Tamoxifen

Source: Wikipedia, the free encyclopedia.

Tamoxifen
Clinical data
Trade namesNolvadex, Genox, Tamifen, others[1]
Other namesTMX; ICI-46474
AHFS/Drugs.comMonograph
MedlinePlusa682414
License data
Pregnancy
category
Routes of
administration
By mouth
Drug classSelective estrogen receptor modulator
ATC code
Legal status
Legal status
conjugates[8][10][11]
Elimination half-life5–7 days[5][8]
ExcretionFeces: 65%
Urine: 9%
Identifiers
  • (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine
JSmol)
  • CN(C)CCOc1ccc(cc1)/C(c2ccccc2)=C(/CC)c3ccccc3
  • InChI=1S/C26H29NO/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3/h5-18H,4,19-20H2,1-3H3/b26-25- checkY
  • Key:NKANXQFJJICGDU-QPLCGJKRSA-N checkY
  (verify)

Tamoxifen, sold under the brand name Nolvadex among others, is a

Albright syndrome.[14] Tamoxifen is typically taken daily by mouth for five years for breast cancer.[14]

Serious side effects include a small increased risk of

selective estrogen-receptor modulator (SERM) and works by decreasing the growth of breast cancer cells.[14][15] It is a member of the triphenylethylene group of compounds.[16]

Tamoxifen was initially made in 1962, by chemist Dora Richardson.

generic medication.[14] In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.[20][21]

Medical uses

Dysmenorrhea

Tamoxifen has been used effectively to improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients.[22]

Breast cancer

Tamoxifen is used for the treatment of both early and advanced

intrauterine system releasing levonorgestrel might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer.[24] Additionally, it is the most common hormone treatment for male breast cancer.[25] It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease.[26] It has been further approved for the reduction of contralateral (in the opposite breast) cancer. The use of tamoxifen is recommended for 10 years.[27]

In 2006, the large STAR clinical study concluded that raloxifene is also effective in reducing the incidence of breast cancer. Updated results after an average of 6.75 years of follow up found that raloxifene retains 76% of tamoxifen's effectiveness in preventing invasive breast cancer, with 45% fewer uterine cancers and 25% fewer blood clots in women taking raloxifene than in women taking tamoxifen.[28][29][30]

Infertility

Tamoxifen is used for ovulation induction to treat infertility in women with anovulatory disorders. It is given at days three to seven of a woman's cycle.[31]

Tamoxifen improves fertility in males with infertility by disinhibiting the hypothalamic–pituitary–gonadal axis (HPG axis) via ER antagonism and thereby increasing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and increasing testicular testosterone production.[32]

Gynecomastia

Tamoxifen is used to prevent and treat gynecomastia.[33][34] It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Other medications are taken for similar purposes such as clomifene and the anti-aromatase drugs which are used in order to try to avoid the hormone-related adverse effects.

Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men
Follow-up
timepoint
Tamoxifen dosage
Placebo 1 mg/day 2.5 mg/day 5 mg/day 10 mg/day 20 mg/day
0 months
6 months 98% 90% 80% 54% 22% 10%
12 months 99% 95% 84% 56% 38% 19%
Notes: Prevention of breast symptoms—specifically gynecomastia and breast pain—induced by 150 mg/day bicalutamide monotherapy with tamoxifen in 282 men with prostate cancer. Bicalutamide and tamoxifen were initiated at the same time (0 months). Estradiol levels were in the range of about 22 to 47 pg/mL in the treated group.[35] Sources: [36][35]

Early puberty

Tamoxifen is useful in the treatment of

bone maturation in girls with precocious puberty, and hence to improve final height in these individuals.[37][38]

Available forms

Nolvadex (tamoxifen) 20 mg tablets.

Tamoxifen is available as a tablet or oral solution.[40][41]

Contraindications

Tamoxifen has a number of

venous thromboembolism (deep vein thrombosis or pulmonary embolism).[12]

Side effects

A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[42]

Endometrial cancer

Tamoxifen is a selective estrogen receptor modulator (SERM).[43] 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. Therefore, endometrial changes, including cancer, are among tamoxifen's side effects.[44] With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years.[45]

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.[46]

Cardiovascular and metabolic

Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect.[47] For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood. In addition, there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility.[48] Use of tamoxifen has been shown to slightly increase risk of deep vein thrombosis, pulmonary embolism, and stroke.[49]

Liver toxicity

Tamoxifen has been associated with a number of cases of

non-alcoholic fatty liver disease in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20 mg/day.[51]

Overdose

Acute

Interactions

Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites.[52][53] On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.[54] Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment.[55] Genotyping therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7–10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications.[56] Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.[57]

Recent studies suggest that taking the

selective serotonin reuptake inhibitors (SSRIs) antidepressants paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms.[58] A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa (citalopram), Lexapro (escitalopram), and Luvox (fluvoxamine) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme.[59] A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration.[60]

Tamoxifen interacts with certain other antiestrogens.[5] The aromatase inhibitor aminoglutethimide induces the metabolism of tamoxifen.[5] Conversely, the aromatase inhibitor letrozole does not affect the metabolism of tamoxifen.[5] However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations.[5]

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator activity

Crystallographic structure of afimoxifene (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (ERα) (cyan ribbon).[61]

Tamoxifen acts as a

osteoclasts, it prevents osteoporosis.[63][64] When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, 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 led to the formulation of the concept of SERMs.[65]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
Medication Breast Bone Liver Uterus Vagina Brain
Lipids
Coagulation SHBGTooltip Sex hormone-binding globulin IGF-1Tooltip Insulin-like growth factor 1 Hot flashes Gonadotropins
Estradiol + + + + + + + + + +
"Ideal SERM" + + ± ± ± + + ±
Bazedoxifene + + + + ? ± ?
Clomifene + + ? + + ? ±
Lasofoxifene + + + ? ? ± ± ?
Ospemifene + + + + + ± ± ±
Raloxifene + + + + + ± ±
Tamoxifen + + + + + + ±
Toremifene + + + + + + ±
Effect: + = Estrogenic / agonistic. ± = Mixed or neutral. = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.

Tamoxifen is a long-acting SERM, with a

ERβ, respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively.[69] Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than tamoxifen.[70] The antiestrogenic potencies of endoxifen and afimoxifene are very similar.[9] However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body.[8][9][71]

Tamoxifen binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells 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

AIB-1 expression is higher than PAX2, tamoxifen/ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.[74][77]

Tamoxifen is

premenopausal women and increases estrogen levels by 6-fold in them.[78] Due to the nature of tamoxifen as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen.[78] The effects of tamoxifen on breast cancer Ki-67 expression, sex hormone-binding globulin (SHBG) levels, and IGF-1 levels are dose-dependent across a dosage range of 1 to 20 mg/day in women with breast cancer.[79] Tamoxifen has been found to decrease insulin-like growth factor 1 (IGF-1) levels by 17 to 38% in women and men.[80] Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs.[80] A 10 mg/day dosage of tamoxifen is nearly as effective as a 20 mg/day dosage in suppressing IGF-1 levels.[5]

Other activities

Afimoxifene is an

affinity.[81] Its affinity for the receptor is in the range of 100 to 1,000 nM, relative to 3 to 6 nM for estradiol.[81]

In addition to its activity as a SERM, afimoxifene binds to both the

Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen), another active metabolite of tamoxifen, has been found to act as a potent competitive aromatase inhibitor (IC50 = 90 nM), and may also be involved in the antiestrogenic activity of tamoxifen.[83]

In addition to its activity as a SERM, tamoxifen is a potent and selective protein kinase C inhibitor, and is active in this regard at therapeutic concentrations.[84] This action is thought to underlie the efficacy of tamoxifen in the treatment of bipolar disorder.[84]

Tamoxifen is an inhibitor of P-glycoprotein.[12]

Pharmacokinetics

Absorption

Tamoxifen is rapidly and extensively

N,N-didesmethyltamoxifen, (Z)-endoxifen, and tamoxifen N-oxide.[10][87]

Distribution

The

plasma proteins are not greatly involved.[88]

Metabolism

Tamoxifen and its metabolites in humans[89]
Compound Mean plasma
concentrations
Effect on ER / affinity for ERa
Tamoxifen 190–420 nmol/L Weak antagonist / 2%
N-Desmethyltamoxifen 280–800 nmol/L Weak antagonist / 1%
N,N-Desmethyltamoxifen
90–120 nmol/L Weak antagonist
Endoxifen 14–130 nmol/L Strong antagonist / equal to afimoxifene
Afimoxifene 3–17 nmol/Lb Strong antagonist / 188%
α-Hydroxytamoxifen 1 nmol/L None
3,4-Dihydroxytamoxifen ? Weak antagonist / high affinity
Tamoxifen N-oxide 15–24 nmol/L Weak antagonistc
Footnotes: a = Estradiol is 100%. b = One study reported a much higher concentration (67 nmol/L). c = Might be due to reduction to tamoxifen.

Tamoxifen is a

conjugation, including glucuronidation and sulfation.[11] Tamoxifen may inhibit its own metabolism.[5]

Elimination

Tamoxifen has a long

enterohepatic recirculation.[7] Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6 weeks.[7] Tamoxifen is excreted in bile and is eliminated in feces, while small amounts are eliminated in urine.[5]

Chemistry

Tamoxifen is a nonsteroidal SERM of the triphenylethylene family and was structurally derived from diethylstilbestrol-like estrogens and antiestrogens such as chlorotrianisene and ethamoxytriphetol.[90][91][92][93] Initially, clomifene was synthesized, and tamoxifen was developed subsequently.[90][92][93] Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene, nafoxidine, ospemifene, toremifene, and numerous others.[94][95] Other SERMs, like raloxifene, are structurally distinct from tamoxifen and other triphenylethylenes.[95]

History

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.[18] It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen, back then known as ICI-46,474, when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching.[96]

This compound was originally created to work as an estrogen inhibitor, but instead was found to stimulate ovulation in participants of the drug testing trial.[17] 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.[97] 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.[18] It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for tamoxifen as a drug that could be used to treat breast cancer. Without Walpole's effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment, tamoxifen could have become a discarded or under-researched idea. Walpole's team consisted of Dora Richardson and G. A. Snow, who worked on the chemistry portion of the project, along with G. E. Paget and J. K. Walley, who focused primarily on the biological side.[17]

Tamoxifen is one of three drugs in an anti-angiogenetic protocol developed by Dr. Judah Folkman, a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that angiogenesis – the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on angiogenesis inhibitors have been underway since 1992 using many different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of celecoxib, doxycycline, and tamoxifen – the treatment subsequently became known as the Navy Protocol.[98] Furthermore, tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's ER antagonist properties.[99]

Other antiestrogens, such as ethamoxytriphetol (MER-25) and clomifene (MRL-41), were assessed for treatment of breast cancer and found to be effective before tamoxifen, but were plagued with toxicity issues.[100][101] The first clinical study of tamoxifen took place at the Christie Hospital in 1971, and showed a convincing effect in advanced breast cancer, but nevertheless ICI's development programme came close to termination when it was reviewed in 1972.[102] In an unpublished article from the early days of the trial, Dora Richardson documented her team's excitement about tamoxifen's effects in counteracting infertility problems and the early positive effects found in breast cancer patients. Unfortunately, this work was not well received by everyone, as the team was supposed to be looking for a contraceptive pill.[17] Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward [103] at the Queen Elizabeth Hospital, Birmingham. Ward's study showed a more definitive response to the drug at a higher dosage. Walpole also may have helped to convince the company to market tamoxifen for late stage breast cancer in 1973.[97] He was also instrumental in funding V. Craig Jordan to work on tamoxifen. In 1972, ICI Pharmaceuticals Division abandoned development of tamoxifen for financial reasons. The drug was subsequently reinvented from a failed contraceptive, to become tamoxifen, the gold standard for the adjuvant treatment of breast cancer and the pioneering medicine for chemprevention for high-risk women.[104][105] Two books, Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health (Imperial College Press 2013) and Tamoxifen: Pioneering Medicine in Breast Cancer (Springer 2013) tell this story.

Comparison of early clinical experience with antiestrogens for advanced breast cancer
Antiestrogen Dosage Year(s) Response rate Adverse effects
Ethamoxytriphetol 500–4,500 mg/day 1960 25%
Acute psychotic episodes
Clomifene 100–300 mg/day 1964–1974 34% Risks of cataracts
Nafoxidine 180–240 mg/day 1976 31% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day 1971–1973 31% Transient thrombocytopeniaa
Footnotes: a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources: [100][106]

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.[107] In advanced disease, tamoxifen is now only recognized as effective in 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.[108] Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued.

The pharmacology of SERMs was discovered, defined, and deciphered during the 1980s.[109] A clinical strategy was described[110] that led to the creation of SERMs as a group of multifunctional medicines aimed at the treatment or prevention of many conditions in postmenopausal women, e.g. osteoporosis and breast cancer. This story is told in: V. Craig Jordan, ed. 2013. "Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health" Imperial College Press, Singapore.

The early sales of tamoxifen in both the UK and in the U.S. far exceeded ICI's original estimate, but despite this, at the annual portfolio review ICI's board members still asserted that "there was no market for cancer", leaving the drug's marketing success to rely on its clinical results and clinicians' and scientists' interests in it. Shortly after, Dora Richardson published a history of tamoxifen that, unusually for that type of paper, included personal accounts and letters from patients who attributed their healing to the drug. It is by giving voice to cancer patients using tamoxifen, and so helping to push it forward, by justifying it both morally and scientifically to corporations.[17]

It was not until 1998 that the meta-analysis of the Oxford-based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen was effective for early breast cancer.[111]

Society and culture

Brand names

Tamoxifen is marketed under the brand names Nolvadex and Soltamox, and a variety of other brand names throughout the world.[1][112]

Economics

Global sales of tamoxifen in 2001 were approximately $1.02 billion.[113] Since the expiration of the patent in 2002, it is widely available as a generic drug around the world. As of 2004, tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.[114]

Research

In

bone maturation which is the result of excessive estrogen and alter predicted adult height (PAH).[115][116] The same effects have also been seen in short pubertal boys.[117] However, one in vitro study in 2007 and later an in vivo study in 2008 have shown that tamoxifen induces apoptosis in growth plate chondrocytes, reduces serum insulin-like growth factor 1 (IGF-1) levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats, leading the researchers to express concern giving tamoxifen to growing individuals.[118][119]

Tamoxifen has been studied in the treatment of the rare conditions of retroperitoneal fibrosis[120] and idiopathic sclerosing mesenteritis.[121] It has also been proposed as part of a treatment plan for Riedel's thyroiditis.[122]

Tamoxifen is used as a research tool to trigger tissue-specific gene expression in many conditional expression constructs in genetically modified animals including a version of the Cre-Lox recombination technique.[123] While widely used in transgenic research, the strong anabolic effect of tamoxifen on bone might confound this approach, especially as it relates to bone-targeted constructs.

Tamoxifen may be effective in the treatment of mania in people with bipolar disorder.[124] This is thought to be due to blockade of protein kinase C (PKC), an enzyme that regulates neuron activity in the brain.[124][125] Researchers believe PKC is overactive during the mania in bipolar patients.[124][125] As of September 2019, endoxifen, a major active metabolite of tamoxifen with a 4-fold more potent PKC inhibition, was in phase III clinical trials for bipolar disorder.[126][127]

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Further reading

External links