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British Medical Journal Jun 1975A randomized clinical trial of nafoxidine, a non-steroidal oestrogen antagonist, and ethinyloestradiol in postmenopausal patients with advanced breast cancer produced... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A randomized clinical trial of nafoxidine, a non-steroidal oestrogen antagonist, and ethinyloestradiol in postmenopausal patients with advanced breast cancer produced objective remissions in 31% of 49 women receiving nafoxidine and in 14% of 49 receiving ethinyloestradiol. The differences in remission rates was almost significant (0.05 less than P less than 0.10). Life-threatening complications were more frequent with ethinyloestradiol than with nafoxidine but the latter produced specific toxic reactions on skin and hair that may limit its practical usefulness. Synthetic oestrogen antagonists may occupy a privileged place in the treatment of breast cancer, and other representatives of this new class of compounds should be accurately assessed in randomized clinical trials.
Topics: Administration, Oral; Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Ethinyl Estradiol; Female; Humans; Menopause; Middle Aged; Nafoxidine; Pyrrolidines; Remission, Spontaneous
PubMed: 1095121
DOI: 10.1136/bmj.2.5973.711 -
British Journal of Pharmacology Jan 20011. We have used the whole-cell patch clamp technique to study the effect of the partial anti-oestrogens clomiphene and nafoxidine, the pure anti-oestrogens ICI 182,780...
1. We have used the whole-cell patch clamp technique to study the effect of the partial anti-oestrogens clomiphene and nafoxidine, the pure anti-oestrogens ICI 182,780 and RU 58,668 and the oestrogen ss-estradiol, on the volume-regulated anion channel (VRAC) in cultured pulmonary artery endothelial (CPAE) cells. 2. In contrast to the pure anti-oestrogens and ss-estradiol, clomiphene and nafoxidine potently inhibited the volume-sensitive chloride current, I(Cl,swell), activated by challenging CPAE cells with a 25% hypotonic solution. For clomiphene, the estimated IC(50) and Hill coefficient were 1.03+/-0.14 microM and 1.40+/-0.21 respectively. In the case of nafoxidine, these values were 1.61+/-0.29 microM and 1.24+/-0.19. 3. The inhibition induced by the pure enantiomers of clomiphene, zuclomiphene and enclomiphene, was not different from that of the racemic mixture, indicating that the interaction between clomiphene and VRAC is not stereoselective. 4. Clomiphene and nafoxidine inhibited proliferation of CPAE cells. Half-maximal inhibition was found at 1.98+/-0.17 and 1.66+/-0.21 microM respectively, concentrations similar to those for half-maximal block of VRAC. 5. In conclusion, the nonsteroidal partial anti-oestrogens nafoxidine and clomiphene are potent inhibitors of volume-regulated anion channels. The inhibition by clomiphene is not stereoselective and occurs at concentrations close to therapeutically relevant concentrations. Finally, both drugs inhibit the proliferation of endothelial cells.
Topics: Cell Division; Cells, Cultured; Chloride Channels; Clomiphene; Enclomiphene; Endothelium, Vascular; Estradiol; Estrogen Antagonists; Fulvestrant; Humans; Membrane Potentials; Nafoxidine; Patch-Clamp Techniques; Pulmonary Artery
PubMed: 11156570
DOI: 10.1038/sj.bjp.0703786 -
Anticancer Research 2004We analyzed the effect of nafoxidine on the earlier biological processes of angiogenesis and explored the role of different signaling pathways involved in the in vitro...
We analyzed the effect of nafoxidine on the earlier biological processes of angiogenesis and explored the role of different signaling pathways involved in the in vitro response of endothelial cells (HUVEC). Nafoxidine significantly inhibited adhesion, spreading, migration and invasion of HUVEC at concentrations ranging from 1 to 2.5 microM. Endothelial cord formation on Matrigel was inhibited by nafoxidine and cotreatment with phorbol-12-myristate-13-acetate (PMA) clearly prevented the antiangiogenic effect of the antiestrogen. On the contrary, cotreatment with the PKC inhibitor bisindolylmaleimide potentiated inhibition of cord formation. PMA also inhibited the nafoxidine-induced secretion of metalloproteinase-2 and tissue inhibitor of metalloproteinases-1 in HUVEC monolayers. Cotreatment with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the cAMP analog N6,2'-o-dibutyryladenosine 3',5'-cyclic monophosphate prevented the inhibition of endothelial cord formation induced by nafoxidine. Our work presents evidence about the signaling pathways involved in the antiangiogenic effect of nafoxidine, suggesting that PKC-dependent signaling pathways are essential in angiogenesis during endothelial cord formation.
Topics: Angiogenesis Inhibitors; Cell Adhesion; Cell Movement; Endothelium, Vascular; Humans; Matrix Metalloproteinase 2; Nafoxidine; Neovascularization, Physiologic; Protein Kinase C; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Umbilical Veins
PubMed: 15274349
DOI: No ID Found -
Proceedings of the National Academy of... Jun 2002Surface plasmon resonance biosensor technology was used to directly measure the binding interactions of small molecules to the ligand-binding domain of human estrogen...
Surface plasmon resonance biosensor technology was used to directly measure the binding interactions of small molecules to the ligand-binding domain of human estrogen receptor. In a screening mode, specific ligands of the receptor were easily discerned from nonligands. In a high-resolution mode, the association and dissociation phase binding responses were shown to be reproducible and could be fit globally to a simple interaction model to extract reaction rate constants. On average, antagonist ligands (such as tamoxifen and nafoxidine) were observed to bind to the receptor with association rates that were 500-fold slower than agonists (such as estriol and beta-estradiol). This finding is consistent with these antagonists binding to an altered conformation of the receptor. The biosensor assay also could identify subtle differences in how the same ligand interacted with two different isoforms of the receptor (alpha and beta). The biosensor's ability to determine kinetic rate constants for small molecule/protein interactions provides unique opportunities to understand the mechanisms associated with complex formation as well as new information to drive the optimization of drug candidates.
Topics: Antibodies, Monoclonal; Benzhydryl Compounds; Dehydroepiandrosterone; Estrogen Receptor alpha; Estrogen Receptor beta; Kinetics; Ligands; Phenols; Receptors, Estrogen; Recombinant Proteins
PubMed: 12077320
DOI: 10.1073/pnas.142288199 -
Steroids Nov 2014The discovery of the first nonsteroidal antiestrogen ethamoxytriphetol (MER25) in 1958, opened the door to a wide range of clinical applications. However, the finding...
The discovery of the first nonsteroidal antiestrogen ethamoxytriphetol (MER25) in 1958, opened the door to a wide range of clinical applications. However, the finding that ethamoxytriphetol was a "morning after" pill in laboratory animals, energized the pharmaceutical industry to discover more potent derivatives. In the wake of the enormous impact of the introduction of the oral contraceptive worldwide, contraceptive research was a central focus in the early 1960's. Numerous compounds were discovered e.g., clomiphene, nafoxidine, and tamoxifen, but the fact that clinical studies showed no contraceptive actions, but, in fact, induced ovulation, dampened enthusiasm for clinical development. Only clomiphene moved forward to pioneer an application to induce ovulation in subfertile women. The fact that all the compounds were antiestrogenic made an application in patients to treat estrogen responsive breast cancer, an obvious choice. However, toxicities and poor projected commercial returns severely retarded clinical development for two decades. In the 1970's a paradigm shift in the laboratory to advocate long term adjuvant tamoxifen treatment for early (non-metastatic) breast cancer changed medical care and dramatically increased survivorship. Tamoxifen pioneered that paradigm shift but it became the medicine of choice in a second paradigm shift for preventing breast cancer during the 1980's and 1990's. This was not surprising as it was the only medicine available and there was laboratory and clinical evidence for the eventual success of this application. Tamoxifen is the first medicine to be approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at high risk. But it was the re-evaluation of the toxicology of tamoxifen in the 1980's and the finding that there was both carcinogenic potential and a significant, but small, risk of endometrial cancer in postmenopausal women that led to a third paradigm shift to identify applications for selective estrogen receptor (ER) modulation. This idea was to establish a new group of medicines now called selective ER modulators (SERMs). Today there are 5 SERMs FDA approved (one other in Europe) for applications ranging from the reduction of breast cancer risk and osteoporosis to the reduction of menopausal hot flashes and improvements in dyspareunia and vaginal lubrication. This article charts the origins of the current path for progress in women's health with SERMs.
Topics: Animals; Breast Neoplasms; Endometrial Neoplasms; Estrogen Receptor Modulators; Female; Humans; Selective Estrogen Receptor Modulators; Tamoxifen
PubMed: 24949934
DOI: 10.1016/j.steroids.2014.06.009 -
The Biochemical Journal Jun 1977Nafoxidine hydrochloride (Upjohn, 11100A)injected with oestradiol into immature chicks inhibits the hormone-induced increase in [3H]oestradiol-binding activity in salt...
Nafoxidine hydrochloride (Upjohn, 11100A)injected with oestradiol into immature chicks inhibits the hormone-induced increase in [3H]oestradiol-binding activity in salt extracts of liver nuclei as well as the subsequent production by liver of egg-yolk phosphoprotein. Substantial inhibition of both oestradiol-induced responses is seen when nafoxidine is given in a dose approximately equimolar with that of oestradiol. In vitro nafoxidine competitively inhibits binding of [3H]oestradiol in nuclear extracts. The Ki for the inhibition is 43 nM, which indicates an affinity of nafoxidine for the binding protein about 4% of that of oestradiol. The inhibitory action of nafoxidine in vivo thus is more potent than the relative binding affinity determined in vitro might indicate. One possible explanation is that the primary site of nafoxidine action is at a point proximal to nuclear receptor interaction. Nafoxidine injected alone into the chick does not induce phosphoprotein synthesis, but it does increase [3H]oestradiol-binding activity in extracts of liver nuclei to a limited extent. No differences in the properties of the oestradiol-binding activity in extracts from nafoxidine-treated chicks or from oestradiol-treated chicks were detected. Chick liver cytosol does not contain detectable high-affinity oestradiol-binding activity. A low-affinity oestradiol-binding component with a sedimentation coefficient of 3.5S was found, but it was unaffected by treatment of chicks with earlier nafoxidine or oestradiol. The results suggest a difference in the mechanism of oestradiol action in the chick liver and in the widely studied rat uterus, on which the usual model for oestradiol action is largely based.
Topics: Animals; Binding, Competitive; Cell Nucleus; Centrifugation, Density Gradient; Chickens; Cytosol; Estradiol; Liver; Nafoxidine; Phosphoproteins; Puromycin; Pyrrolidines; Receptors, Estrogen; Temperature
PubMed: 883957
DOI: 10.1042/bj1640659 -
Frontiers in Pharmacology 2016Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer...
Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytotoxic effects in cancers devoid of ERs, indicating a non-estrogenic mechanism of action. Indicative of a potential ER-independent target, reports demonstrate that tamoxifen binds to cannabinoid receptors (CBRs) with affinity in the low μM range and acts as an inverse agonist. To identify cannabinoids with improved pharmacological properties relative to tamoxifen, and further investigate the use of different SERM scaffolds for future cannabinoid drug development, this study characterized the affinity and activity of SERMs in newer structural classes at CBRs. Fourteen SERMs from five structurally distinct classes were screened for binding to human CBRs. Compounds from four of five SERM classes examined bound to CBRs. Subsequent studies fully characterized CBR affinity and activity of one compound from each class. Ospemifine (a triphenylethylene) selectively bound to CB1Rs, while bazedoxifine (an indole) bound to CB2Rs with highest affinity. Nafoxidine (a tetrahydronaphthalene) and raloxifene (RAL; a benzothiaphene) bound to CB1 and CB2Rs non-selectively. All four compounds acted as inverse agonists at CB1 and CB2Rs, reducing basal G-protein activity with IC values in the nM to low μM range. Ospemifine, bazedoxifene and RAL also acted as inverse agonists to elevate basal intracellular cAMP levels in intact CHO-hCB2 cells. The four SERMs examined also acted as CB1 and CB2R antagonists in the cAMP assay, producing rightward shifts in the concentration-effect curve of the CBR agonist CP-55,940. In conclusion, newer classes of SERMs exhibit improved pharmacological characteristics (e.g., in CBR affinity and selectivity) relative to initial studies with tamoxifen, and thus suggest that different SERM scaffolds may be useful for development of safe and selective drugs acting via CBRs.
PubMed: 28066250
DOI: 10.3389/fphar.2016.00503 -
The Journal of Biological Chemistry Mar 1984This paper further characterizes the estrogen-binding protein we have described in the cytosol of the yeast Saccharomyces cerevisiae. [3H]Estradiol was used as the...
This paper further characterizes the estrogen-binding protein we have described in the cytosol of the yeast Saccharomyces cerevisiae. [3H]Estradiol was used as the radioprobe, and specific binding of cytosol fractions was measured by chromatography on Sephadex minicolumns. Other 3H-steroids did not exhibit specific binding. [3H]Estradiol binding was destroyed by treatment with trypsin, but not RNase, DNase, or phospholipase; N-ethylmaleimide substantially decreased the binding. The yeast did not metabolize estradiol added to the medium, and extraction and chromatography of the bound moiety showed it to be unmetabolized estradiol. Scatchard analysis of cytosol from both a and alpha mating types as well as the a/alpha diploid cell revealed similar binding properties: an apparent dissociation constant or Kd(25 degrees) for [3H]estradiol of 1.6-1.8 nM and a maximal binding capacity or Nmax of approximately 2000-2800 fmol/mg of cytosol protein. Gel exclusion chromatography on Sephacryl S-200 and high performance liquid chromatography suggested a Stokes radius of approximately 30 A. Sucrose gradient centrifugation showed a sedimentation coefficient of approximately 5 S, and the complex did not exhibit ionic dependent aggregation. The estrogen binder in S. cerevisiae differed in its steroidal specificities from classical mammalian estrogen receptors in rat uterus. 17 beta-Estradiol was the best competitor, 17 alpha-estradiol had about 5% the activity, and diethylstilbestrol exhibited negligible binding affinity as did tamoxifen, nafoxidine, and the zearalenones. In summary, a high affinity, stereospecific, steroid-selective binding protein has been demonstrated in the cytosol of the simple yeast S. cerevisiae. We speculate that this molecule may represent a primitive hormone receptor system, possibly for an estrogen-like message molecule.
Topics: Cytosol; Drug Stability; Estradiol; Kinetics; Molecular Weight; Receptors, Estrogen; Saccharomyces cerevisiae
PubMed: 6368545
DOI: No ID Found -
British Medical Journal Jun 1975L-Dopa lowers plasma prolactin levels, and there have been reports that patients with advanced breast cancer have been successfully treated with L-dopa. To test the... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
L-Dopa lowers plasma prolactin levels, and there have been reports that patients with advanced breast cancer have been successfully treated with L-dopa. To test the potential value of L-dopa in this disease a randomized clinical trial of L-dopa and nafoxidine (as the reference compound) was conducted in postmenopausal women with advanced breast cancer. Objective remissions were obtained in sever out of 36 patients (19%) treated with nafoxidine but in none out of 40 patients treated with L-dopa. L-Dopa in the dose schedule used seems to be ineffective in advanced breast cancer.
Topics: Administration, Oral; Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Levodopa; Menopause; Middle Aged; Nafoxidine; Prolactin; Pyrrolidines; Remission, Spontaneous
PubMed: 1095122
DOI: 10.1136/bmj.2.5973.714 -
Fertility and Sterility Mar 1972
Topics: Animals; Biological Transport; Chlormadinone Acetate; Chorionic Gonadotropin; Clomiphene; Contraceptive Agents; Depression, Chemical; Dydrogesterone; Estradiol; Fallopian Tubes; Female; Fertilization; Fluoxymesterone; Hydroxyprogesterones; Male; Norethindrone; Ovulation; Progesterone; Progestins; Pyrrolidines; Rabbits; Sperm Capacitation; Spermatozoa; Testosterone; Uterus
PubMed: 4110310
DOI: No ID Found