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Tamoxifen
Systematic (IUPAC) name
(Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine
Identifiers
CAS number 10540-29-1
ATC code L02BA01
PubChem 5376
DrugBank APRD00123
Chemical data
Formula C26H29NO 
Mol. mass 371. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 515 g/mol
563. 638 g/mol (citrate salt)
Pharmacokinetic data
Bioavailability  ?
Metabolism Hepatic (CYP3A4, 2C9 and 2D6)
Half life 5–7 days
Excretion Fecal
Therapeutic considerations
Pregnancy cat.

B3 (Au) D (US)
Legal status

POM(UK) ℞-only(US)
Routes Oral

Tamoxifen is an orally active selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer and is currently the world's largest selling drug for that purpose. A citrate can refer either to the Conjugate base of Citric acid, (C3H5O(COO33&minus or to the Esters of citric In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals Cytochrome P450 3A4 (abbreviated CYP3A4) ( a member of the Cytochrome P450 mixed-function oxidase system is one of the most important enzymes involved in the metabolism Cytochrome P450 2C9 (abbreviated CYP2C9) is an important Cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds Cytochrome P450 2D6 (CYP2D6 a member of the Cytochrome P450 mixed-function oxidase system is one of the most important enzymes involved in the metabolism of Xenobiotics The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United States of America —commonly referred to as the In Pharmacology and Toxicology, a route Selective Estrogen Receptor Modulators ( SERMs) are a class of Medication that acts on the Estrogen receptor. Breast cancer is a Cancer that starts in the cells of the Breast in women and men

Tamoxifen was discovered by ICI Pharmaceuticals[1] (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. Imperial Chemical Industries ( ICI) is a British chemical subsidiary of a Dutch conglomerate and one of the largest chemical producers AstraZeneca PLC (,) is a large Anglo-Swedish Pharmaceutical company formed on 6 April 1999 by the remerger of Swedish Astra AB However, the drug, even before its patent expiration, was and still is widely referred to by its generic name "tamoxifen. "

Contents

Breast cancer treatment

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women. Menopause is the permanent shutting down of the female Reproductive system, a considerable length of time before the end of the lifespan [2] It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. [3] It has been further approved for the reduction of contralateral (in the opposite breast) cancer.

In 2006, the large STAR clinical study concluded that raloxifene is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36 % fewer uterine cancers and 29 % fewer blood clots than in women taking tamoxifen. Raloxifene is an oral Selective estrogen receptor modulator (SERM that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast The term uterine cancer may refer to any of several different types of Cancer which occur in the Uterus, namely Uterine sarcomas [4][5]

In 2005, the ATAC trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received anastrozole (Arimidex) had significantly better results than the tamoxifen group. Anastrozole ( INN, trade name Arimidex) is a drug indicated in the treatment of Breast cancer in post- menopausal women Anastrozole ( INN, trade name Arimidex) is a drug indicated in the treatment of Breast cancer in post- menopausal women Anastrozole vs tamoxifen: deaths - 575 vs 651, recurrences - 402 vs 498, distant metastases - 324 vs 375, second breast cancer - 35 vs 59 (42% reduction). The trial suggested that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is estrogen receptor positive. The estrogen receptor (ER is a member of the nuclear hormone family of Intracellular receptors which is activated by the Hormone 17β-estradiol [6]

Other uses

Tamoxifen is used to treat infertility in women with anovulatory disorders. The anovulatory cycle is a Menstrual cycle characterized by varying degrees of menstrual intervals and the absence of Ovulation and a Luteal phase. A dose of 10–40 mg per day is administered in days 3–7 of a woman's cycle. [7] In addition, a rare condition occasionally treated with tamoxifen is retroperitoneal fibrosis. Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the Retroperitoneum, the compartment of the body containing [8]

In men, tamoxifen is sometimes used to treat gynecomastia that arises for example as a side effect of antiandrogen prostate cancer treatment. Gynecomastia, or gynaecomastia, ˌgaɪnəkoʊˈmæstiə is the development of abnormally large Mammary glands in Males resulting in breast enlargement which An antiandrogen, or androgen antagonist, is any of a group of Hormone Receptor antagonist compounds that are capable of preventing or inhibiting the biologic [9] Tamoxifen is also used by bodybuilders to prevent or reduce drug-induced gynecomastia caused by the estrogenic metabolites of anabolic steroids. Estrogens (US otherwise oestrogens or œstrogens) are a group of Steroid compounds named for their importance in the Estrous cycle, Anabolic steroids, or anabolic-androgenic steroids ( AAS) are a class of Steroid hormones related to the hormone Testosterone. [10] Tamoxifen is also sometimes used to treat or prevent gynecomastia in sex offenders undergoing treatment by temporary chemical castration. A sex offender is a person who has been criminally charged and convicted of or has pled guilty to or pled Nolo contendere to a Sex crime. Chemical castration is a form of Castration caused by hormonal Medication. [11]

Tamoxifen has been shown to be effective in the treatment of mania in patients with bipolar disorder by blocking protein kinase C (PKC), an enzyme that regulates neuron activity in the brain. Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition Protein kinase C ('PKC') is a family of protein kinases consisting of ~10 Isozymes. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Researchers believe PKC is over-active during the mania in bipolar patients. [12][13]

Finally tamoxifen is used as a research tool to trigger tissue selective gene expression in genetically modified animals using the Cre-Lox recombination technique. Cre-Lox recombination is a special type of site-specific recombination which was patented in the 1980s by DuPont. [14]

Mechanism

Crystallographic structure (PDB 3ERT) of 4-hydroxytamoxifen (white sticks) complexed with the ligand binding domain of the estrogen receptor (cyan cartoon diagram).
Crystallographic structure (PDB 3ERT) of 4-hydroxytamoxifen (white sticks) complexed with the ligand binding domain of the estrogen receptor (cyan cartoon diagram). The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography

Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Cell signaling is part of a Complex system of Communication that governs basic cellular activities and coordinates cell actions Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. The cell cycle, or cell-division cycle, is the series of events that take place in a eukaryotic cell leading to its replication Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal.

Tamoxifen itself is a prodrug, having very little affinity for its target protein, the estrogen receptor. A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form The estrogen receptor (ER is a member of the nuclear hormone family of Intracellular receptors which is activated by the Hormone 17β-estradiol It must first be metabolized in the liver by the cytochrome P450 isoform CYP2D6 into the active metabolites 4-hydroxytamoxifen and des-N-methyl-4-hydroxytamoxifen (endoxifen). Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains Cytochrome P450 2D6 (CYP2D6 a member of the Cytochrome P450 mixed-function oxidase system is one of the most important enzymes involved in the metabolism of Xenobiotics [15] These active metabolites compete with estrogen in the body for binding to the estrogen receptor. The estrogen receptor (ER is a member of the nuclear hormone family of Intracellular receptors which is activated by the Hormone 17β-estradiol In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited. A receptor antagonist is a type of receptor ligand or Drug that does not provoke a biological response itself upon binding to a receptor, but blocks [16]

Side effects

Tamoxifen is a selective estrogen receptor modulator. [17] Even though it is an antagonist in breast tissue it acts as partial agonist on the endometrium and has been linked to endometrial cancer in some women. A receptor antagonist is a type of receptor ligand or Drug that does not provoke a biological response itself upon binding to a receptor, but blocks An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. The endometrium is the inner membrane of the Mammalian Uterus. Endometrial cancer refers to several types of malignancy which arise from the Endometrium, or lining of the Uterus. Therefore endometrial changes, including cancer, are among tamoxifen's side effects. [18]

The American Cancer Society lists tamoxifen as a known carcinogen, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence. The American Cancer Society ( ACS) is the "nationwide community-based voluntary health organization dedicated to [19] The ACS states that its use should not be avoided in cases where the risk of breast cancer recurrence without the drug is higher than the risk of developing uterine cancer with the drug.

For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood. (more properly known as, TAG or triacylglyceride) is Glyceride in which the Glycerol is Esterified with three Fatty acids It is the In addition there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility. Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory [20] Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis. Fatty liver, also known as fatty liver disease ( FLD) steatorrhoeic hepatosis, or steatosis hepatitis, is a reversible condition where [21]

A significant number of tamoxifen treated breast cancer patients experience a reduction of libido. Libido in its common usage means Sexual desire however more technical definitions such as those found in the work of Carl Jung, are more general referring to libido [22][23]

A beneficial side effect of tamoxifen is that it prevents bone loss by inhibiting osteoclasts by acting as an estrogen receptor agonist (i. An osteoclast (from the Greek words for "bone" and "broken" is a type of Bone cell that removes Bone tissue by removing its Mineralized matrix An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. e. , mimicking the effects of estrogen) in this cell type, and therefore it prevents osteoporosis. Osteoporosis is a Disease of Bone that leads to an increased risk of fracture. [24][25] When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an estrogen receptor antagonist in all tissue, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly lead to the formulation of the concept of selective estrogen receptor modulators (SERMs). [26]

Pharmacogenetics

Patients with variant forms of the gene CYP2D6 (also called simply 2D6) may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolite 4-hydroxytamoxifen. Cytochrome P450 2D6 (CYP2D6 a member of the Cytochrome P450 mixed-function oxidase system is one of the most important enzymes involved in the metabolism of Xenobiotics [27][28] On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert. [29] Recent studies suggest that taking selective serotonin reuptake inhibitor (SSRI) antidepressants such as Paxil, Prozac, etc. , can decrease the effectiveness of tamoxifen, because these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into the active form endoxifen. [30]

Market

Global sales of tamoxifen in 2001 were $1,024 million. [31] Since the expiration of the patent, it is now widely available as a generic drug around the world. A generic drug (generic drugs short generics is a drug which is produced and distributed without Patent protection

Discovery

In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. Arthur L Walpole was a reproductive endocrinologist who led such a team at the Alderley Park research laboratories of ICI Pharmaceuticals. Endocrinology (from Greek grc ἔνδον endon, "within" grc κρῑνω krīnō, "to separate" and grc -λογία It was there in 1962 that Dora Richardson first synthesised tamoxifen, known then as ICI-46,474. [32] Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s. [33] Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection. [1]

The first clinical study took place at the Christie Hospital in 1971, and showed a convincing effect in advanced breast cancer,[34] but nevertheless ICI's development programme came close to termination when it was reviewed in 1972. The Christie Hospital NHS Foundation Trust is located in Withington, Manchester, and is one of the largest Cancer treatment centres in Europe It appears to have been Walpole again who convinced the company to market tamoxifen for late stage breast cancer in 1973. [33] He was also instrumental in funding V. Craig Jordan to work on tamoxifen. Virgil Craig Jordan, OBE PhD DSc (born Texas, USA) is a scientist specializing in drugs for breast cancer treatment and prevention Approval in the US followed in 1977, but the drug was competing against other hormonal agents in a relatively small marketplace and was not at this stage either clinically or financially remarkable.

1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer. [35] In advanced disease, tamoxifen is now only recognised as effective in estrogen receptor positive (ER+) patients, but the early trials did not select ER+ patients, and by the mid 1980s the clinical trial picture was not showing a major advantage for tamoxifen. The estrogen receptor (ER is a member of the nuclear hormone family of Intracellular receptors which is activated by the Hormone 17β-estradiol [36] Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued. It was not until 1998 that the meta-analysis of the Oxford based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen saved lives in early breast cancer. [37]

References

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