Tamoxifen

Tamoxifen is an orally active selective estrogen receptor modulator (SERM) which is used in the treatment of breast cancer and is currently the world's largest selling drug for that purpose.

Tamoxifen was discovered by ICI Pharmaceuticals^[1] (now AstraZeneca) 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."

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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.^[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) breast cancer.

At the conclusion of the large STAR clinical study, it was reported in 2006 that raloxifene is equally effective in reducing the incidence of breast cancer, but caused fewer side effects (e.g., endometrial cancer).^[4][5]

The large ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial showed that the group that received anastrozole had significantly better clinical results after five years than the tamoxifen group. The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor positive.^[6]

Other uses

Tamoxifen is used to treat infertility in women with anovulatory disorders. 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.^[8]

In men, tamoxifen is sometimes used to treat gynecomastia which arises for example as a side effect of antiandrogen prostate cancer treatment.^[9] Tamoxifen is also used by bodybuilders to prevent or reduce drug-induced gynecomastia caused by the estrogenic metabolites of anabolic steroids.^[10] Tamoxifen is also sometimes used to treat or prevent gynecomastia in sex offenders undergoing treatment by temporary chemical castration.^[11]

Finally tamoxifen is used as a research tool to trigger tissue selective gene expression in genetically modified animals using the Cre-Lox recombination technique.^[12]

Mechanism

Competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects; nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues; cells accumulate in the G0 and G1 phases; therefore, tamoxifen is cytostatic rather than cytocidal.

Tamoxifen itself is a prodrug, having very little affinity for its target protein, the estrogen receptor. 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).^[13] These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an antagonist so that transcription of estrogen-responsive genes is inhibited.^[14]

Side effects

Tamoxifen is a selective estrogen receptor modulator.^[15] 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.^[16]

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.^[17] Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.^[18]

A significant number of tamoxifen treated breast cancer patients experience a reduction of libido.^[19][20]

A beneficial side effect of tamoxifen is that behaves as an agonist in bone, preventing bone loss by inhibiting osteoclasts, and therefore it prevents osteoporosis. 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).^[21]

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.^[22][23] On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.^[24] Recent studies suggest that taking 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.^[25]

Market

Global sales of tamoxifen in 2001 were $1,024 million.^[26] Since the expiration of the patent, it is now widely available as a generic drug around the world.

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. It was there in 1962 that Dora Richardson first synthesised tamoxifen, known then as ICI-46,474.^[27] 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.^[28] 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,^[29] but nevertheless ICI's development programme came close to termination when it was reviewed in 1972. It appears to have been Walpole again who convinced the company to market tamoxifen for late stage breast cancer in 1973.^[28] He was also instrumental in funding V. Craig Jordan 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.^[30] 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.^[31] 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.^[32]

Patent protection in most of the world ran from around 1965. In 1985, around the time this protection was being lost, the unclear position in the US was resolved, awarding Zeneca, as ICI Pharmaceuticals had now become, 17 years of protection there.^[28]

References