Description
In 1966, ICI Pharmaceuticals (now AstraZeneca) first synthesized
tamoxifen in the hope of developing a morning-after
contraceptive pill. The UK patent for this compound was in
place in 1962, whereas the US patent was repeatedly denied
until the 1980s. Tamoxifen was approved for a fertility treatment
but it was not proven as useful in regulating human
contraception. Even though there was a link between estrogen
and breast cancer, developing a cancer treatment was not
a priority at the time. In 1971, the first clinical study showed
a convincing effect of tamoxifen in treating advanced breast
cancer. From 1971 to 1977, this drug was neither clinically nor
financially remarkable. In 1980s, however, publications first
showed that tamoxifen, in addition to chemotherapy,
improved survival for patients with early stage breast cancer. In
1998, the meta-analysis by the Oxford-based Early Breast
Cancer Trialists’ Collaborative Group showed that tamoxifen
did indeed save lives in early breast cancer. In 2001, tamoxifen
sales were over $1.024 billion. Since the expiration of the
patent in 2002, it is now widely available as a generic drug. By
2004, tamoxifen was the best selling hormonal drug for the
treatment of breast cancer.
Chemical Properties
White Crystalline Solid
Originator
Nolvadex,I.C.I.,UK,1973
Definition
ChEBI: Tamoxifen is a tertiary amino compound and a stilbenoid. It has a role as an estrogen receptor antagonist, a bone density conservation agent, an estrogen receptor modulator, an estrogen antagonist, an angiogenesis inhibitor, an EC 2.7.11.13 (protein kinase C) inhibitor, an EC 1.2.3.1 (aldehyde oxidase) inhibitor and an antineoplastic agent. It derives from a hydride of a stilbene.
Indications
Tamoxifen (Nolvadex) is a synthetic antiestrogen used in the treatment of breast cancer.
Normally, estrogens act by binding to a cytoplasmic protein
receptor, and the resulting hormone–receptor complex
is then translocated into the nucleus, where it induces
the synthesis of ribosomal RNA (rRNA) and messenger
RNA (mRNA) at specific sites on the DNA of the target
cell. Tamoxifen also avidly binds to estrogen receptors and
competes with endogenous estrogens for these critical sites.
The drug–receptor complex has little or no estrogen agonist
activity.Tamoxifen directly inhibits growth of human
breast cancer cells that contain estrogen receptors but has
little effect on cells without such receptors.
Indications
Tamoxifen is a partial estrogen agonist in breast and
thus is used as a treatment and chemopreventative for
breast cancer. Tamoxifen is a full agonist in bone and
endometrium, and prolonged use of tamoxifen leads to
a fourfold to fivefold increase in the incidence of endometrial
cancer. See Chapter 56 for a detailed discussion
of the use of tamoxifen in breast cancer.
Manufacturing Process
To the Grignard reagent prepared from 0.59 part of magnesium, 3.95 parts of
bromobenzene and 50 parts of ether there are added 7.5 parts of 4-(β-
dimethylaminoethoxy)-α-ethyldesoxybenzoin in 50 parts of ether. After
heating under reflux for 3 hours, the mixture is decomposed by the addition
of a solution of 60 parts of ammonium chloride in 150 parts of water. The
mixture is separated, and the ethereal layer is dried with anhydrous sodium
sulfate, and the ether is evaporated. The residue is crystallized from
methanol. There is thus obtained 1-(p-β-dimethylaminoethoxyphenyl)-1,2-
diphenylbutan-1-ol, melting point 120°C to 121°C.
2.15 parts of 1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbutan-1-ol, 25
parts of ethanol and 0.8 part of 10 N hydrochloric acid are heated together
under reflux for 3 hours. The solution is evaporated to dryness under reduced
pressure and the residue is extracted with methylene chloride. The methylene
chloride extract is decolorized with charcoal and then evaporated to dryness.
The residue is dissolved in 100 parts of water, the solution is basified by the
addition of sodium hydroxide solution, and the precipitated solid is extracted
three times, each time with 50 parts of ether. The combined extracts are dried with anhydrous sodium sulfate and then evaporated. The residue is
crystallized from aqueous methanol, and there is thus obtained 1-(p-β-
dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, melting point 95°C to
96°C.
Brand name
Nolvadex (AstraZeneca); Soltamox (Savient).
Therapeutic Function
Antiestrogen, Antineoplastic
World Health Organization (WHO)
Tamoxifen is an anti-estrogen agent used mainly to treat breast
cancer. Tamoxifen is listed in the WHO Model List of Essential Drugs.
General Description
Tamoxifen is a selective estrogen response modifier (SERM), protein kinase C inhibitor and anti-angiogenetic factor. Tamoxifen is a prodrug that is metabolized to active metabolites 4-hydroxytamoxifen (4-OHT) and endoxifen by cytochrome P450 isoforms CYP2D6 and CYP3A4. In breast cancer, the gene repressor activity of tamoxifen against ERBB2 is dependent upon PAX2. Blocks estradiol-stimulated VEGF production in breast tumor cells.
Biochem/physiol Actions
Protein kinase C inhibitor. Induces apoptosis in human malignant glioma cell lines. Tamoxifen and its metabolite 4-hydroxytamoxifen are selective estrogen response modifiers (SERMs) that act as estrogen antagonists in mammary gland. Blocks estradiol-stimulated VEGF production in breast tumor cells.
Mechanism of action
Tamoxifen is slowly absorbed, and maximum serum
levels are achieved 4 to 7 hours after oral administration.
The drug is concentrated in estrogen target tissues, such
as the ovaries, uterus, vaginal epithelium, and breasts.
Hydroxylation and glucuronidation of the aromatic
rings are the major pathways of metabolism; excretion
occurs primarily in the feces.
Clinical Use
Tamoxifen is a SERM that is used as an antiestrogen in the treatment of estrogen-dependent breas Tcancer following prim ary treatment (c hemotherapy and/or surgery).
Synthesis
Tamoxifen, (Z)-2-[p-(1,2-diphenyl-1-butenyl)phenoxy]N,N-dimethylethylamine
(28.2.8), is synthesized from |á-ethyldezoxybenzoin. Interaction of this with 4-
methoxyphenylmagnesium bromide gives the corresponding carbinol (28.2.5). Its
dehydration in acidic conditions gives a derivative of stilbene (28.2.6), and further heating
of which with quinidine hydrochloride as a demethylating agent gives 2-[p-(1,2-diphenyl-
1-butenyl)phenol] (28.2.7). The phenolic hydroxyl is further alkylated by dimethylaminoethylchoride
using sodium ethoxide as a base, which forms a mixture of E and Z
isomers of the final product. The desired Z isomer, tamoxifen (28.2.8) is isolated by fractional
crystallization from petroleum ester.
in vitro
ic50s for growth inhibition ranged from 5.5–10 μm, and were not affected by estrogen. tamoxifen-mediated growth inhibition was not associated with induction of tgf-β. however, tamoxifen treatment was associated with inhibition of pkc, which was followed by induction of p21waf1/cip1, rb dephosphorylation, and g1/s phase cell cycle arrest [1].
in vivo
the tumor cell kinetics of mcf-7 human breast carcinoma xenografts grown in nude mice can be significantly altered by hormonal manipu lation. tamoxifen treatment or e2 deprivation resulted in an approximate doubling of the tpol and an approximately 40% reduction in labeling index as compared to e2-stimulated tumors. an increase in cell loss rate was calculated for both tamoxifen treatment and e2 deprivation [2].
Carcinogenicity
Tamoxifen is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Metabolism
Tamoxifen is extensively metabolised by cytochrome
P450 isoenzymes, to active metabolites that include
N-desmethyltamoxifen, 4-hydroxytamoxifen, and
4-hydroxy-N-desmethyltamoxifen (endoxifen).
Metabolism is by hydroxylation, demethylation and
conjugation.
In-vitro studies suggest that both N-desmethyltamoxifen
and 4-hydroxytamoxifen are further metabolised to
endoxifen.
Elimination occurs, chiefly as conjugates with practically
no unchanged drug, principally through the faeces and to
a lesser extent through the kidneys.
References
[1] rohlff c, blagosklonny mv, kyle e, kesari a, kim iy, zelner dj, hakim f, trepel j, bergan rc. prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase c and induction of p21(waf1/cip1). prostate. 1998 sep 15;37(1):51-9.
[2] jann n. sarkaria, david f. c. gibson, v. craig jordan, john f. fowler, mary j. lindstrom, andr. timothy mulcahy. tamoxifen-induced increase in the potential doubling time of mcf-7 xenografts as determined by bromodeoxyuridine labeling and flow cytometry. cancer research 5.1. 4413-1417, september 15, 1993.
[3] osborne ck. tamoxifen in the treatment of breast cancer. n engl j med. 1998 nov 26;339(22):1609-18.
