Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In situ photoaffinity labelling of the human androgen receptor has been performed in the LNCaP (Lymph Node Carcinoma of the Prostate) cell line. The covalently labelled receptors were identified by SDS-PAGE. Intact LNCaP cells, incubated with [3H]-R1881 and subsequently irradiated with u.v. light and directly solubilized in SDS-buffer, revealed two photolabelled protein bands at 110 and 50 kDa. Irradiation of intact cells and subsequent isolation of nuclei followed by extraction with 0.5 M NaCl resulted in one major photolabelled protein band at 110 kDa. The labelling of this band could be completely suppressed by a 100-fold molar excess of non-radioactive R1881. Photolabelling of androgen receptors in a cytosolic preparation of LNCaP cells after anion exchange chromatography resulted in a much lower labelling efficiency compared with the in situ labelling procedure, although the androgen receptor was purified 100-fold. The steroid binding domain of the human androgen receptor has been partially mapped with chymotrypsin and S. aureus V8 protease digestion. Proteolytic digestion with chymotrypsin of purified photoaffinity-labelled 110 kDa human androgen receptor resulted in the generation of a 15 kDa peptide which still contains the covalently linked hormone. It is concluded that the in situ photoaffinity labelling technique can be applied successfully for characterization of the steroid binding domain of androgen receptors in prostate cancer cells and in other androgen target cells. Furthermore, it was demonstrated that the human androgen receptor is a monomer with a molecular mass of 110 kDa, of which the steroid binding site is confined to a 15 kDa domain.
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PMID:In situ photolabelling of the human androgen receptor. 326 Mar 9

A nuclear binding (NB) assay has been developed for the measurement in intact viable cells of biologically active (functional) estrogen and progesterone receptors, i.e. those capable of binding to nuclear acceptor sites [Spelsberg et al., Endocrinology 121: 631 (1987)]. This paper describes the application of this assay to analyses of androgen receptors in the guinea pig seminal vesicle and in human prostatic carcinoma. Cells from fresh animal seminal vesicles or human prostate carcinoma are isolated using collagenase and are incubated with [3H]R1881 for 1 h at 22 degrees C, after which nuclei are isolated at 4 degrees C and assayed for DNA and radioactivity. This NB assay demonstrates a saturable, temperature dependent, steroid and tissue specific nuclear binding of [3H]R1881 for the guinea pig-seminal vesicle system. The nuclear binding is of high affinity and low capacity. The NB assay reveals several important aspects of the androgen and estrogen receptors in target tissues: (1) the nuclear acceptor sites for androgen receptor (AR) are steroid receptor specific; (2) there are different concentrations of the androgen and estrogen receptors between the epithelium and the fibromuscular components of the guinea pig seminal vesicle; and finally (3) some biopsies of human prostate cancer appear to contain biologically inactive AR. This assay may be useful in the analyses of functional receptors in biopsies of human cancer cells.
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PMID:A nuclear binding assay for measurement of biologically active androgen receptors in animal tissues and human prostate cancer. 326 Sep 78

The present study describes a method for the measurement of the plasma levels of hydroxy-flutamide (Flu-OH), the biologically active and main circulating metabolite of flutamide. We have observed that two to four hours after oral administration of 250 mg of flutamide to healthy young men, as well as to patients with prostate cancer, the plasma concentration of Flu-OH reaches a peak at approximately 1.7 microM. The plasma concentration of Flu-OH measured at months 6, 12, and 18 of treatment shows a minimal basal level of 3.4 microM with a maximal increase at 6.8 to 8.5 microM at 2 to 4 hours. Since the serum levels of testosterone in these patients are approximately 1 nM, the levels of the active antiandrogen are at a 5000- to 10000-fold excess. However, due to the low affinity of the antiandrogen for the androgen receptor, it is extremely important to maintain this concentration of the antiandrogen in plasma constant.
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PMID:Plasma levels of hydroxy-flutamide in patients with prostatic cancer receiving the combined hormonal therapy: an LHRH agonist and flutamide. 327 9

The relative success with which the response of breast cancer to endocrine therapy can be predicted by assay of female sex steroid receptors has led to attempts to use measurement of androgen receptors in neoplastic prostate tissue for predicting the success of anti-androgen therapy in prostate cancer. Hitherto hopes have not been fulfilled. Androgen receptors are present in almost all prostate samples, but with inhomogeneous distribution. No relationship was found between androgen receptor levels in needle aspirate and prognosis in prostatic carcinoma. Receptors for oestrogen, progestin and prolactin were also studied for identification of possible prognostic indicators. Progestin receptors appear to be present in prostatic tissue. Lack of consensus regarding prostatic oestrogen and prolactin receptors is due partly to their low (if any) concentrations and partly to differing methodology and interpretation of results. Oestrogen, progestin and prolactin receptors seem to lack prognostic significance in prostatic cancer. These findings and the high initial response rate of prostatic carcinoma to endocrine therapy indicate that further studies should focus on elucidating how such tumours become hormone-independent.
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PMID:Hormone receptors in human prostate cancer. 328 96

The design of a new drug is conditioned by knowledge of the biochemical mechanisms involved in the etiology of the disease to be treated. With regard to endocrine pathologies, such knowledge can be obtained in the clinic from systematic assays of urinary and plasma hormones, enzyme activities and target tissue receptor concentrations. The present paper describes the results of our assays of plasma 3 alpha-androstanediol glucuronide, 5 alpha-reductase and androgen receptor in prostate cancer patients. The activity of the nonsteroid antiandrogen anandron is discussed in relation to these parameters: anandron may inhibit slightly adrenal androgen biosynthesis but, in particular, counters the action of these adrenal androgens on the prostate. It does not inhibit rat prostate 5 alpha-reductase activity but interacts with androgen receptor to exert an antiandrogen action.
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PMID:Design of antiandrogens and their mechanisms of action: a case study (anandron). 333 76

The nuclear androgen receptor (ARn) content of cancerous prostatic tissue has been investigated as a prognosticator for time to progression under endocrine therapy. In 1981 a prospective study was started to investigate whether the ARn content in biopsy specimens of patients with prostatic carcinoma predicts the duration of response following hormonal treatment. ARn was estimated by a microassay which involves extraction of nuclear pellets with a heparin-containing buffer, exchange labeling of the nuclear extract with 3H-R1881, and quantitation of the receptor with protamine sulphate precipitation. One hundred and fifteen patients with prostatic cancer entered this study; 47 patients had evidence of metastatic disease as proven by bone scan. Forty-two patients were treated by orchiectomy; 37 of these patients are evaluable with a minimal follow-up of 30 months. A relationship between the nuclear androgen receptor content and the time to progression following orchiectomy in these patients with metastatic disease of the prostate was not found. This could possibly be attributed to the heterogeneous nature of the prostatic tumor tissue with respect to the distribution of the ARn. We conclude that androgen receptor assay in needle biopsies, at least in this study, had no value for the prediction of the time to progression after orchiectomy.
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PMID:Prediction of time to progression after orchiectomy by the nuclear androgen receptor content from multiple biopsy specimens in patients with advanced prostate cancer. 337 41

A cDNA clone has been isolated from a library prepared of mRNA of human breast cancer T47D cells with an oligonucleotide probe homologous to part of the region encoding the DNA-binding domain of steroid receptors. The clone has a size of 1505 bp and sequence analysis revealed an open reading frame of 1356 bp. The deduced amino acid sequence displays two highly conserved regions identified as the putative DNA-binding and hormone binding domains respectively of steroid receptors. Expression of this cDNA clone in COS cells produces a nuclear protein with all the binding characteristics of the human androgen receptor (hAR). The gene encoding the cDNA is assigned to the human X-chromosome. High levels of three hybridizing mRNA species of 11, 8.5 and 4.7 kb respectively are found in the human prostate cancer cell line (LNCaP), which contains elevated levels of hAR. The present data provide evidence that we have isolated a cDNA that encodes a major part of the human androgen receptor.
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PMID:Cloning, structure and expression of a cDNA encoding the human androgen receptor. 337 88

Increasing concentrations of 17 beta-estradiol (E2) led to a maximal 7-fold stimulation of growth of the highly androgen-sensitive clone (SEM-1) of the mammary carcinoma Shionogi cell line. Half-maximal stimulation by the estrogen was observed at 100 nM E2. Diethylstilbestrol (DES), on the other hand, a synthetic estrogen with no affinity for the androgen receptor, had no significant stimulatory effect on cell growth but caused growth inhibition at concentrations above 1 microM. Mediation of the action of E2 by the androgen receptor is indicated by the absence of interference of E2 action by the antiestrogen LY156758 while the antiandrogen hydroxyflutamide (3 microM) caused a 50% inhibition of E2 action. While increasing concentrations of E2 led to a progressive increase in cell growth, a progressive shift in the ED50 value of action of dihydrotestosterone (DHT) was observed at intermediate (10-100 nM) concentrations of E2 while 10 microM E2 completely inhibited DHT action. At those high E2 concentrations, however, E2 itself led to a stimulation of cell growth equivalent to approximately 50% of the maximal value achieved by DHT. E2 competed with the specific uptake of [3H]testosterone in intact cells at an inhibition constant (Ki) value of 15 nM, thus indicating direct interaction of E2 with the androgen receptor. Preincubation with E2 had no influence on the apparent affinity of testosterone for the androgen receptor nor on the number of androgen binding sites. The present data demonstrate that both the stimulatory and antiandrogenic action of E2 on the growth of the androgen-sensitive mammary carcinoma cell line SEM-1 are mediated through direct interaction of the estrogen with the androgen receptor. Such data may offer an explanation for the subjective improvements reported in prostate cancer patients receiving a high dose of E2 when relapsing after castration.
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PMID:Mediation by the androgen receptor of the stimulatory and antiandrogenic actions of 17 beta-estradiol on the growth of androgen-sensitive Shionogi mammary carcinoma cells in culture. 340 89

Needle biopsy specimens of primary adenocarcinoma and surgical specimens of carcinomatous nodal tissue were obtained from previously untreated clinical D stage prostatic adenocarcinoma patients. Assessment of the relation between specimen androgen receptor site content and survival using either scatterplots or Kaplan-Meier analyses showed specimen receptor content was a poor prognostic P greater than 0.1, of survival subsequent to orchiectomy or diethylstilbestrol (DES) therapy. The possibility that heterogeneity of specimen androgen receptor site content contributed to this finding was evaluated by comparing receptor content of multiple small or large tissue specimens from the same prostate gland of patients with benign prostatic hyperplasia or nonmetastatic prostatic cancer. This evaluation showed significant microheterogeneity of human prostate androgen receptor site content which was substantially masked in large tissue specimens. We conclude that microheterogeneity of human prostate androgen receptor site content compromises the use of biopsy specimen androgen receptor measurements as a prognostic of patient survival subsequent to initiation of hormonal therapy.
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PMID:Androgen receptors in biopsy specimens of prostate adenocarcinoma. Heterogeneity of distribution and relation to prognostic significance of receptor measurements for survival of advanced cancer patients. 359 58

Conventional antiandrogen therapy for prostatic cancer generally results in the death of androgen-dependent cells, resulting in shrinkage of the tumor, followed by regrowth of the tumor as androgen-insensitive cells take over. Because of reported antigonadotropic and antineoplastic effects of the pineal hormone melatonin (MEL), we hypothesized that this indole might provide an effective therapy for prostate cancer, as it would be effective against both populations of tumor cells. We used three sublines of the Dunning R3327 rat prostatic adenocarcinoma to determine whether MEL could suppress the growth of these tumors and, if so, by what mechanisms this occurs. In one experiments, we compared the growth of a well-differentiated slow-growing Dunning tumor in rats given MEL combined with the potentiating procedure olfactory bulbectomy (BULBX), with that in rats pinealectomized (PINX) or untreated. Tumor growth in BULBX-MEL rats was significantly suppressed over that in the other two groups, as were the weights of the gonads and accessory sex glands. Tumor morphology, DNA concentration, and androgen receptor concentration and distribution were identical in untreated controls and in BULBX-MEL rats, suggesting that the treatment affected all populations of tumor cells equally. With another strain of well-differentiated slow-growing Dunning tumor, we examined the effects of MEL in rats with and without BULBX. Reproductive parameters were not suppressed in BULBX-MEL rats and, while there was a trend toward slower tumor growth in this group, this was not significant. Intact rats given MEL grew larger tumors than did control rats but, again, differences were not significant. In a third experiment, we examined a fast-growing androgen-insensitive anaplastic Dunning tumor. PINX was without effect on this tumor, but BULBX-MEL resulted in a significant suppression of one of the constants in the logistic equation fitted to the growth curves. This indicates that there were some direct antitumor effects of BULBX-MEL on this tumor strain. We conclude that MEL suppresses growth of some Dunning tumor strains.
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PMID:Effects of olfactory bulbectomy, melatonin, and/or pinealectomy on three sublines of the Dunning R3327 rat prostatic adenocarcinoma. 362 64


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