumor. Since sexual steroids seem to act upon their target organs by means of specific steroid receptors the determination of receptor concentration in PCA is of great theoretical and practical interest. The state of art of receptor research in PCA can be summarized as follows: 1. The prognostic relevance of receptor determinations in PCA is controversial. The contradictory assessments of the value of receptor measurements may be mainly caused by methodical problems. 2. A possible heterogeneity of the receptor distribution in PCA tissue can not be detected by biochemical receptor determinations. 3. This heterogeneity could be one reason for a lack of response to endocrine therapy in cases which are biochemically receptor-rich (selection of receptor-poor cell clones). 4. The available (immuno)histochemical fluorescence techniques, which have been developed for direct detection of heterogeneous receptor distribution in the tissue, are neither sufficiently sensitive nor specific. 5. It is an open question whether the development of an appropriate (immuno)histochemical method will succeed.

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Male Wistar rats were castrated and implantated with testosterone-filled silastic depots (in vitro release rate: 60 micrograms/24 h) prior to treatment with 10 mg cyproterone acetate (CyAc) on day 1, and 5 mg on days 4, 7, 10 and 13. Animals were sacrificed on day 14. Control animals were treated identically, with the exception of CyAc administration. Blood was collected and the ventral prostates of 6-8 animals were pooled, homogenized and processed into cytosol and purified nuclei. Steroid determinations (CyAc, testosterone, 5 alpha-dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol)) were performed by RIA. Specifically bound DHT (charcoal resistant DHT = CR-DHT) represents DHT values (RIA) following treatment of cytosol or nuclear extract with dextran coated charcoal. The androgen receptor was determined in cytosol and nuclear extract by 'exchange assay' using [3H]methyltrienolone (MT) (18 h, 15 degrees C). The main results were: 1) The steroid levels in plasma (testosterone, DHT, 3 alpha-diol) were in the range of untreated adult animals and not significantly influenced by the CyAc treatment. Final CyAc levels were 305 +/- 58 nmol/l (mean +/- SD, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

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