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  • 1
    ISSN: 1600-0757
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To evaluate the presence of androgen receptors in the human melanoma cell line IIBMEL-J, a Scatchard plot analysis was performed. Cells in culture revealed a single binding component with an apparent dissociation constant (KD) at 37°C of 11 nM and a binding capacity of 326 fmol/mg protein when measured with [3H]-R1881. Competition analysis revealed an atypical relaxation of specificity, since not only androgen (testosterone, dihydrotestosterone [DHT], R1881) and antiandrogen (hydroxy-flutamide [OH-FLU]) competed for [3H]-R1881 binding, but also estradiol, progesterone, and cortisol at 500-fold excess concentration. Binding of [3H]-estradiol and [3H]-R5020 in the absence of unlabeled DHT were completely suppressed in its presence. Immunohistochemistry of androgen receptor with a monoclonal antibody showed that nuclei were vigorously stained.Different doses of flutamide (FLU) and OH-FLU tested on cultured IIB-MEL-J cells in the presence of serum inhibited significantly cell proliferation in a dose-dependent manner. When cells were incubated with 10 nM DHT and 1%charcoal-adsorbed serum, a significant stimulation of growth that was observed was inhibited by 4 μM OH-FLU. DHT stimulation was completely reversed by the antiestrogen tamoxifen.In addition, male nude mice transplanted with IIB-MEL-J tumor were treated with FLU when tumors were palpable. FLU was effective in diminishing tumor growth and increasing survival rate of the animals.As a conclusion, the presence of functional androgen receptors in these cells has been demonstrated by growth inhibition in vitro and in vivo with antiandrogens, and their atypical nature is suggested by binding cross-reactivity and competition studies.
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  • 2
    ISSN: 1573-7217
    Keywords: α2‐adrenergic agonists ; α2‐adrenergic antagonists ; α2‐adrenoceptor ; breast cancer ; catecholamines ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract (-)Epinephrine (Epi) and –Norepinephrine (NEpi) significantly stimulated tritiated Thymidine incorporation in MCF‐7 cells at concentrations 10–30 pM to 10 nM, with an EC50 of 10 pM for Epi and 14.2 pM for NEpi. To characterize this action, cells were incubated in the presence of NEpi or Epi and different antagonists. The β‐adrenergic antagonist Propanolol showed no effect on the agonist's stimulation, whereas the α‐adrenergic antagonist Phentolamine, reverted it completely at high concentrations (100 μM). The α1‐adrenergic antagonist Prazosin (Pra) acted only at high concentrations, while the α2‐adrenergic antagonist Yohimbine (Yo) reverted the stimulation at an EC50 of 0.11μM. Likewise, when the cells were incubated in the presence of the specific α2‐adrenergic agonist Clonidine (Clo), Thymidine incorporation was significantly stimulated at an EC50 of 0.298 pM. Again, the incubation of the cells in the presence of the α1‐adrenergic antagonist Pra exerted its action at high concentrations, whereas the α2‐adrenergic antagonist Yo showed a clear reversal of the agonist's enhancement at an EC50 of 0.136 μM. Moreover, Clo caused a clear and significant inhibition of stimulated cAMP levels both in the intracellular and the extracellular fractions. Yo showed a complete reversion of cAMP levels to control values in the presence of Clo, while Pra had the opposite effect. These data suggest that the stimulation provoked in Thymidine incorporation by the agonists Epi, NEpi, and Clo is, at least in part, due to an α2‐adrenergic mechanism directly on tumoral cells, and that the effect is coupled with inhibition of cAMP levels, as described for this kind of receptors.
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  • 3
    ISSN: 1573-7217
    Keywords: cell proliferation ; mammary tumors ; medroxyprogesterone acetate ; primary cultures ; progestins ; serum factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of progesterone (Pg), medroxyprogesterone acetate (MPA), estradiol (E2), dihydrotestosterone (DHT) and dexamethasone (DEXA) was studied on thein vitro growth rate of a progestin-dependent (PD), estrogen-sensitive mammary tumor line originated in an MPA-treated BALB/c mouse (C4-HD), and on its estrogen-resistant variant (C4-HDR). The specificity of hormone action was further investigated using the anti-hormones RU-486 and hydroxyflutamide (FLU). Cell growth was evaluated in epithelial and fibroblastenriched cultures using3H-thymidine and/or autoradiography and immunocytochemistry. The results indicate that cell growth is directly stimulated by MPA and Pg at concentrations ranging from 10−11 to 10−7 M. RU486 prevented MPA-induced stimulation in concentrations 10 to 100 fold lower than those of MPA. When used alone, it inhibited cell proliferation only in concentrations higher than 10−11 M. At nM concentrations, neither DEXA nor DHT stimulated3H-thyrnidine uptake except DEXA at 100 nM. MPA-induced stimulation was not reverted by micromolar concentrations of FLU. As for E2 (10−7–10−9 M) it prevented MPA stimulation only in cultures of estrogen-sensitive tumors. Progesterone receptors (PR) (475 ± 115 fmoles/105 cells, n = 5) and estrogen receptors (ER) (ND-115 fmoles/105 cells, n = 5) were detected only in epithelial-enriched cultures. Serum from 7 day-MPA-treated mice induced a significant increase of3H-thymidine uptake; an increase was also obtained with serum from untreated ovariectomized animals to which 1 nM-100 nM concentrations of MPA had been added. The stimulatory effect of the exogenous MPA was much lower than that of the serum obtained from MPA-treated animals. It is concluded that MPA stimulates cell growth of primary cultures of MPA-induced PD tumors via PR. The results provide support for a direct effect of MPA which may be mediated or potentiated by serum factors.
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  • 4
    ISSN: 1573-7233
    Keywords: antiandrogen ; adrenal androgens ; dihydrotestosterone ; LHRH agonist ; [D-Trp6]LHRH ethylamide ; Flutamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In 1941, Huggins and his colleagues discovered that testicular androgens exert a stimulatory effect on prostate cancer growth. Our group has made the key observations that the human adrenals, in addition to the tests, also secrete important amounts of androgens and cancer cells exhibit a marked heterogeneity of androgen sensitivity. In fact, human adrenals secrete large amounts of precursor steroids that are converted into active androgens in peripheral tissues (including the prostate), thus providing 40% to 50% of total androgens in adult men. The action of these androgens remaining after castration can be inhibited in prostatic cancer tissue by administering a pure antiandrogen that also decreases the local concentration of dihydrotestosterone (DHT). The castration levels of serum testosterone left in men after castration have an important stimulatory activity on the growth of androgen-sensitive normal as well as cancer tissues. Cancer cells have markedly different requirements for androgens. Some cell clones can grow in the presence of minimal amounts of androgens, requiring more complete androgen blockade and more potent antiandrogens for inhibiting growth. Among the compounds recommended as antiandrogens, the most unexpected finding is that many of them are devoid of any antiandrogenic activity. In fact, medroxyprogesterone acetate, chlormadinone acetate, and megestrol acetate have androgenic activity, but do not inhibit the peripheral action of DHT in prostatic tissue. These compounds should not be classified as antiandrogens. Cyproterone acetate, on the other hand, is a mixed agonist-antagonist. The only compounds showing pure antiandrogenic activity are Flutamide and its analogues. There is thus a need for a more complete blockade of androgens of both testicular and adrenal origins in order to exert a maximal inhibitory effect on cancer growth. We have therefore performed clinical studies in previously untreated stage D2 and C prostate cancer patients with the combination therapy using the LHRH agonist [D-Trp6, des Gly NH2 10] LHRH ethylamide and the antiandrogen Flutamide. There was a significant increase in patients with a complete response, as compared with studies limited to the removal or blockade of testicular androgens. There was also a significant decrease in the number of non-responders, an increased duration of positive response, and a decrease in the death rate. This was achieved with minimal or no side effects, thus preserving a good quality of life.
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