Antiestrogens as targeted tumor therapeutics

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Antiestrogens; hormone antagonists

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Antiestrogenic tumour therapeutics do not have a direct cytotoxic effect in the narrower sense, but block cell growth by way of hormone withdrawal, thereby driving the tumour cell into apoptosis. The substances either block the hormone receptor or suppress hormone production itself.

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Targeted tumour therapeutics with anti-oestrogenic effect are classified as follows:

  • Selective Estrogen Receptor Modulators (SERMs): SERMs form a heterogeneous class of non-steroidal substances that act not only as estrogens but also as antiestrogens. After binding to the estrogen receptors -ERalpha + ERbeta-, "selective estrogen receptor modulators" initiate a ligand-specific conformational change of both receptors, which determines the type of interaction with DNA and certain regulatory proteins. In the inactive state, the estrogen receptors -ERalpha + ERbeta- are located in the cytoplasm of cells and bound to so-called heat shock proteins such as HSP90. When estrogens bind to the estrogen receptor, the heat shock protein is released. In a next step, a translocation of the hormone receptor complex into the cell nucleus takes place. There the hormone receptor complexes can bind to so-called "estrogen-responsive elements" of the DNA in the form of dimers. By recruiting further coactivators or core compressors, the gene expression of target genes can then be activated or inhibited. The quality and quantity of the coregulatory proteins in the cell are thus decisive for an agonistic or antagonistic effect of the estrogen receptor on target gene expression. The exact profile of the SERM depends on its chemical structure: tamoxifen is antagonistic in breast tissue and agonistic in utero. ADR: vasomotor symptoms, thrombosis, venous thromboembolism and the estrogen-agonistic increase in the risk of endometrial carcinoma. Also: fatigue, disinterest, hot flushes, slight loss of hair, nausea, constipation, dizziness, dry mucous membranes, rash, itching. Arthralgia, myalgia. Representatives of this group are:
    • Tamoxifen
    • Toremifene (metastasized breast carcinoma)
    • Fulvestrant (advanced or metastasized breast carcinoma)
  • Aromatase inhibitors (aromatase inhibitors) suppress the synthesis of estradiol and reduce estradiol levels by preventing the conversion of androgens into estrogens by the enzyme aromatase. This inhibits the growth of estrogen-dependent (ER-positive) tumours. The preparations are approved for use in metastatic breast cancer. UAW: Arthralgia, myalgia, loss of bone density. In comparison to the estrogen receptor antagonists, fewer thromboembolic events and endometrial carcinomas occur.
    • Anastrozole (oral application; advanced or metastasized breast cancer in postmenopausal patients)
    • Exemestan (oral application; advanced or metastasized breast cancer in postmenopausal patients)
    • Letrozole (oral application; advanced or metastasized breast cancer in postmenopausal patients)

Spectrum of action
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In certain neoplasias, tumour growth can be particularly stimulated by hormones. These hormone-dependent neoplasias include many breast carcinomas (stimulation by estrogens and progesterone) and most prostate carcinomas (stimulation by testosterone). The growth-stimulating effect takes place via hormone receptors, which induce an increased synthesis of growth factors via a downstream signal cascade. This assumes that the tumour cells still show relative differentiation, which enables them to express hormone receptors. Progressive de-differentiation increasingly precludes receptor formation, which means that this therapeutic approach can no longer be effective.

Antiestrogenic tumor therapeutics therefore do not act directly but via hormone withdrawal, which drives the tumor cell into apoptosis.

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Last updated on: 29.10.2020