Jump to content

Tamoxifen

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Jrfw51 (talk | contribs) at 11:38, 16 August 2015 (→‎Medical uses: Sclerosing mesenteritis). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Tamoxifen
Clinical data
Trade namesNolvadex, Istubal, Valodex, Genox
AHFS/Drugs.comMonograph
MedlinePlusa682414
Pregnancy
category
  • AU: B3
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding99%
MetabolismHepatic (CYP3A4, 2C9 and 2D6)
Elimination half-life5-7 days [1]
ExcretionFaeces (65%), urine (9%)
Identifiers
  • (Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.031.004 Edit this at Wikidata
Chemical and physical data
FormulaC26H29NO
Molar mass371.515 g/mol
563.638 g/mol (citrate salt) g·mol−1
3D model (JSmol)
  • O(c1ccc(cc1)/C(c2ccccc2)=C(\c3ccccc3)CC)CCN(C)C
  • 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 is an antagonist of the estrogen receptor in breast tissue via its active metabolite, 4-hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, and thus may be characterized as a selective estrogen-receptor modulator. Tamoxifen is the usual endocrine (anti-estrogen) therapy for hormone receptor-positive breast cancer in pre-menopausal women, and is also a standard in post-menopausal women although aromatase inhibitors are also frequently used in that setting.[2]

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 antagonism, 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, blocking cancer cell growth.

Tamoxifen was discovered by pharmaceutical company Imperial Chemical Industries[3] (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, Valodex, and Genox. However, the drug has been widely referred to by its generic name "tamoxifen", even before its patent expiration.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]

Medical uses

Breast cancer

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women.[5] Additionally, it is the most common hormone treatment for male breast cancer.[6] It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease.[7] It has been further approved for the reduction of contralateral (in the opposite breast) cancer. The use of tamoxifen is recommended for 10 years.[8]

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 in women taking raloxifene than in women taking tamoxifen, although the difference is not statistically significant.[9][10][11]

Infertility

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.[12]

Gynecomastia

Tamoxifen is used to prevent estrogen-related gynecomastia, resulting from elevated estrogenic levels. 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 drugs are taken for similar purposes 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 offenders undergoing temporary chemical castration.[13]

Other conditions

Occasionally tamoxifen is used in treatment of the rare conditions of retroperitoneal fibrosis[14] and idiopathic sclerosing mesenteritis.[15]

Mechanism of action

Crystallographic structure of 4-hydroxy-tamoxifen (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (cyan ribbon).[16]

Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen)[17] 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 antagonist so that transcription of estrogen-responsive genes is inhibited.[18]

4-hydroxytamoxifen binds to estrogen receptors (ER), the ER/tamoxifen complex recruits other proteins known as co-repressors and then binds to DNA to modulate gene expression. Some of these proteins include NCoR and SMRT.[19] Tamoxifen function can be regulated by a number of different variables including growth factors.[20] Tamoxifen needs to block growth factor proteins such as ErbB2/HER2[21] because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.[22] Tamoxifen seems to require a protein PAX2 for its full anticancer effect.[21][23] In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative ERBB2 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.[21][24]

4-Hydroxytamoxifen binds to estrogen receptors 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 binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal.

The scientific literature is complex with respect to the activity of tamoxifen, and care should be taken to establish whether tamoxifen, or the 4-hydroxy metabolite was used, especially in in vitro assays.

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.[25] Some cases of lower-limb lymphedema have been associated with the use of tamoxifen, due to the blood clots and deep vein thrombosis (DVT) that can be caused by this medication. Resolution of the blood clots or DVT is needed before lymphedema treatment can be initiated.

Bone

A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an estrogen receptor agonist (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis.[26][27] 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 modulators (SERMs).[28] In contrast tamoxifen appears to be associated with bone loss in premenopausal women who continue to menstruate after adjuvant chemotherapy.[29]

Endometrial cancer

Tamoxifen is a selective estrogen receptor modulator.[30] 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.[31] With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for 5 years.[32]

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.[33] 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.[34] For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood.[citation needed] In addition there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility.[35] Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.[36]

Central nervous system

Tamoxifen-treated breast cancer patients show evidence of reduced cognition,[37] a major side effect of tamoxifen, and semantic memory scores.[38] However memory impairment in patients treated with tamoxifen was less severe compared with those treated with anastrozole (an aromatase inhibitor).[39]

A significant number of tamoxifen treated breast cancer patients experience a reduction of libido.[40][41]

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.[42]

Pharmacogenetics and drug interactions

Nolvadex (tamoxifen) 20 mg tablets

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.[43][44] On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.[45]

Certain CYP2D6 variations in breast cancer patients leads to a worse clinical outcome for tamoxifen treatment.[46] 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 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 the active form, endoxifen.[47] 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 (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.[48] 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.[49]

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.[50] Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.[51]

Market

Global sales of tamoxifen in 2001 were $1,024 million.[52] Since the expiration of the patent in 2002, it is now 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.[53]

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. It was there in 1966 that Dora Richardson first synthesised tamoxifen, known then as ICI-46,474.[54] 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.[55] 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.[3]

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 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 celecoxib, doxycycline, and tamoxifen – the treatment subsequently became known as the Navy Protocol.[56] 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 receptor antagonist properties.[57]

The first clinical study took place at the Christie Hospital in 1971, and showed a convincing effect in advanced breast cancer,[58] 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 [59] 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.[55] 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.[60] 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.

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.[61] 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.[62] 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 [63] A clinical strategy was described [64] 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.

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.[65]

Research

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.[66]

The drug has also been studied in several additional indications.

Riedel's thyroiditis

Tamoxifen has been proposed as part of a treatment plan for Riedel's thyroiditis.[67]

Bipolar disorder

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. Researchers believe PKC is over-active during the mania in bipolar patients.[68][69]

McCune-Albright syndrome

In McCune-Albright syndrome (MAS) tamoxifen has been used to treat premature puberty and the consequences of premature puberty. Tamoxifen has been seen to decrease rapid bone maturation which is the result of excessive estrogen and alter predicted adult height (PAH).[70][71][72] The same effects have also been seen in short pubertal boys.[73]

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 IGF-I levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats, leading the researches to express concern giving tamoxifen to growing individuals.[74][75]

See also

References

  1. ^ http://www.drugs.com/pro/tamoxifen.html
  2. ^ The BIG 1-98 Collaborative Group (2009). "Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer". N Engl J Med. 361: 766–776. doi:10.1056/nejmoa0810818.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  3. ^ a b Jordan VC (2006). "Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer". Br J Pharmacol. 147 (Suppl 1): S269–76. doi:10.1038/sj.bjp.0706399. PMC 1760730. PMID 16402113.
  4. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  5. ^ Jordan VC (1993). "Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer". Br J Pharmacol. 110 (2): 507–17. doi:10.1111/j.1476-5381.1993.tb13840.x. PMC 2175926. PMID 8242225.
  6. ^ "Breast cancer in men". CancerHelp UK. Cancer Research UK. 2007-09-28. Retrieved 2009-03-22. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  7. ^ Center for Drug Evaluation and Research (July 7, 2005). "Tamoxifen Information: reducing the incidence of breast cancer in women at high risk". U.S. Food and Drug Administration. Archived from the original on June 19, 2007. Retrieved July 3, 2007.
  8. ^ Burstein, HJ; Temin, S; Anderson, H; Buchholz, TA; Davidson, NE; Gelmon, KE; Giordano, SH; Hudis, CA; Rowden, D; Solky, AJ; Stearns, V; Winer, EP; Griggs, JJ (May 27, 2014). "Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update". Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 32 (21): 2255–69. doi:10.1200/JCO.2013.54.2258. PMID 24868023.
  9. ^ National Cancer Institute (2006-04-26). "Study of Tamoxifen and Raloxifene (STAR) Trial". U.S. National Institutes of Health. Retrieved July 3, 2007.
  10. ^ University of Pittsburgh. "STAR Study of Tamoxifen and Raloxifen". Archived from the original on June 11, 2007. Retrieved July 3, 2007.
  11. ^ Dr Susan Love (April 22, 2006). "Study Finds New Use for Raloxifene: Reducing Breast Cancer in High-Risk Postmenopausal Women". Retrieved March 19, 2009.
  12. ^ Steiner AZ, Terplan M, Paulson RJ (2005). "Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis". Hum. Reprod. 20 (6): 1511–5. doi:10.1093/humrep/deh840. PMID 15845599.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Sample, Ian (2007-06-13). "Q&A: Chemical castration". Guardian Unlimited. Retrieved 2007-09-10.
  14. ^ van Bommel EF, Hendriksz TR, Huiskes AW, Zeegers AG (2006). "Brief communication: tamoxifen therapy for nonmalignant retroperitoneal fibrosis". Annals of Internal Medicine. 144 (2): 101–6. doi:10.7326/0003-4819-144-2-200601170-00007. PMID 16418409.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Akram S, Pardi DS, Schaffner JA, Smyrk TC (2007). "Sclerosing mesenteritis: clinical features, treatment, and outcome in ninety-two patients". Clin Gastroenterol Hepatol. 5 (5): 589–96. doi:10.1016/j.cgh.2007.02.032. PMID 17478346.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ PDB: 3ERT​; Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (December 1998). "The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen". Cell. 95 (7): 927–37. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Desta Z, Ward BA, Soukhova NV, Flockhart DA (2004). "Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6". J Pharmacol Exp Ther. 310 (3): 1062–75. doi:10.1124/jpet.104.065607. PMID 15159443.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Wang DY, Fulthorpe R, Liss SN, Edwards EA (2004). "Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1". Mol Endocrinol. 18 (2): 402–11. doi:10.1210/me.2003-0202. PMID 14605097.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M (December 2000). "Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription". Cell. 103 (6): 843–52. doi:10.1016/S0092-8674(00)00188-4. PMID 11136970.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R (February 2008). "Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function". Cancer Res. 68 (3): 826–33. doi:10.1158/0008-5472.CAN-07-2707. PMID 18245484.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ a b c Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS (December 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature. 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "Hurtado_2008" was defined multiple times with different content (see the help page).
  22. ^ Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM, Schiff R (March 2003). "Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer". J. Natl. Cancer Inst. 95 (5): 353–61. doi:10.1093/jnci/95.5.353. PMID 12618500.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ "New Mechanism Predicts Tamoxifen Response: PAX2 gene implicated in tamoxifen-induced inhibition of ERBB2/HER2-mediated tumor growth". www.modernmedicine.com. 2008-11-13. Retrieved 2008-11-14. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  24. ^ "Study sheds new light on tamoxifen resistance". News. CORDIS News. Retrieved 2008-11-14. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  25. ^ OncoGenetics.Org (September 2009). "Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects". OncoGenetics.Org. Retrieved 2009-09-14. [dead link]
  26. ^ Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007). "Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts". Cell. 130 (5): 811–23. doi:10.1016/j.cell.2007.07.025. PMID 17803905.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, Brown M (2008). "Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival". EMBO J. 27 (3): 535–45. doi:10.1038/sj.emboj.7601984. PMC 2241656. PMID 18219273.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Mincey BA, Moraghan TJ, Perez EA (2000). "Prevention and treatment of osteoporosis in women with breast cancer". Mayo Clin Proc. 75 (8): 821–9. doi:10.4065/75.8.821. PMID 10943237.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Vehmanen L, Elomaa I, Blomqvist C, Saarto T (February 2006). "Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status". J. Clin. Oncol. 24 (4): 675–80. doi:10.1200/JCO.2005.02.3515. PMID 16446340.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ Gallo MA, Kaufman D (1997). "Antagonistic and agonistic effects of tamoxifen: significance in human cancer". Semin Oncol. 24 (Suppl 1): S1–71–S1–80. PMID 9045319.
  31. ^ Grilli S (2006). "Tamoxifen (TAM): the dispute goes on" (PDF). Ann Ist Super Sanita. 42 (2): 170–3. PMID 17033137.
  32. ^ "Tamoxifen for Breast Cancer & Side Effects". Health and Life.
  33. ^ "Known and Probable Carcinogens". American Cancer Society. 2006-02-03. Retrieved 2008-03-21. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  34. ^ Esteva FJ, Hortobagyi GN (June 2006). "Comparative assessment of lipid effects of endocrine therapy for breast cancer: implications for cardiovascular disease prevention in postmenopausal women". Breast (Edinburgh, Scotland). 15 (3): 301–12. doi:10.1016/j.breast.2005.08.033. PMID 16230014.
  35. ^ Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, Salvioni A, Travaglini R, Oliviero P, D'Aiuto G, Gulisano M, Gucciardo G, del Turco MR, Pizzichetta MA, Conforti S, Bonanni B, Boyle P, Veronesi U (2005). "Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial". Circulation. 111 (5): 650–6. doi:10.1161/01.CIR.0000154545.84124.AC. PMID 15699284.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  36. ^ Khalid A Osman; Meissa M Osman; Mohamed H Ahmed (2007). "Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going?". Expert opinion on drug safety. 6 (1): 1–4. doi:10.1517/14740338.6.1.1. PMID 17181445.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  37. ^ Paganini-Hill A, Clark LJ (November 2000). "Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen". Breast Cancer Research and Treatment. 64 (2): 165–76. doi:10.1023/A:1006426132338. PMID 11194452.
  38. ^ Eberling JL, Wu C, Tong-Turnbeaugh R, Jagust WJ (January 2004). "Estrogen- and tamoxifen-associated effects on brain structure and function". NeuroImage. 21 (1): 364–71. doi:10.1016/j.neuroimage.2003.08.037. PMID 14741674.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  39. ^ Bender CM, Sereika SM, Brufsky AM, Ryan CM, Vogel VG, Rastogi P, Cohen SM, Casillo FE, Berga SL (2007). "Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer". Menopause. 14 (6): 995–8. doi:10.1097/gme.0b013e318148b28b. PMC 2831410. PMID 17898668.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ Mortimer JE, Boucher L, Baty J, Knapp DL, Ryan E, Rowland JH (1999). "Effect of tamoxifen on sexual functioning in patients with breast cancer" (abstract). J. Clin. Oncol. 17 (5): 1488–92. PMID 10334535.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  41. ^ Cella D, Fallowfield L, Barker P, Cuzick J, Locker G, Howell A (2006). "Quality of life of post-menopausal women in the ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer". Breast Cancer Res. Treat. 100 (3): 273–84. doi:10.1007/s10549-006-9260-6. PMID 16944295.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ Karimian E, Chagin AS, Gjerde J, Heino T, Lien EA, Ohlsson C, Sävendahl L (August 2008). "Tamoxifen impairs both longitudinal and cortical bone growth in young male rats". J. Bone Miner. Res. 23 (8): 1267–77. doi:10.1359/jbmr.080319. PMID 18348701.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  43. ^ Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN (2005). "Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes". J Clin Oncol. 23 (36): 9312–8. doi:10.1200/JCO.2005.03.3266. PMID 16361630.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  44. ^ Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD (2007). "CYP2D6 polymorphisms and the impact on tamoxifen therapy". J Pharm Sci. 96 (9): 2224–31. doi:10.1002/jps.20892. PMID 17518364.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  45. ^ Information about CYP2D6 and tamoxifen from DNADirect's website
  46. ^ Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Boländer J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H (October 2009). "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen". JAMA. 302 (13): 1429–36. doi:10.1001/jama.2009.1420. PMID 19809024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  47. ^ Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA (2005). "CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment". J Natl Cancer Inst. 97 (1): 30–9. doi:10.1093/jnci/dji005. PMID 15632378.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  48. ^ Staff Reports (Summer 2009). "ASCO Updates: Antidepressants Reduce the Effectiveness of Tamoxifen". CURE (Cancer Updates, Research and Education).
  49. ^ BMJ 2010;340:c693
  50. ^ Information about Tamoxitest and how DNA testing can help in the selection of the best treatment methodology from Genelex's website
  51. ^ Criscitiello C, Fumagalli D, Saini KS, Loi S (2011). "Tamoxifen in early-stage estrogen receptor-positive breast cancer: overview of clinical use and molecular biomarkers for patient selection". Onco Targets Ther. 4: 1–11. doi:10.2147/OTT.S10155. PMC 3084302. PMID 21552410.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  52. ^ "Cancer the generic impact". BioPortfolio Limited. Archived from the original on 2008-05-16. Retrieved 2008-11-14. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  53. ^ Vose B. "AstraZenecain Cancer: Slide #15:" (PDF). AstraZeneca Annual Business Review. www.astrazeneca.com. Retrieved 2009-03-28. 2004 tamoxifen market share: 70% Source: IMS HEALTH, IMS MIDAS Monthly. July 2004. Aromatase Inhibitors + Tamoxifen {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  54. ^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 472 pages. ISBN 0-471-89979-8.
  55. ^ a b Jordan VC (2003). "Tamoxifen: a most unlikely pioneering medicine". Nature Reviews Drug Discovery. 2 (3): 205–13. doi:10.1038/nrd1031. PMID 12612646.
  56. ^ Kirk E (2002-07-24). "Dog's tale of survival opens door in cancer research". Health and Behavior. USA Today. Retrieved 2008-06-24. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  57. ^ Blackwell KL, Haroon ZA, Shan S, Saito W, Broadwater G, Greenberg CS, Dewhirst MW (November 2000). "Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models". Clin. Cancer Res. 6 (11): 4359–64. PMID 11106254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  58. ^ Cole MP, Jones CT, Todd ID (1971). "A new anti-estrogenic agent in late breast cancer. An early clinical appraisal of ICI46474". Br. J. Cancer. 25 (2): 270–5. doi:10.1038/bjc.1971.33. PMC 2008453. PMID 5115829.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  59. ^ Ward HW (January 1973). "Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels". Br Med J. 1 (5844): 13–4. doi:10.1136/bmj.1.5844.13. PMC 1588574. PMID 4567104.
  60. ^ http://www.yorkshirepost.co.uk/news/features/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838
  61. ^ Baum M, Brinkley DM, Dossett JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Lea JC, Richards D, Ellis SH (1983). "Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer". Lancet. 2 (8347): 450. doi:10.1016/S0140-6736(83)90406-3. PMID 6135926.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  62. ^ Furr BJ, Jordan VC (1984). "The pharmacology and clinical uses of tamoxifen". Pharmacol. Ther. 25 (2): 127–205. doi:10.1016/0163-7258(84)90043-3. PMID 6438654.
  63. ^ Jordan, VC (2001). "Selective Receptor Modulation: a Personal Perspective". Cancer Research. 61: 5683–5687.
  64. ^ Lerner; Jordan, VC (1990). "Development of antiestrogens and their use in breast cancer: eighth Bruce Cain Memorial Award Lecture". Cancer Research. 50: 4177–4189.
  65. ^ Early Breast Cancer Trialists' Collaborative Group (1998). "Tamoxifen for early breast cancer: an overview of the randomised trials". Lancet. 351 (9114): 1451–67. doi:10.1016/S0140-6736(97)11423-4. PMID 9605801.
  66. ^ Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P (1996). "Ligand-activated site-specific recombination in mice". Proc. Natl. Acad. Sci. U.S.A. 93 (20): 10887–90. doi:10.1073/pnas.93.20.10887. PMC 38252. PMID 8855277.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  67. ^ Dabelic N, Jukic T, Labar Z, Novosel SA, Matesa N, Kusic Z (April 2003). "Riedel's thyroiditis treated with tamoxifen" (PDF). Croat. Med. J. 44 (2): 239–41. PMID 12698518.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  68. ^ "Manic Phase of Bipolar Disorder Benefits from Breast Cancer Medication". National Institute of Mental Health (NIMH). September 12, 2007. Retrieved 2008-03-10.
  69. ^ Yildiz A, Guleryuz S, Ankerst DP, Ongür D, Renshaw PF (2008). "Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen". Arch. Gen. Psychiatry. 65 (3): 255–63. doi:10.1001/archgenpsychiatry.2007.43. PMID 18316672.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  70. ^ "Tamoxifen treatment of pr... [J Pediatr Endocrinol Metab. 1999 Sep-Oct] - PubMed - NCBI". Ncbi.nlm.nih.gov. 2012-10-19. Retrieved 2013-01-06.
  71. ^ "Tamoxifen treatment for precocious puberty in McCu... [J Pediatr. 2003] - PubMed - NCBI". Ncbi.nlm.nih.gov. 2012-10-19. Retrieved 2013-01-06.
  72. ^ "Tamoxifen improved final height p... [J Pediatr Endocrinol Metab. 2006] - PubMed - NCBI". Ncbi.nlm.nih.gov. 2012-10-19. Retrieved 2013-01-06.
  73. ^ "The use of tamoxifen to improve height potential ... [Pediatrics. 2005] - PubMed - NCBI". Ncbi.nlm.nih.gov. 2012-12-12. Retrieved 2013-01-06.
  74. ^ "Tamoxifen induces permanent growth arrest through selec... [Bone. 2007] - PubMed - NCBI". Ncbi.nlm.nih.gov. 2012-10-19. Retrieved 2013-01-06.
  75. ^ "Tamoxifen impairs both longitudinal and cor... [J Bone Miner Res. 2008] - PubMed - NCBI". Ncbi.nlm.nih.gov. 2012-10-19. Retrieved 2013-01-06.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Tamoxifen&oldid=676348256"