Tamoxifen is an
antagonistA 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 or dampens agonist-mediated responses...
of the
estrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the
endometrium-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
, it behaves as an
agonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
, hence tamoxifen may be characterized as a mixed agonist/antagonist. Tamoxifen is the usual endocrine (anti-
estrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
) therapy for
hormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
receptor-positive
breast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
in
pre-menopausalMenopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
women, and is also a standard in post-menopausal women although aromatase inhibitors are also frequently used in that setting.
Some breast cancer cells require estrogen to grow. Estrogen binds to and activates the estrogen receptor in these cells. Tamoxifen is metabolized into compounds that also bind to the estrogen receptor but do not activate it. Because of this
competitive antagonismA competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...
, tamoxifen acts like a key broken off in the lock that prevents any other key from being inserted, preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked.
Tamoxifen was discovered by
ICIImperial Chemical Industries was a British chemical company, taken over by AkzoNobel, a Dutch conglomerate, one of the largest chemical producers in the world. In its heyday, ICI was the largest manufacturing company in the British Empire, and commonly regarded as a "bellwether of the British...
Pharmaceuticals (now
AstraZenecaAstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
) and is sold under the trade names
Nolvadex,
Istubal, and
Valodex. However, the drug, even before its patent expiration, was and still is widely referred to by its generic name "tamoxifen."
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. Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the
FDAThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer.
Comparative studies
In 2006, the large STAR clinical study concluded that
raloxifeneRaloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast...
is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36% fewer
uterine cancerThe term uterine cancer may refer to any of several different types of cancer which occur in the uterus, namely:*Uterine sarcomas: sarcomas of the myometrium, or muscular layer of the uterus, are most commonly leiomyosarcomas.*Endometrial cancer:...
s and 29% fewer blood clots in women taking raloxifene than in women taking tamoxifen, although the difference is not statistically significant.
In 2005, the
ATACATAC may refer to:* Asbestos Testing and Consultancy Association, a UK trade association* Atac Supermarket* Lakehead University's Advanced Technology and Academic Centre which opened in 2004* ATAC, the transit system in Rome, Italy...
trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received
anastrozoleAnastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...
(Arimidex) had significantly better results than the tamoxifen group in measures like disease free survival, but no overall mortality benefit. Data from the trial suggest that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is
estrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) positive. Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to anastrozole.
Infertility
Tamoxifen is used to treat infertility in women with
anovulatoryThe anovulatory cycle is a menstrual cycle characterized by varying degrees of menstrual intervals and the absence of ovulation and a luteal phase...
disorders. A dose of 10–40 mg per day is administered in days 3–7 of a woman's cycle. In addition, a rare condition occasionally treated with tamoxifen is
retroperitoneal fibrosisRetroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract and various other structures. It may present with lower back pain, renal failure, hypertension, deep...
.
Gynecomastia
Tamoxifen is used to prevent estrogen related
gynecomastiaGynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
, resulting from elevated estrogenic levels. It is taken as a preventative measure in small doses, or used at the onset of any symptoms e.g. nipple soreness/sensitivity. Other drugs are taken for the similar purposeses such as clomiphene citrate and the anti-aromatase drugs which are used in order to try to avoid the hormone related adverse effects.
Tamoxifen is also sometimes used to treat or prevent gynecomastia in
sex offenderA sex offender is a person who has committed a sex crime. What constitutes a sex crime differs by culture and by legal jurisdiction. Most jurisdictions compile their laws into sections such as traffic, assault, sexual, etc. The majority of convicted sex offenders have convictions for crimes of a...
s undergoing temporary
chemical castrationChemical castration is the administration of medication designed to reduce libido and sexual activity, usually in the hope of preventing rapists, child molesters and other sex offenders from repeating their crimes...
.
Bipolar disorder
Tamoxifen has been shown to be effective in the treatment of
maniaMania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
in patients with
bipolar disorderBipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
by blocking
protein kinase CProtein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC), an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that regulates
neuronA neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
activity in the
brainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Researchers believe PKC is over-active during the mania in bipolar patients.
Angiogenesis and cancer
Tamoxifen is one of three drugs in an
anti-angiogeneticAn angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels . Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet....
protocol developed by
Dr. Judah FolkmanMoses Judah Folkman was an American medical scientist best known for his research on tumor angiogenesis, the process by which a tumor attracts blood vessels to nourish itself and sustain its existence...
, a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that
angiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
– 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 inhibitorAn angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels . Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet....
s have been underway since 1992 using myriad 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
celecoxibCelecoxib INN is a sulfa non-steroidal anti-inflammatory drug and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial...
,
doxycyclineDoxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
, and tamoxifen – the treatment subsequently became known as the Navy Protocol. 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
estrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
antagonist properties.
Control of gene expression
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 recombinationCre-Lox recombination is a special type of site-specific recombination developed by Dr. Brian Sauer initially for use in activating gene expression in mammalian cell lines and transgenic mice . Subsequently, the laboratory of Dr...
technique.
Mechanism of action
Tamoxifen competitively binds to
estrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
s 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 sitesCell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
in breast and other tissues. Tamoxifen causes cells to remain in the G
0 and G
1 phases of the
cell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal.
Tamoxifen itself is a
prodrugA prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
and
CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
into active metabolites such as 4-hydroxytamoxifen (see
AfimoxifeneAfimoxifene is a selective estrogen receptor modulator which is the active metabolite of tamoxifen. Afimoxifene is a transdermal gel formulation and is being developed by Ascend Therapeutics, Inc...
) and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor
antagonistA 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 or dampens agonist-mediated responses...
so that transcription of estrogen-responsive genes is inhibited.
Tamoxifen binds to estrogen receptor (ER) which in turn interacts with DNA. The ER/tamoxifen complex recruits other proteins known as
co-repressorsIn molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
to stop genes being switched on by estrogen. Some of these proteins include
NCoRThe nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene....
and
SMRTThe nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target...
. Tamoxifen function can be regulated by a number of different variables including growth factors. Tamoxifen needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers. Tamoxifen seems to require a protein
PAX2Paired box gene 2, also known as PAX2 is a protein which in humans is encoded by the PAX2 gene.-Function:PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding...
for its full anticancer effect. In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative
ERBB2HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.
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.
Bone
A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an estrogen receptor
agonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
(i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents
osteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. 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 led to the formulation of the concept of
selective estrogen receptor modulatorSelective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s (SERMs). In contrast tamoxifen appears to be associated with bone loss in premenopausal women who continue to menstruate after adjuvant chemotherapy.
Endometrial cancer
Tamoxifen is a selective estrogen receptor modulator. Even though it is an
antagonistA 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 or dampens agonist-mediated responses...
in breast tissue it acts as
partial agonistPartial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
on the
endometrium-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
and has been linked to
endometrial cancerEndometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
in some women. Therefore endometrial changes, including cancer, are among tamoxifen's side effects. With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for 5 years.
The
American Cancer SocietyThe American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
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 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.
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. For some women, tamoxifen can cause a rapid increase in
triglycerideA triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
concentration in the blood. In addition there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility. Tamoxifen is also a cause of
fatty liverFatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...
, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.
Central nervous system
Tamoxifen treated breast cancer patients show evidence of reduced
cognitionIn science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
and
semantic memorySemantic memory refers to the memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences. The conscious recollection of factual information and general knowledge about the world is generally thought to be independent of context and personal relevance...
scores. However memory impairment in patients treated with tamoxifen was less severe compared with those treated with
anastrozoleAnastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...
(an
aromatase inhibitorAromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men....
).
A significant number of tamoxifen treated breast cancer patients experience a reduction of
libidoLibido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
.
Premature growth plate fusion
While tamoxifen has been shown to antagonize the actions of estrogen in tissues such as the breast, its effects in other tissues such as bones has not been documented fully. There have been studies done in mice showing tamoxifen mimic the effects of estrogen on bone metabolism and skeletal growth. Thus increasing the possibility of pre-mature bone fusion. This effect would be less of a concern in adults who have stopped growing.
Pharmacogenetics and drug interactions
Patients with variant forms of the gene
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
(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. On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.
Certain
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
variations in breast cancer patients leads to a worse clinical outcome for tamoxifen treatment.
GenotypingGenotyping is the process of determining differences in the genetic make-up of an individual by examining the individual's DNA sequence using biological assays and comparing it to another individual's sequence or a reference sequence. It reveals the alleles an individual has inherited from their...
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 studies suggest that taking the selective serotonin reuptake inhibitors (SSRIs) antidepressants;
paroxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil),
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac), and
sertralineSertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft), can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into the active form; endoxifen. A U.S study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5 percent of women who took only tamoxifen had a recurrence, compared with 16 percent who took either paroxetine, fluoxetine or sertraline; drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120 percent increase in the risk of breast cancer recurrence. Patients taking the SSRIs; Celexa (
citalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
), Lexapro (
escitalopramEscitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
), and Luvox (
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
), did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme. 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.
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 unique 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. Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.
Market
Global sales of tamoxifen in 2001 were $1,024 million.
Since the expiration of the patent in 2002, it is now widely available as a
generic drugA generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
around the world. Barr Labs Inc had challenged the patent (which in 1992 was ruled unenforcable) but later came to an agreement with Zeneca to licence the patent and sell tamoxifen at close to Zeneca's price.
As of 2004, tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.
In the US, 20 mg tamoxifen tablets cost under $20 per month in quantity. In the UK, the NHS pays £1.90 a month (patients receive them either free or for the standard prescription charge of £7.10 in England, £4 in Scotland, £3 in Northern Ireland and free in Wales). In Estonia tamoxifen costs less than $2 for 30 tablets of 20 mg when used for treatment of a neoplasm or lymphangioma. Other countries report similar prices.
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
ICIImperial Chemical Industries was a British chemical company, taken over by AkzoNobel, a Dutch conglomerate, one of the largest chemical producers in the world. In its heyday, ICI was the largest manufacturing company in the British Empire, and commonly regarded as a "bellwether of the British...
Pharmaceuticals. It was there in 1966 that Dora Richardson first synthesised tamoxifen, known then as ICI-46,474.
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. 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.
The first clinical study took place at the
Christie HospitalThe Christie NHS Foundation Trust is located in Withington, Manchester, and is one of the largest cancer treatment centres in Europe. The Christie became a NHS Foundation Trust in April 2007 and is also an international leader in cancer research and development, and home to the Paterson Institute...
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. Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward at the
Queen Elizabeth Hospital, BirminghamThe Queen Elizabeth Hospital Birmingham is an NHS hospital in the Edgbaston area of Birmingham, situated very close to the University of Birmingham. The hospital, which cost £545 million to construct, opened in June 2010 replacing the previous Queen Elizabeth Hospital and Selly Oak Hospital...
. Ward's study showed a more definitive response to the drug at a higher dosage. It appears to have been Walpole again who convinced the company to market tamoxifen for late stage breast cancer in 1973. He was also instrumental in funding
V. Craig JordanVirgil Craig Jordan, OBE is a scientist specializing in drugs for breast cancer treatment and prevention...
to work on tamoxifen. 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. In advanced disease, tamoxifen is now only recognised as effective in
estrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
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. 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.
External links