Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Morphometric analysis on two human prostate cancer cell lines (PC3 and DU-145) was carried out to better characterize these cells and to approach some problems concerning their polymorphism. In our hands, these cells appear to differ either in their ability to oxidize testosterone or in their androgen receptor content. Morphometric evaluation was performed by means of an Interactive Image Analysis System (IBAS 1), which computes several parameters related to the whole cell and to the nucleus. Our results clearly indicate that nuclear parameters alone may discriminate PC3 from DU-145 cells. Particularly, the Nuclear Roundness Factor appeared important, since it quantifies changes in nuclear shape. Nevertheless, the value of this parameter for "in vitro" morphometry may be overshadowed by the polymorphism common to the cultured cells. However, morphometric evaluation of PC3 and DU-145 cells is relevant to a better understanding and definition of the biologic nature of these cells, even if polymorphism, heterogeneity and genetic instability, specially of PC3, require further investigations.
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PMID:Morphometry of in vitro systems. An image analysis of two human prostate cancer cell lines (PC3 and DU-145). 262 79

Hybrid cell lines were prepared by the fusion of BALB/c myeloma NS-1 cells with the lymphocytes of BALB/c mice that were immunized with partially purified androgen receptor (AR) from human prostates. Nine clones of the hybrid progeny were determined for the production of antibodies against AR by immunoprecipitation assay. One of the clones, referred to as "5F4", was chosen for analysis of the detailed specificity. The clone "5F4" secreted IgM class antibodies against AR. Competition study demonstrated that "5F4" antibody inhibited androgen binding of AR, suggesting that the antibody identifies androgen binding site of AR. Immunoblotting analysis showed that the antibody identified the ARs as two proteins, 95 kD and 41 kD proteins, on a sodium dodecyl sulfate polyacrylamide gel. It is suspected that a 95 kD protein should be a monomeric AR and a 41 kD protein is a proteolytic fragment of AR. Immunohistochemical analysis demonstrated that androgen-dependent tissues--human prostatic hypertrophy tissues, an AR abundant prostatic cancer tissue and fibroblast cells from human genital skin--were stained intensely with "5F4" monoclonal antibody, while androgen-independent tissues--fibroblast cells from lymph nodes, an AR deficient prostatic cancer tissue and human prostatic cancer cell line, PC-3--showed no staining. These results also support the specificity of the antibody for AR.
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PMID:Establishment and characterization of monoclonal antibody against androgen receptor. 268 92

To aid in the design of new inhibitors of steroidal 5 alpha-reductase for treatment of prostate cancer, we have studied the topography of the 5 alpha-reductase active site (5 alpha-R) and of the related androgen (RA) and progesterone (RP) receptors in the region complementary to C.6 of progesterone. To this end we have determined the total structures of 17 alpha-acetoxy-6-methylene-4-pregnene-3,20-dione (VII; R = H) and of 17 beta-hydroxy-6,6-ethylene-4-androsten-3-one (VIa) by X-ray crystal structure analysis and, using these data, have developed Newman projections of the 6 alpha-Me, 6 beta-Me, 6-methylene and 6,6-ethylene derivatives of progesterone. From them we have developed a Newman projection of a composite model formed from steroids (V), (VI), (VIIIa) and (VIIIb). This is shown in Fig. 4 and illustrates the relative conformations of these substituents around C.6. From there we proceeded to receptor-binding studies. Our results led to the conclusion that androgen receptor, (RA), takes up preferred but different conformations when bound to testosterone (T) and to 17 beta-hydroxy-5 alpha-androstan-3-one (5 alpha-dihydrotestosterone, DHT), respectively, and that the resulting steroid-receptor complexes bind preferentially to different chromatin acceptor sites. We have therefore used the convention RT and RDHT in place of RA as appropriate. Working on the assumption that binding affinities reflect spatial contours, we have developed comparative silhouettes for the 5 alpha-R, RP and RDHT protein binding sites complementary to C.6 of the steroidal ligand. These data show that the 5 alpha-reductase active site is characterized by a hydrophobic pocket which specifically accommodates a 6-methylenic moiety and partially accommodates a 6 beta-methyl group. RDHT, in contrast, shows much less specificity and largely accommodates all the above substituents. Progesterone receptor differs in failing to accommodate 6,6-ethylene and 6 beta-methyl, with minimal accommodation of 6-methylene. It possesses a hydrophobic pocket skewed towards the alpha-face of the steroid, thereby allowing optimal binding of the 6 alpha-methyl substituent to the receptor. 6-Methylene-4-pregnene-3,20-dione (V) fails to bind significantly to androgen and progesterone receptors thereby supporting the postulate that its antiprostatic activity stems primarily from 5 alpha-reductase inhibition.
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PMID:Prostate. III--A structural feature characteristic of the rat prostate 5 alpha-reductase active site. 270 37

The relative radioresponsiveness of human prostate cancer compared to malignant melanoma is well known. The effects of beta-estradiol or testosterone on the X-irradiation survival of several human cell lines were studied, including: human prostate carcinoma cell lines PC3 and DU145 and human malignant melanoma cell lines A375 and A875. Lines PC3 and DU145 demonstrated 55-61 fmol per 10(6) cells of androgen receptor with no detectable estrogen or progesterone receptor. Cells were irradiated at 120 cGy/min dose rate. There was no detectable toxicity of up to 10(-4) M testosterone or beta-estradiol on PC3 or DU145 cells in the absence of X-irradiation. At plating efficiencies from 11-13%, and plating densities of 1 x 10(4) cells per 60 cm2 flask, cell lines PC3 and DU145 demonstrated a Do of 108.5 +/- 6.5, n 2.1 +/- 0.7 cGy, and Do of 143.5 +/- 1.5 cGy, n 2.4 +/- 0.5, respectively. The addition of testosterone or beta-estradiol at 10(-4) to 10(-10) M prior to or after, X-irradiation did not alter radiosensitivity. At the same dose rate of 120 cGy/min, malignant melanoma cell lines A375 and A875 had a Do of 125 +/- 2.5 cGy, n 1.56 +/- 0.8 SF2 0.65 +/- 0.03 and line A875 demonstrated a Do of 129 +/- 4.5 cGy, n 1.58 +/- 0.4 SF2 0.55 +/- 0.04, respectively. The radiosensitivity of melanoma cell lines did not decrease at low dose rate 5 cGy/min. Thus, the in vitro radiosensitivity of androgen receptor positive prostate cancer cell lines is not necessarily altered by the presence of androgen before or after irradiation. The data support the concept that all malignant melanoma cell lines do not show a broad-shouldered cell survival curve in vitro and intrinsic cellular radioresistance.
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PMID:Radiosensitivity of human prostate cancer and malignant melanoma cell lines. 277 56

Using methods for cell lysis and fractionation which yield essentially quantitative recovery of rat prostate cancer cell cytosolic and nuclear androgen receptors, we examined androgen modulation of androgen receptor content of clonally derived prostate cancer cell lines. We showed that testosterone elicited a concentration-dependent 2.3-fold increase in T5 cell androgen receptor content which was maximum after 48 h and was maintained through at least 72 h of culture. Testosterone caused only a 1.4-fold elevation in D2 cell androgen receptor content which was maximum between 6 and 12 h of culture and was maintained through at least 72 h culture. In contrast, testosterone did not cause a change in C3 cell androgen receptor content. Cycloheximide inhibition showed that both the testosterone-mediated increase in and maintenance of basal prostate cancer cell androgen receptor content required protein synthesis. Because testosterone and the nonmetabolizable androgen R1881 were essentially equipotent as effectors of the increase in T5 cell androgen receptor content, findings using testosterone appear to represent maximum effects. RU 23908 antagonized both R1881 and testosterone promoted elevations of prostate cancer cell androgen receptor content. Effectiveness of RU 23908 was comparable to the relative binding affinity of R1881, testosterone and RU 23908 for androgen receptors. This implies that at least part of the androgen-promoted increase in prostate cancer cell androgen receptor content is mediated through the action of androgen receptors and suggests that androgen receptors may act as both cis and trans regulatory elements. The mechanisms which determine basal or androgen-modulated prostate cancer cell androgen receptor content remain to be elucidated.
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PMID:Androgen modulation of prostate cancer cell androgen receptor content is cell line specific. 278 64

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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PMID:Androgens, adrenal androgen precursors, and their metabolism in untreated primary tumors and lymph node metastases of human prostatic cancer. 285 35

Since there is convincing evidence for a role of adrenal steroids as precursors of active sex steroids in peripheral tissues, especially prostate cancer, we have studied the effect of the four main adrenal steroids, namely dehydroepiandrosterone sulfate (DHEA-S), DHEA, 5-androstene-3 beta,17 beta-diol (delta 5-diol) and 4-androstene-3,17-dione (delta 4-dione) on the growth of an androgen-sensitive clone (SEM-1) of the mouse mammary carcinoma Shionogi. From a control doubling time of 6.69 +/- 0.03 days, 0.1 microM DHT, 1.0 microM delta 4-dione, 10 microM delta 5-diol, 10 microM DHEA-S and 10 microM DHEA decreased generation time to 1.60 +/- 0.01, 1.69 +/- 0.01, 1.95 +/- 0.01, 4.37 +/- 0.02 and 5.66 +/- 0.03 days, respectively (P less than 0.01 vs. control). The same compounds exerted their stimulatory effects on cell growth at the following ED50 values: 0.06 nM, 16 nM, 90 nM, 150 nM and 16 microM for DHT, delta 4-dione, DHEA, delta 5-diol and DHEA-S, respectively. The stimulatory effect of all compounds was inhibited in a competitive manner by the pure antiandrogen hydroxyflutamide. Further evidence for an action of the adrenal steroids through the androgen receptor is indicated by competition of [3H]testosterone uptake in the tumor cells at the following IC50 values: 0.21 nM, 0.63 nM, 50 nM, 75 nM and 680 nM for DHT, testosterone, delta 4-dione, delta 5-diol and DHEA, respectively. The present data show that the four main adrenal steroids present in the serum of adult men can exert potent stimulatory effects on the growth of an androgen-sensitive cancer cell line through an androgen receptor-mediated mechanism.
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PMID:Adrenal precursor C19 steroids are potent stimulators of growth of androgen-sensitive mouse mammary carcinoma Shionogi cells in vitro. 297 15

To improve the inhibition of prostate cancer growth obtained by surgical or chemical castration (estrogens or LHRH analogs), blockade of the action of residual androgens of adrenal origin has been proposed. Among antiandrogens acting through the androgen receptor (AR), the nonsteroid anandron (RU 23908) has several advantages over available compounds: megestrol acetate and cyproterone acetate, both steroids, bind substantially to other hormone receptors (progestin, gluco- and mineralocorticoid); and anandron binds only to AR. The nonsteroid flutamide is a prodrug converted to the active metabolite, hydroxyflutamide; anandron is well absorbed on oral administration of an active dose and intact compound disappears slowly from plasma. This may explain why, although in vitro anandron interacts very transiently with AR, in vivo a high level of untransformed anandron is present at the receptor site to induce its antiandrogenic activity. Animal experiments confirm that anandron can counteract the effect of adrenal androgens and inhibit the LHRH analog-induced initial increase in androgen ("flare-up"). Thus, in rats castrated either surgically or by buserelin or DES and supplemented with adrenal androgens (since endogenous adrenal secretion is very low in this species compared to man), anandron decreased prostate weight to control levels. The administration of buserelin to intact rats over 15 days resulted in a significant increase in prostate weight between Days 1 and 5. The addition of anandron to the buserelin inhibited this increase and, furthermore, led to a far greater decrease in prostate weight than that due to buserelin alone at 15 days, indicating a synergy of action.
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PMID:Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer. 300 70

Antiandrogens can be used in various androgen-dependent diseases. Depending upon the therapeutic indication, they can be administered systemically or topically. Systemic treatment with an antiandrogen will inhibit androgen action not only in the desired target site but also in all other target tissues; thus, it will block the androgen-dependent feedback regulating the secretion (hypothalamo-pituitary-testis axis) or the action (protein factors) of androgens. In contrast, topical treatment (acting through cutaneous receptors or local metabolism) should not produce systemic side effects especially in man. Pharmacological assays which can select antiandrogens irrespective of the mechanism measure changes in the final androgenic response, but they consume a great deal of time and test compound and bear little relation to therapeutic activity. Therefore, the biological strategy that we report here and which, at Roussel-Uclaf, has led to the selection of a systemic and a topical antiandrogen (RU 23908 and RU 38882) has consisted in successively performing: (1) in vitro assays which measure an effect at a specific level in the mechanism of antiandrogen action, e.g. interaction with the androgen receptor. Assessing interactions with other classes of steroid hormone receptor can be used to predict possible hormonal side-effects, (2) in vitro determinations of agonist or antagonist activity, e.g. in pituitary cells (LH response to LHRH) or mammary tumor cells (induction of androgen-dependent proteins), (3) in vivo antiandrogen assays after a single treatment (induction of mouse kidney proteins, rat prostatic binding protein) or after repeated treatment (inhibition of the growth of rat accessory glands or of hamster sebaceous glands), to determine the active dose of the compound and possibly the absence of systemic effects by the topical route, (4) assays in animal models designed to mimic a therapeutic context e.g. for prostate cancer: inhibition of the "flare-up" effect of LHRH-A or of the trophic effect of perfused adrenal androgens on rat prostate, antitumoral activity in experimental cancer models. For hyperseborrhoea and acne: histological and stereological analysis of rat skin biopsies to measure the volume density of the smooth endoplasmic reticulum vesicles of the differentiating cells of the sebaceous gland.
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PMID:How the study of the biological activities of antiandrogens can be oriented towards the clinic. 305 62

The rationale of the combination of a nonsteroid antiandrogen with an LH-RH analogue (LH-RH-A) in the treatment of prostate cancer is discussed. Whereas the LH-RH-A depresses testosterone (T) levels via an action on the hypothalamus-pituitary-gonad axis, the antiandrogen counters the effect of any residual T, from the testes or adrenals, on the target organ, the prostate. Although bilateral orchiectomy and administration of estrogen or LH-RH-A give equivalent low T levels over long-term treatment, the manner and rate at which T suppression is achieved vary and each treatment presents characteristic disadvantages. Orchiectomy is irreversible, and it is known that approximately 20% of patients will not benefit from such endocrine manipulation, estrogen use is associated with cardiovascular disease, and LH-RH analogues produce an early surge in T. None of these treatments has any significant effect on adrenal androgen levels, which may contribute toward the progression of disease. Nonsteroid antiandrogens such as anandron and flutamide inhibit the uptake of androgen by the prostate by an action that probably involves the androgen receptor. They do not possess the progestational and glucocorticoid component of steroid antiandrogens or their pituitary inhibitory activity but do exert some inhibition of the 17 alpha-hydroxylase and 17,20-lyase enzyme systems. Unlike steroids, the nonsteroid antiandrogens potentiate the activity of LH-RH-A at the central level in the rat. The inhibitory action of the combined treatment of "anandron + buserelin" on the prostate is greater than that of each compound alone. Clinical pharmacology studies have demonstrated that both steroid and nonsteroid antiandrogens can help to control the effect of increased T levels (disease flare) that occur on initiating LH-RH-A administration. Prostatic acid phosphatase (PAP) levels decrease immediately in spite of the increase in T. The decrease appears faster when nonsteroid antiandrogens are used. Nonsteroid antiandrogens sensitize the pituitary to stimulation by LH-RH in eugonadal volunteers. The results of randomized clinical studies with the combination of "nonsteroid antiandrogen + LH-RH-A" have established a definite trend toward greater efficacy of the combined treatment over monotherapy. Further data are needed to confirm this trend. In particular, further dose-ranging studies are warranted since the need for LH-RH-A doses that reduce T down to castration levels may not be justified in the presence of a potent antiandrogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antiandrogens in combination with LH-RH agonists in prostate cancer. 307 51


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