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  • 1
    Electronic Resource
    Electronic Resource
    Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate (1986)
    Springer
    Journal of cancer research and clinical oncology 111 (1986), S. 110-114 
    Details
    ISSN: 1432-1335
    Keywords: Diethylstilbestrol ; Diethylstilbestrol monophosphate ; Diethylstilbestrol diphosphate ; Estrogen receptor affinity ; Estrogenic potency ; Mammary tumor inhibiting activity in vivo and in vitro
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Diethylstilbestrol (DES), diethylstilbestrol monophosphate (DES-MP) and diethylstilbestrol diphosphate (DES-DP) were tested for their estrogen receptor affinity, estrogenic potency and mammary tumor-inhibiting activity in vitro and in vivo. DES had a much higher receptor binding affinity than its mono-or diphosphate. All three compounds inhibited the growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer line only at relatively high concentrations. The estrogenic potency in the immature mouse uterine weight test decreased in the order DES〉DES-MP≫DES-DP. The hormone-dependent MXT mammary tumor of the mouse was inhibited by all three compounds at a dosage of 1.0 mg/kg per week. At a dose of 0.01 mg/kg, DES, DES-MP, and DES-DP stimulated the tumor growth. Thus, for the first time, a biphasic effect on tumor growth was demonstrated in intact mature animals. As the effects of all three compounds were similar in this assay, a cleavage of the phosphate groups is likely. A decrease in estrogenic potency concomitant with a retained antitumor effect of DES-MP and DES-DP compared to DES was not demonstrable in the mature mouse using the MXT assay, only in the uterotrophic test in the immature mouse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400747
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  • 2
    Electronic Resource
    Electronic Resource
    The future of antihormone therapy: innovations based on an established principle (1996)
    Springer
    Journal of cancer research and clinical oncology 122 (1996), S. 383-396 
    Details
    ISSN: 1432-1335
    Keywords: Antihormones ; Total receptor blockade ; Ligand-independent activation ; Receptor gene amplification and mutation ; Differentiation ; Apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Endocrine therapy of mammary and prostate cancer has been established for decades. The therapies available to block sex-hormone-receptor-mediated tumor growth are based on two principles: (i) ligand depletion, which can be achieved surgically, by use of luteinizinghormone-releasing hormone analogues or inhibitors of enzymes involved in steroid biosynthesis or by interfering with the feedback mechanisms of sex hormone synthesis at the pituitary/hypothalamic level; (ii) blockade of sex hormone receptor function by use of antihormones. The antiestrogen tamoxifen, which is the compound of choice for the treatment of mammary carcinoma, has the drawback of being a partial agonist. A complete blockade of estrogen receptor (ER) function can be achieved by a new class of compounds, pure antiestrogens. In contrast to aromatase inhibitors, pure antiestrogens are able to block ER activation by ligands other than estradiol and can also interfere with ligand-independent ER activation. In addition to estradiol, progesterone has a strong proliferative effect in mammary carcinomas. Antiprogestins are promising new tools for clinical breast cancer therapy. These compounds clearly need a functionally expressed progesterone receptor to block tumor growth, but there is strong experimental evidence that their tumor inhibition is based on more than just progesterone antagonism. The ability of these compounds to induce tumor cell differentiation that leads to apoptosis is unique among all other endocrine therapeutics. In prostate tumors that have relapsed from current androgen-ablation therapies the androgen receptor (AR) is still expressed and, compared to the primary tumors, its level is often even enhanced. Mutated AR that can be activated by other compounds such as adrenal steroids, estrogens, progestins and even antiandrogens have been detected in recurrent tumors. Thus, relapse of tumors under the selective pressure of common androgen-ablation therapies can be caused by acquired androgen hypersensitivity and AR activation by ligands other than (dihydro-)testosterone. There is a clinical need for future compounds that produce a complete blockade of AR activity even in recurrent tumors. Preclinical experiments indicate that combination therapy as well as the extension of endocrine treatments to several other tumor entities are promising approaches for further developments. Examples are the combination of antiestrogens and antiprogestins for breast cancer treatment, or the treatment of prostate carcinomas with antiprogestins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01212877
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  • 3
    Electronic Resource
    Electronic Resource
    Cytotoxic esters of 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but-1-ene with selective antitumor activity against estrogen receptor-containing mammary tumors (1987)
    Springer
    Journal of cancer research and clinical oncology 113 (1987), S. 230-234 
    Details
    ISSN: 1432-1335
    Keywords: Cytotoxic triphenylbutenes ; Estrogen receptor affinity ; Selective mammary tumor inhibiting activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summmary Both hydroxy groups of 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but-1-ene (1) were esterified with the β-chloropropionate (2), β-bromopropionate (3) and acrylate functions (4). Linkage of these cytotoxic moieties reduced the estrogen receptor affinities of these compounds, especially in the case of the β-haloesters only slightly compared with the affinity of the unsubstituted carrier molecule 1. The estrogenic potencies of the derivatives 2–4 and of 1 were nearly identical. The alkylating activities increased in the order 2, 3, and 4. Because of their alkylating activities, all cytotoxic esters showed an irreversible mode of binding to the estrogen receptor. In vitro, 3 in particular, exerted better growth inhibition of the hormone-dependent MCF-7 cell line than of the hormone-independent MDA cell line. In vivo, all cytotoxic derivatives caused almost complete inhibition of the growth of the hormone-dependent MXT M3.2 mouse mammary tumor, whereas growth of the hormone-independent MXT-Ovex tumor was much less inhibited. In all tumor models, the antitumor effect of the cytotoxic esters was better than that of the unsubstituted carrier. Therefore, the antitumor activity of these esters could be due not only to their improved pharmacokinetic properties compared to 1, but also to a selective estrogen receptor-mediated cytotoxic action.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00396378
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  • 4
    Electronic Resource
    Electronic Resource
    Crystal structure and hormonal activity of 1,1-bis(4-hydroxyphenyl)-2-phenylethene (1993)
    Springer
    Monatshefte für Chemie 124 (1993), S. 1181-1193 
    Details
    ISSN: 1434-4475
    Keywords: 1,1-Bis(4-hydroxyphenyl)-2-phenylethene ; X-ray analysis ; Estrogenic and antiestrogenic activity ; Estrogen receptor affinity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Es wurde eine komplette dreidimensionale Röntgenstrukturanalyse von 1,1-Bis(4-hydroxyphenyl)-2-phenylethen (BHPE) durchgeführt, wobei die Reflexe bei Raumtemperatur gesammelt wurden. Nach isotroper Verfeinerung derF-Werte ergab sich einR-Wert von 0.163.BHPE kristallisiert mit 8 Molekülen in einer Einheitszelle von monokliner Symmetrie mit Raumgruppe C2/c und den Zelldimensionena=20.851,b=15.505,c=10.536 Å, β=107.54°. DasBHPE-Molekül ist nicht flach. Die aromatischen Ringe sind aus der Ethen-Ebene mit Winkeln von −30.16° (Ring B), −51.45° (Ring C) und −33.49° (Ring A) herausgedreht. Der Bindungswinkel zwischen den 1,1-ständigen, 4-hydroxysubstituierten Phenylringen beträgt 115.3°, wobei dies einen Abstand von 9.636 Å für die Hydroxylgruppen ergibt. Es stellte sich heraus, daßBHPE ein „impeded“ Estrogen mit geringer antiestrogener Wirkung ist, obwohl seine Estrogen-Receptor-Affinität sehr hoch ist (29%, Estradiol 100%). Es wird der Einfluß der räumlichen Gegebenheiten inBHPE und verwandten Substanzen im Hinblick auf ihre estrogene/antiestrogene und Brustkrebs-hemmende Wirkung diskutiert.
    Notes: Summary A complete three-dimensional X-ray crystal structure analysis of 1,1-bis(4-hydroxyphenyl)-2-phenylethene (BHPE) has been carried out. Reflexes were collected at room temperature. After isotropic refinement ofF-values by least-squares,R is 0.163.BHPE crystallizes with 8 molecules in a unit cell of monoclinic symmetry, space group C2/c and cell dimensionsa=20.851,b=15.505,c=10.536 Å, β=107.54°. The molecule ofBHPE is not flat, the aromatic rings are twisted out of the ethene plane with angles of −30.16° (ring B), −51.45° (ring C) and −33.49° (ring A). The bond angle between the 1,1-standing, 4-hydroxy-substituted phenyl rings amounts to 115.3° resulting in a distance between the hydroxy groups of 9.636 Å.BHPE proved to be a weak “impeded” estrogen with minor antiestrogenic potency, though its estrogen receptor affinity is very high (29%, estradiol 100%). A discussion of the influence of the spatial structure ofBHPE and related substances on its estrogenic/antiestrogenic and mammary tumor-inhibiting potency is given.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00810027
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