Tamoxifen Case Study
Abstract
Tamoxifen, most commonly sold under the brand name Nolvadex, is the most widely used drug in the treatment of breast cancer during both early and late stages. It belongs to a class of drugs known as SERMs (Selective Estrogen Receptor Modulators). SERMs work by blocking the estrogen receptors in breast cells to prevent any binding with estrogen. It is consumed orally as a tablet or as a liquid (Anon., 2017). The following paper discusses the discovery of Tamoxifen, its laboratory synthesis and mechanism of action. The limitations of Tamoxifen are also briefly reviewed in this paper.
Introduction and Origin
Breast cancer is the most commonly occurring cancer in women, both in the developed and less developed world. It is estimated that …show more content…
Dr. A.L Walpole led the team of reproductive endocrinologists that discovered a viable solution to the desmosterol problem at Imperial Clinical Industries (ICI) Pharmaceuticals Division (now AstraZeneca) (Jordan, 2006, p. S270). They discovered the compound ICI46,474, which later became tamoxifen (Walpole, 1967). Walpole’s team succeeded in identifying the trans isomer of a substituted triphenylethylene (ICI46,474), which was a partial estrogen agonist/antagonist in rats but a full estrogen agonist in mice. Most importantly, this trans isomer of substituted ICI46,474 exhibited unaffected levels of desmosterol, which satisfied the concerns of the pharmaceutical community. Tamoxifen was subsequently developed (Jordan, 2006, p. …show more content…
Only the trans isomer of tamoxifen is active in breast cancer treatment. The cis isomer of the drug, on the other hand, has no clinical use and is not an estrogen antagonist (Tanner, 2017).
Tamoxifen is most often described as an anti-estrogen, which is an inaccurate description of its clinical behaviour. Depending on the target tissue, tamoxifen exhibits both pro- and anti-estrogenic properties. This is why tamoxifen is more accurately referred to as a Selective Estrogen Receptor Modulator (SERM) (Khetrapal, 2015). Structurally speaking, tamoxifen is very similar to estrogen. The main difference between the structure of the two molecules is the extra chain in the tamoxifen molecule, which is responsible for its antagonistic property (Khetrapal, 2015).
A condensed explanation of the mechanism of action of tamoxifen is that it is mediated by binding to estrogen receptors in breast cells thereby blocking the proliferative action of estrogen on the breast cells. The mechanism of action of tamoxifen, however, is much more complex (Michael Sporn, 2003). Tamoxifen, in its unaltered self, has a low affinity for estrogen receptors. It is metabolised by the cytochrome CYP2D6 enzyme to form the active metabolite endoxifen (4-hydroxy-N-desmethyl-tamoxifen) (Philipp Y. Maximov, 2013). This metabolite has exhibited a much greater affinity (100-fold)
Tamoxifen, most commonly sold under the brand name Nolvadex, is the most widely used drug in the treatment of breast cancer during both early and late stages. It belongs to a class of drugs known as SERMs (Selective Estrogen Receptor Modulators). SERMs work by blocking the estrogen receptors in breast cells to prevent any binding with estrogen. It is consumed orally as a tablet or as a liquid (Anon., 2017). The following paper discusses the discovery of Tamoxifen, its laboratory synthesis and mechanism of action. The limitations of Tamoxifen are also briefly reviewed in this paper.
Introduction and Origin
Breast cancer is the most commonly occurring cancer in women, both in the developed and less developed world. It is estimated that …show more content…
Dr. A.L Walpole led the team of reproductive endocrinologists that discovered a viable solution to the desmosterol problem at Imperial Clinical Industries (ICI) Pharmaceuticals Division (now AstraZeneca) (Jordan, 2006, p. S270). They discovered the compound ICI46,474, which later became tamoxifen (Walpole, 1967). Walpole’s team succeeded in identifying the trans isomer of a substituted triphenylethylene (ICI46,474), which was a partial estrogen agonist/antagonist in rats but a full estrogen agonist in mice. Most importantly, this trans isomer of substituted ICI46,474 exhibited unaffected levels of desmosterol, which satisfied the concerns of the pharmaceutical community. Tamoxifen was subsequently developed (Jordan, 2006, p. …show more content…
Only the trans isomer of tamoxifen is active in breast cancer treatment. The cis isomer of the drug, on the other hand, has no clinical use and is not an estrogen antagonist (Tanner, 2017).
Tamoxifen is most often described as an anti-estrogen, which is an inaccurate description of its clinical behaviour. Depending on the target tissue, tamoxifen exhibits both pro- and anti-estrogenic properties. This is why tamoxifen is more accurately referred to as a Selective Estrogen Receptor Modulator (SERM) (Khetrapal, 2015). Structurally speaking, tamoxifen is very similar to estrogen. The main difference between the structure of the two molecules is the extra chain in the tamoxifen molecule, which is responsible for its antagonistic property (Khetrapal, 2015).
A condensed explanation of the mechanism of action of tamoxifen is that it is mediated by binding to estrogen receptors in breast cells thereby blocking the proliferative action of estrogen on the breast cells. The mechanism of action of tamoxifen, however, is much more complex (Michael Sporn, 2003). Tamoxifen, in its unaltered self, has a low affinity for estrogen receptors. It is metabolised by the cytochrome CYP2D6 enzyme to form the active metabolite endoxifen (4-hydroxy-N-desmethyl-tamoxifen) (Philipp Y. Maximov, 2013). This metabolite has exhibited a much greater affinity (100-fold)