Estrogen receptor downregulator (ERD)
An estrogen receptor downregulator (ERD) is a type of medication that prevents the action of estrogen by inhibiting estrogen-receptor-mediated transcription and suppressing the expression of estrogen-dependent genes. The primary example of an ERD is fulvestrant (Faslodex), which is characterized as a "pure" estrogen receptor antagonist because it does not exhibit the agonistic effects seen in other estrogen receptor modulators. This class of drugs is particularly relevant in the treatment of hormone-sensitive cancers, such as breast cancer, where estrogen can promote the proliferation of cancerous cells.
Fulvestrant works by binding to estrogen receptors, blocking the activation of downstream processes that lead to gene expression associated with cell growth. It also promotes the degradation of the estrogen receptor protein, resulting in a significant reduction of receptor levels in the body. Approved by the FDA in 2002, fulvestrant is specifically indicated for postmenopausal women with metastatic breast cancer that is unresponsive to other treatments, such as tamoxifen. Unlike tamoxifen, fulvestrant does not mimic estrogen's effects in the uterus, making it a more targeted approach in certain patient populations. While effective, common side effects of fulvestrant include nausea, vomiting, and hot flashes. Recent developments include the FDA's approval of capivasertib in combination with fulvestrant for enhanced treatment options in breast cancer therapy.
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Estrogen receptor downregulator (ERD)
ATC CODE: L02BA03
DEFINITION: An estrogen receptor downregulator (ERD) is a compound that prevents estrogen's action by attenuating estrogen-receptor-mediated transcription and suppressing estrogen-dependent gene expression. The only known ERD is fulvestrant (Faslodex), which is described as a “pure” ER antagonist because it lacks the agonistic effects exhibited by other estrogen receptor modulators.
Subclasses of this drug group are antiestrogens and selective estrogen receptor modulators (SERMs), the latter of which also downregulate the estrogen receptor but are selective in their antagonistic action.
Cancers treated or prevented:Breast cancer
Delivery routes: injection
How this drug works: Estrogen is the female hormone mainly secreted in the ovaries that acts on female organs, such as the breasts and uterus. Estrogen is responsible for activating the endothelial cells of the uterus during menstrual cycles. It performs its function by binding with specific receptors, called estrogen receptors (ER), present in various body parts. This binding is critical in inducing conformational changes of the ER protein, resulting in the induction of expression in associated genes, ultimately leading to the proliferation of endothelial cells. In cancer patients, the proliferation of cancerous cells is triggered by estrogen binding to the ER. Therefore, preventing estrogen from binding to its receptor is a viable pharmacological strategy in cancer research.
The estrogen receptor downregulator fulvestrant (Faslodex) is a steroidal analog of the hormone 17β-estradiol. Fulvestrant was approved by the Food and Drug Administration (FDA) in 2002 for treating cancer. It binds to estrogen receptors and blocks downstream processes such as receptor dimerization, leading to the blockade of induction of gene expression. Fulvestrant also expedites the degradation of ER protein, resulting in drastic downregulation of ER levels. Estrogen cannot exert its proliferative action in the absence of ER, and thus, fulvestrant treatment can treat and limit the spread of cancer.
Fulvestrant is administered to postmenopausal women whose cancer has metastasized and does not respond to traditional medications, such as the classic antiestrogen tamoxifen. Fulvestrant has about a hundredfold higher affinity for ER than tamoxifen and, unlike tamoxifen, has no agonistic effects on ER. Tamoxifen (Nolvadex) prevents the proliferation of cells in the breast but acts like estrogen and exerts agonistic effects on the uterus. Clinical trials using fulvestrant have shown decelerated cancer growth and delayed recurrence rates. Using fulvestrant in combination therapy for cancer is a treatment option. In late 2023, the FDA approved capivasertib (Truqap) with fulvestrant for breast cancer treatment.
Side effects: The side effects of fulvestrant are nausea, vomiting, constipation, diarrhea, abdominal pain, and hot flashes.
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