Structural components necessary for the antiestrogenic activity of tamoxifen

Murphy, Catherine S.; Jordan, V. Craig

doi:10.1016/0022-4731(89)90117-9

Cited by 22 publications

(7 citation statements)

References 10 publications

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“…In an effort to develop endocrine treatment for breast cancer, a variety of antiestrogenic compounds have been synthesized throughout the last 50 years. − The majority of these compounds, including the clinically important Tamoxifen, are nonsteroids , that exhibit various nonspecific pharmacological interactions. − More recently, a series of 7α-substituted estradiols such as ICI-164,384 have been identified as pure estrogen antagonists with little cytotoxicity. − However, all of these compounds represent molecular structures quite deviant from the natural estrogen, estradiol-17β (E 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…The ability of antiestrogens to block estrogen receptor (ER) regulated cellular events is frequently defined as the capacity to inhibit estrogen specific growth of breast cancer cells. − In some cases, specific aspects of the antiestrogen-ER complex or the control of estrogen specific genes are also characterized. ,− With the identification of a transcription activation function (AF-2) in the ligand binding domain of ER by others, − a hypothesis has been presented by this laboratory which suggests that ligands with subtle structure alterations might effectively control specific ER regulated genes through novel interaction with the AF-2 site. , Examination of this concept has resulted in the characterization of the 2- and 4-hydroxy isomers of E 2 as high affinity ligands for ER which are capable of stimulating certain genes while being inactive in the regulation of other estrogen responsive genes. − Structure analysis of these isomers has revealed conformation features as well as electrostatic characteristics that may account for the unique estrogenic properties of these ligands. ,, However, determinations have yet to be made regarding the potential of these and other estrogen analogues to regulate estrogen specific growth of cells.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15][16] In some cases, specific aspects of the antiestrogen-ER complex or the control of estrogen specific genes are also characterized. 4,[17][18][19][20][21][22] With the identification of a transcription activation function (AF-2) in the ligand binding domain of ER by others, [23][24][25] a hypothesis has been presented by this laboratory which suggests that ligands with subtle structure alterations might effectively control specific ER regulated genes through novel interaction with the AF-2 site. 26,27 Examination of this concept has resulted in the characterization of the 2-and 4-hydroxy isomers of E 2 as high affinity ligands for ER which are capable of stimulating certain genes while being inactive in the regulation of other estrogen responsive genes.…”

Section: Introductionmentioning

confidence: 99%

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Induction of the Estrogen Specific Mitogenic Response of MCF-7 Cells by Selected Analogues of Estradiol-17β: A 3D QSAR Study

et al. 1997

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Analogues of estradiol-17 beta (E2) have been evaluated for estrogen receptor (ER) binding affinity and mitogenic potential in the human breast cancer cell line MCF-7. These 42 compounds represent subtle modifications of the natural estrogen structure through the placement of hydroxyl, amino, nitro, or iodo groups around the ring system in addition to, or as replacement of, the 3- and 17 beta-hydroxyls of E2. The mitogenic activity of the analogues was found to be related to ER binding only to a limited extent. In order to elucidate structural features that are uniquely responsible for receptor binding affinity or mitogen potential of estrogens, the three-dimensional quantitative structure-activity (QSAR) method Comparative Molecular Field Analysis (CoMFA) was employed. Separate CoMFA models for receptor binding and cell growth stimulation were optimized through the use of various alignment rules and region step size. Whereas the CoMFA contour plots did outline the shared structural requirements for the two measured biological properties, specific topological features in this set of estrogens were delineated that distinguish mitogenic potential from ER binding ability. In particular, steric interference zones which affected growth extend in a band from above the A-ring to position 4 and below, whereas the ER binding steric interference zones are limited to isolated polyhedra in the 1, 2 and 4 positions and the alpha face of the B-ring. In addition, electronegative features located around the A-, B-, or C-rings contribute to receptor affinity. However, growth is dependent only on electronegative and electropositive properties near the 3-position. In a final QSAR model for the mitogenic response, the value of ER binding was included along with structural features as a descriptor in CoMFA. The resulting 3D-QSAR has the most predictive potential of the models in this study and can be considered a prototype model for the general evaluation of a steroidal estrogen's growth stimulating ability in MCF-7 cells. For example, the location of D-ring contours illustrate the model's preference for 17 beta-hydroxy steroids over the less mitogenic 17 alpha- and 16 alpha-hydroxy compounds. In addition, the enhanced mitogenic effect of steric bulk in the 11 alpha-position is also evident. The QSAR studies in this report illustrate the fact that while ER binding may be a required factor of the estrogen dependent growth response in MCF-7 cells, particular structural characteristics, in addition to those responsible for tight receptor binding, must be present to induce an optimal mitogenic response. Therefore, this report demonstrates that the CoMFA QSAR method can be utilized to characterize structural features of test compounds that account for different types of estrogenic responses.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of the Estrogen Specific Mitogenic Response of MCF-7 Cells by Selected Analogues of Estradiol-17β: A 3D QSAR Study

et al. 1997

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“…1). It is thought that it is the composition and positioning of the side chains of tamoxifen and 4-hydroxytamoxifen that give these compounds anti-oestrogenic rather than oestrogenic activity in breast cancer cells, which is mediated through the oestrogen receptor [17]. Similarly, membrane stabilization effects would be expected to reflect structural mimicry of 1713-oestradiol by tamoxifen and in particular 4-hydroxytamoxifen.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of inhibition of lipid peroxidation by tamoxifen and 4‐hydroxytamoxifen introduced into liposomes

et al. 1990

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The anticancer drug tamoxifen when introduced into phospholipid liposomes during their preparation inhibited Fe(III)-ascorbate induced lipid peroxidation to a greater extent than similarly introduced cholesterol. Ergosterol was equipotent with tamoxifen, but much less effective than 4-hydroxytamoxifen. Possible mechanisms underlying these effects are discussed in relation to structural mimicry of the sterols by these triphenylethylene drugs as membrane stabilizers against lipid peroxidation.

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“…Extensive structure function relationship studies classified ligands as antagonist, partial agonist and agonist (46-50) based on structure. This investigation at an estrogen responsive gene was subsequently expanded to map the structure function relationships of breast cancer cell replication (51)(52)(53). The model developed was referred to as the "crocodile model" as the anti-estrogenic sidechain was predicted to prevent "the jaws of the crocodile" from closing (54).…”

Section: B) An Estrogen Receptor Model Of Antiestrogen Actionmentioning

confidence: 99%

The SERM Saga, Something from Nothing: American Cancer Society/SSO Basic Science Lecture

Jordan

2019

Ann Surg Oncol

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Background-The discovery of non-steroidal anti-estrogens created a new group of medicines looking for an application. However, at the time cytotoxic chemotherapy was the modality of choice to treat all cancers. Anti-estrogens were orphan drugs until 1971 with the passing of the National Cancer Act. This enabled laboratory innovations to aid patient care.Methods-This article traces the strategic application of tamoxifen to treat breast cancer by targeting the estrogen receptor (ER), deploying long-term adjuvant tamoxifen therapy, and becoming the first chemo-preventive for any cancer. Laboratory discoveries from the University of Wisconsin Clinical Cancer Center are described that addressed a broad range of biological issues with tamoxifen. These translated to improvements in clinical care.Results-Tamoxifen was studied extensively at Wisconsin in the 1980s, for the development of acquired resistance to long-term therapy. Additionally, the long-term metabolism of tamoxifen and regulation of growth factors were studied. A concern with tamoxifen use for chemoprevention was that an anti-estrogen would increase bone loss and atherosclerosis. Laboratory studies with tamoxifen and keoxifene (subsequently named raloxifene) demonstrated that "non-steroidal antiestrogens" maintained bone density. This translated into successful clinical trials with tamoxifen at Wisconsin. However, tamoxifen also increased endometrial cancer growth. This discovery in the laboratory translated into changes in clinical care. SERMs were born at Wisconsin.Conclusions-There are now five FDA approved SERMs all with discovery origins at Wisconsin. Women's health was revolutionized, as SERMs have the ability to treat multiple diseases by switching on or off target sites around a woman's body. (250)The successful treatment of childhood leukemia during the 1960s became the evidencebased catalyst to develop a lexicon of chemotherapies to cure all cancers, including breast cancer. The treatment of breast cancer evolved from radical surgery and radiation to

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Structural components necessary for the antiestrogenic activity of tamoxifen

Cited by 22 publications

References 10 publications

Induction of the Estrogen Specific Mitogenic Response of MCF-7 Cells by Selected Analogues of Estradiol-17β: A 3D QSAR Study

Induction of the Estrogen Specific Mitogenic Response of MCF-7 Cells by Selected Analogues of Estradiol-17β: A 3D QSAR Study

Mechanism of inhibition of lipid peroxidation by tamoxifen and 4‐hydroxytamoxifen introduced into liposomes

The SERM Saga, Something from Nothing: American Cancer Society/SSO Basic Science Lecture

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