Carcinogenesis, Vol. 20, No. 7, 1153-1160,
July 1999
© 1999 Oxford University Press
The tamoxifen dilemma
Ian N.H. White
MRC Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK
 |
Abstract
|
|---|
The anti-oestrogen tamoxifen is widely used for adjuvant therapy
in the treatment of women with breast cancer and has a low incidence
of serious side-effects. It could also play a role as a breast
cancer chemopreventive agent. However, epidemiological studies
in both tamoxifen-treated breast cancer patients and in healthy
women have shown that treatment results in a small increase
in the incidence of endometrial cancers. While the use of tamoxifen
in breast cancer patients is clearly justified, the situation
for its use as a chemopreventive agent in healthy women is not
so clear cut. Reasons for caution come from studies in rats
that show that tamoxifen is a genotoxic mutagenic liver carcinogen.
Initiation of tumours in the rat is the result of metabolic
activation of tamoxifen by CYP enzymes to an electrophile(s)
that binds irreversibly to DNA. This is not related to the oestrogen
receptor status of the tissue. The extent of DNA damage, detected
by
32P-post-labelling or accelerator mass spectrometry, is dependent
both on the dose and the length of exposure. Studies have been
carried out to see if such binding occurs in the uterine endometrium
from tamoxifen-treated women. Results are presently inconclusive,
but if such irreversible DNA binding occurs, it is at very low
levels. Based on a mechanistic understanding of tamoxifen-induced
liver carcinogenesis in the rat, it seems that in humans hepatic
DNA damage will be close to the limit of detection by
32P-post-labelling
and liver cancer will not be a significant carcinogenic risk.
We cannot be certain of the mode of action of tamoxifen that
results in the increase in endometrial cancers in treated women
but it seems unlikely that this will be associated with a classical
genotoxic mechanism.
Abbreviations: ER, oestrogen receptor; ICI 182 780, 7
-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17ß-diol; raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone; SERMS, selective oestrogen receptor modulators; tamoxifen, (Z)-1-[4-[(dimethylamino)ethoxy]phenyl]-1,1-diphenyl-1-butene; toremifene, (Z)-4-chloro-1-[4-[2(N,N-dimethylamino)ethoxy]phenyl]-1-butene.
|
Introduction
|
|---|
The anti-oestrogen (
Z)-1-[4-[(dimethylamino)ethoxy]phenyl]-1,1-diphenyl-1-butene
(tamoxifen) (Figure 1
) is a drug widely used for adjuvant therapy
in the treatment of women with oestrogen receptor (ER)-positive
breast tumours and has a low incidence of serious side-effects.
Since 1971 it has been used successfully to treat many millions
of women (
1,
2). Treatment results in an increase in disease-free
survival (
3) and a decrease in recurrence rates of breast cancer
(
2). Retrospective reviews of adjuvant therapy studies show
an ~39% reduction in the incidence of contralateral primary
breast carcinoma in tamoxifen-treated women, indicating that
this drug could play a role as a breast cancer chemopreventive
agent (
4,
5). A planned 5 year trial involving >13 000 healthy
women who were at high risk of developing breast cancer (Breast
Cancer Prevention Trial BCPT P1) in the USA was stopped 14 months
early when results showed that tamoxifen treatment led to a
49% reduction in breast cancer (
6). Two smaller studies carried
out in the UK and in Italy failed to show such protection (
7,
8).
Many factors are responsible for the high incidence of breast
cancer in the developed world, including the environment and
diet. Some familial tendency to develop breast cancer is associated
with susceptibility genes, including
BRCA1 and
BRCA2. Aberrant
expression of these genes accounts for only ~6% of the total
incidence of breast cancers (
9) and is not known to be associated
with endometrial cancer.
|
Carcinogenic risk in women associated with tamoxifen therapy
|
|---|
Epidemiological data indicated that in women taking tamoxifen
there was an increased risk of endometrial cancer (
10,
11). In
the studies of Rutqvist
et al. (
11), involving >4900 Scandinavian
breast cancer patients, there was a 4-fold increase in endometrial
cancers during a follow-up time of 8–9 years. In the National
Surgical Adjuvant Breast and Bowel Program (NSABP B-14) in the
USA involving 2823 patients with node-negative, ER-positive
breast cancers, tamoxifen treatment over a 5 year follow-up
period resulted in a relative risk of 7.5 over the placebo group
(
3). A case–control study in the USA of the Surveillance,
Epidemiology and End Results (SEER) also showed an ~1.6-fold
increase in the incidence of uterine tumours in the treated
group receiving 20 mg/day tamoxifen (
12). In healthy women participating
in the Breast Cancer Prevention Trial (BCPT P1) that were treated
with tamoxifen, there was a 1.35- to 4.97-fold increased risk
of endometrial cancers. In reviewing these data, the IARC concluded
that there was sufficient evidence in humans of tamoxifen increasing
the risk for endometrial cancer (
4). The increased risk occurred
predominantly in women aged 50 years or older (
6). There is
a comparatively rapid onset of these tumours within 2–5
years of the start of treatment, suggesting that the mechanism
of action may be via an oestrogen agonist effect rather than
as a classical chemical carcinogen. There is some evidence (albeit
weak) for an increase in gastrointestinal tract cancers in breast
cancer patients (
11). This has not been confirmed by other studies
(reviewed in ref. 4). It has been pointed out by Jordan (
13)
that in the order of 30 lives are saved by tamoxifen treatment
to each lost through its side-effects. In the case of breast
cancer patients, this represents a clear therapeutic advantage.
|
Carcinogenicity of tamoxifen in rodents
|
|---|
One of the main causes for concern with respect to the chemopreventive
use of tamoxifen in healthy women was the finding, initially
reported by Greaves
et al. (
14), that lifetime exposure of rats
to tamoxifen resulted in an increase in the incidence of hepatocellular
tumours. This did not appear to occur via an ER-based mechanism.
The incidence of tumours was similar in male and female animals
and showed a dose-dependent increase over the range 5–35
mg/kg/day. This is 10- to 100-fold higher than the dose used
in humans. A number of studies in many strains of rat has confirmed
this original finding (
14–
17). In contrast, mice were resistant
(
18,
19). It was established that tamoxifen given as a single
dose was not able to act as a tumour initiator (
20), although
it could promote liver cancer initiated by
N-nitrosodiethylamine
(
21). In the rat, lifetime exposure is not necessary for the
induction of liver tumours. Following exposure to dietary tamoxifen
(equivalent to ~40 mg/kg/day) for only 3 months, after discontinuation
of treatment five of 15 rats developed liver tumours after 20
months without any subsequent promotion (
20). Promotion of tumour
development with phenobarbitone after discontinuation of tamoxifen
resulted in earlier formation of liver carcinomas and, after
20 months, 12 of 14 animals had liver tumours (
20). Of the tamoxifen-induced
adenomas and carcinomas examined, 90% showed depleted nuclear
ER expression. Preneoplastic foci also showed a progressive
higher incidence of ER depletion as they increased in size,
indicating that this effect was associated with promotion of
foci to tumours (
22). It is not presently clear if this down-regulation
of the ER is causally related to the promotion process.
A long-term dietary tamoxifen study using three inbred mouse strains has been carried out in an attempt to establish if mice could develop liver tumours. Certain strains (C57Bl/6 and DBA/2) would not tolerate long-term dosing due to the oestrogenic effects of tamoxifen resulting in bone remodelling, leading to kyphosis. However, B6C3F1 mice were more resistant, surviving the full 2 years. These mice did not develop liver tumours even when phenobarbital was used as a promoter (19).
|
Response of the mouse or rat uterus after tamoxifen treatment
|
|---|
No significant increase in uterine tumours was seen following
continuous exposure of rats or mice to tamoxifen (
18). In rats
given dietary tamoxifen for 3 months (420 p.p.m.), uteri were
decreased in size, with an absence of glands in the endometrium,
reflecting the action of tamoxifen as an oestrogen antagonist.
In B6C3F1 mice given tamoxifen for up to 2 years there was hyperplasia
of the epithelium of the uterine endometrium for the first 3
months, followed by atrophy of the endometrial component (
19).
More recently, it has been shown that when newborn CD-1 mice
were given tamoxifen for the first 5 days after birth, uterine
adenocarcinoma were seen in 50% of animals dosed at 10 µg/pup/day
tamoxifen at 14–17 months. No similar tumours were observed
in corresponding control mice (
23). These results raise the
exciting possibility that this model may be an appropriate experimental
system for studying the mechanisms of tamoxifen-related endometrial
tumours in women. It needs to be established if tamoxifen treatment
of mice at this early stage results in DNA damage (see below)
in the reproductive tract or if the resulting endometrial tumours
are the result of alternative mechanisms, such as a loss of
imprinting.
|
Mechanistic basis for hepatic DNA damage in rats and mice given tamoxifen
|
|---|
Following dosing of rats with tamoxifen, DNA damage, detected
by
32P-post-labelling, was found in their livers (
24,
25). DNA
adducts, separated by TLC or more recently by HPLC, were resolved
into at least 12 components (
25,
26). The extent of DNA damage
was related to the time of exposure and to the dose of tamoxifen.
In long-term feeding studies of rats given dietary tamoxifen
(equivalent to ~40 mg/kg/day), adduct levels increased from
~500 adducts/10
8 nucleotides at 30 days to almost 3000 adducts/10
8 nucleotides at 180 days (
27). Following long-term dosing of
rats,
32P-post-labelled adducts were found in no other organs
apart from the kidney (
28). The triphenylethylene analogues
(
Z)-4-chloro-1-[4-[2(
N,N-dimethylamino)ethoxy]phenyl]-1-butene
(toremifene), droloxifene and idoxifene (Figure 1
), when administered
to rats at comparative dose levels, caused little or no hepatic
DNA damage as determined by
32P-post-labelling (
16,
25,
28–
30).
Using the more sensitive technique of accelerator mass spectrometry,
following a single dose of [
14C]tamoxifen, low levels of irreversible
binding to DNA from the liver, reproductive and gastrointestinal
tracts could be detected (
32). In this study, dose-dependent
DNA binding in the liver occurred at dose levels equivalent
to that used therapeutically in women. When [
14C]toremifene
was used, irreversible binding to the DNA of liver or other
organs was not seen. In the livers of tamoxifen-dosed mice,
levels of
32P-post-labelled adducts were about one-third of
those detected in the rat, although the pattern of adducts following
HPLC or TLC was similar to that seen in rats (
16,
27,
29,
33).
Following long-term dosing of mice, the level of major DNA adducts
did not increase with time of exposure but after the first month
decreased, so that by 1 and 2 years it was barely above background.
While there are many steps between the initiation of DNA damage
and the subsequent development of tumours, the evidence suggests
that with tamoxifen there is a causal link between the presence
of adducts and the subsequent development of hepatocarcinogenicity.
In rats, loss of 32P-post-labelled adducts from the liver after cessation of dosing with tamoxifen takes many weeks, suggesting either that DNA repair mechanisms became saturated or that removal of tamoxifen adducts is slow. However, when a similar study was carried out using mice, the initial level of hepatic DNA damage was lower than in the rat. The more rapid hepatic detoxification of tamoxifen in mice, compared with the rat, resulting in a shorter plasma half-life, contributes to the lower level of DNA damage. However, over longer time periods, DNA damage does not accumulate in the liver as seen in rats. It has been suggested that factors such as the induction of multidrug resistance proteins may contribute to this, in addition to the more rapid repair of the damaged DNA in mice (19). These differences almost certainly contribute to the resistance of mice to the hepatocarcinogenic effects of tamoxifen.
If hepatic DNA damage is not repaired, it can be translated into gene mutations. Tamoxifen given to transgenic F344 (Big Blue) rats results in a dose-related increase in the mutation frequency at lacI in the livers following 6 weeks oral dosing (34,35). The spectrum of mutations at lacI showed 60% G:C
T:A transversions compared with 21% G:CT:A in controls. Toremifene, in contrast, did not induce mutations. No mutations were found at lacI in the DNA extracted from uterine tissues. This pattern of mutations is different from the AG and CT transitions found at p53 in liver tumours of rats following tamoxifen treatment (36). Changes in expression of p53 in liver tumours are late events occurring after many months treatment, while mutations at lacI are seen within a few weeks of the start of treatment. This may account for the different pattern of mutations. Although rare in rats, in humans many types of cancer are associated with mutations at p53 (37,38). One preliminary report suggested that mutations at p53 in endometrial tumours associated with tamoxifen therapy in women had a similar spectrum of mutations to those found in the livers of tamoxifen-treated rats (39). This might infer a genotoxic mechanism of tamoxifen associated with tumour formation. However, these data have not been confirmed and a more recent publication showed only a random pattern of p53 mutations in tamoxifen-mediated endometrial tumours in women (40).
|
Enzymes involved in the metabolism and activation of tamoxifen
|
|---|
The pattern of metabolites formed from tamoxifen in the presence
of liver microsomal systems
in vitro are qualitatively similar
in humans, mice and rats (
41–
43). These detoxification
products include the major Phase I detoxification metabolites
N-demethyltamoxifen, 4-hydroxytamoxifen and tamoxifen
N-oxide
(Figure 2
). Quantitatively, rates of metabolism by human liver
microsomes are about one-third those seen in rats (
41,
44). The
most important enzyme for carrying out the
N-demethylation reaction
in human liver is CYP3A4 (
45,
46). The expression of cDNAs for
different CYP forms, expressed in
Escherichia coli, has confirmed
this observation, but additionally has shown that a number of
other CYP isoenzymes have the capability to catalyse this reaction.
CYP2D6 was involved in 4-hydroxylation (
47), although there
is evidence from the use of human liver microsomes that other
CYP forms may also participate (
48).
In order to be genotoxic, tamoxifen has to undergo metabolic
activation by CYP monooxygenases to give a reactive intermediate.
In order to establish which human CYP isoenzymes could carry
out such activation reactions, a human lymphoblastoma cell line
expressing cDNAs for human P450s has been used in a micronucleus
assay. CYP3A4 was the major form catalysing the clastogenic
response (
49). Tamoxifen, toremifene and metabolites such as
4-hydroxytamoxifen and 4-hydroxytoremifene all caused the formation
of micronuclei (
25,
49). Droloxifene was negative in this assay.
Irreversible binding of [14C]tamoxifen to microsomal protein or to DNA has been used as a means of comparing the potential of rat or human hepatic systems. The results showed that CYP3A4 catalysed this reaction (50,51). Similar levels of irreversible binding were seen using rat and human liver microsomal mixtures, whereas mice showed ~3-fold higher activities (32). [14C]Toremifene also underwent activation and became covalently bound to DNA and to protein in all three species (51). Microsomal systems are useful for demonstrating the potential for metabolic activation, but do not necessarily accurately reflect the extent to which this will occur in humans.
Many putative reactive metabolites of tamoxifen have been proposed. There is now good evidence that a minor metabolite, -hydroxytamoxifen, bioactivated as a sulphate ester (52,53), has a role in the formation of the DNA damage in the livers of tamoxifen-treated rats (Figure 3). Originally proposed by Potter et al. (54), -hydroxytamoxifen has been found in the plasma of women treated with tamoxifen (55) and as the glucuronide in the bile of rats treated with tamoxifen, where it accounts for ~0.1% of the administered dose (45). Evidence for the formation of this intermediate came from the studies of Phillips et al. (56), who showed a reduced genotoxicity of [D5-ethyl]tamoxifen. Subsequently, the same group demonstrated that in isolated hepatocytes DNA damage, determined by 32P-post-labelling, was increased in a concentration-dependent manner when sulphate was added to the culture medium (57). The rates of formation of -hydroxytamoxifen by human liver microsomal preparations were about half those seen in rats (45). -Acetoxytamoxifen and -sulphate tamoxifen prepared synthetically bind to DNA in vitro giving rise to higher levels of adducts than the parent alcohol (58,59). The major product of this reaction has a similar Rf value on TLC and retention time following HPLC to the major adduct spot in DNA extracted from the livers of tamoxifen-treated rats. It has been identified as one in which the position of tamoxifen is covalently linked to the exocyclic amino group of deoxyguanosine to form cis–trans isomers of -(N2-deoxyguanosinyl)tamoxifen (58,60,61). Reaction with the exocyclic amino function of guanine is unlike that seen with many chemical hepatocarcinogens, such as the nitrogen mustards, nitrosamines or aflatoxins, where ring nitrogens or exocylic oxygen atoms are the primary targets for attack (62). The possibility of more than one reactive intermediate cannot be excluded. Other reactive species include conversion to 3,4-epoxytamoxifen (42,63), further rearrangement via 4-hydroxytamoxifen to a quinone methide (64), carbon or oxygen centred free radical species derived from 4-hydroxytamoxifen either through the action of CYP or peroxidases (63,65,66) or conversion to 3,4-dihydroxytamoxifen (Figure 3) (67).
|
DNA damage in tissues of women taking tamoxifen
|
|---|
It is appreciated that there are many steps between the initiation
of DNA damage and the subsequent promotion and progression to
tumours. However, results using rodent model systems suggested
that, following the administration of tamoxifen, DNA damage,
determined by
32P-post-labelling or by accelerator mass spectrometry,
was causally related to the subsequent development of tumours.
These techniques were therefore used to look at the extent of
DNA damage in women given tamoxifen therapeutically. In a study
of DNA extracted from the livers of breast cancer patients taking
tamoxifen, no tamoxifen-specific DNA damage could be detected
by
32P-post-labelling. Overall levels of DNA damage were not
significantly different from those individuals not taking the
drug (
68). No
32P-post-labelled adducts could be detected in
DNA from human white blood cells obtained from tamoxifen-treated
women (
69). Human recombinant hydroxysteroid sulphotransferase
(SULT2A1) was able to catalyse the formation of tamoxifen–DNA
adducts in the presence of
-hydroxytamoxifen, but the activity
of this enzyme was 3-fold lower than the equivalent rat enzyme
(
70). This would offer a degree of protection to humans compared
with rats. There is controversial evidence as to the extent
that tamoxifen administration to women results in damage to
endometrial DNA. The work of Carmichael
et al. (
71,
72) failed
to find evidence of genotoxicity in patients treated with either
tamoxifen or toremifene, whereas Hemminki
et al. (
73) detected
low levels of ~0.27 adducts/10
8 nucleotides. This is very much
less than the 3000 adducts/10
8 nucleotides seen in rat livers
that develop tumours (
27). The long-term biological relevance
in humans of such low levels of DNA damage are not known. However,
on the basis of the present evidence, the rat liver model of
genotoxicity of tamoxifen does not appear as an appropriate
one for uterine tumours in women caused by this drug (Table
I
).
|
The future: designer selective oestrogen receptor modulators (SERMS)?
|
|---|
Second generation SERMS include 7
-[9-(4,4,5,5,5-pentafluoro-pentylsulfinyl)nonyl]estra-1,3,5(
10)-triene-3,17ß-diol
(ICI 182 780, Faslodex
TM) and [6-hydroxy-2-(4-hydroxyphenyl)-benzo[
b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]meth-anone
(raloxifene, Evista
TM) (Figure 4
). Wakeling
et al. (
79,
80) designed
ICI 182 780 as a 7
-substituted oestradiol analogue with potent
pure anti-oestrogen action. It was hoped that this might offer
advantages in breast cancer treatment compared with partial
agonists like tamoxifen. ICI 182 780 has a high relative affinity
for the oestrogen receptor and completely blocked the trophic
action of oestradiol on the uterus of ovariectomized adult rats
and on bone (
81,
82). In women, ICI 182 780 did not affect cell
proliferation in the uterine or vaginal tissues (
83). Short-term
treatment of patients with advanced breast cancer resistant
to tamoxifen with this drug resulted in significant decreases
in tumour proliferation. In oestrogen receptor-positive breast
tumours there was also a decrease in the level of receptor protein
that could be detected immunocytochemically (
84). Fasolodex
is usually administrated by monthly intramuscular injection
rather than orally. Although clinically promising it has so
far not gained the widespread acceptance of tamoxifen.
Raloxifene, based on the benzothiaphene structure (Figure 4
),
is used as an anti-osteoporosis agent for post-menopausal women
(
85–
87). Although it has an oestrogen agonist action on
bone, it has little proliferative effects on the endometrium
of post-menopausal women (
88) and only a weak uterotrophic action
in ovariectomised rats (
89). Like tamoxifen, raloxifene may
be effective as a chemopreventive agent against breast cancer.
In early 1999, a comparative Study of Tamoxifen And Raloxifene
(STAR) will be carried out to include 22 000 post-menopausal
women who are at increased risk of developing breast cancer.
Daily doses of tamoxifen (20 mg) and raloxifene (60 mg) or placebo
will be given for 5 years.
There is a mechanistic basis for hoping that the endometrial tumours seen following tamoxifen therapy would not occur with raloxifene. Studies by Yang et al. (90) showed that this drug could have different tissue specificities. Using bone-derived MG63 cells they found that the signal transduction mediated via TGF-ß3 was not routed through the classical oestrogen response element but rather through adapter proteins and a novel raloxifene response element. X-ray crystallography of the oestrogen receptor has shown that both oestradiol and raloxifene can interact with the ligand-binding domain of the receptor but binding results in different conformational states (91). In oestrogen receptor-negative human breast cancer cells that have been transfected with cDNAs from wild-type or mutant ER, it has been found that mutation of the single Asp351 to Tyr is sufficient to change the actions of raloxifene from an anti-oestrogen to an oestrogen (92). The presence of two ERs, ER and ERß, that can either homo or heterodimerize further complicates the potential action of these SERMS. Both ER and ERß have a high degree of homology between the amino acid residues in the ligand-binding domain (AF2) and many ligands have a similar affinity for both receptor subtypes (93). However, it has been shown that tamoxifen and raloxifene have oestrogen agonist/antagonist function via ER but a pure antagonist effect through ERß (94). The second generation SERMS as well as the triphenylethylene analogues toremifene, droloxifene and idoxifene do not have the clinical track record of tamoxifen. It is presumed, but not proven, that induction of uterine cell proliferation is associated with the subsequent development of endometrial tumours. We will have to await the outcome of long-term clinical trials and of epidemiological studies to demonstrate the long-term safety of these drugs.
|
Conclusions
|
|---|
The use of tamoxifen as adjuvant therapy in the treatment of
breast cancer on balance is beneficial, although there are concerns
with regard to the development of endometrial cancer in treated
women. There is no epidemiological evidence for an increase
in liver tumours in women receiving tamoxifen therapy (
4) and
on the basis of our mechanistic understanding of the action
of this drug in rodents, it seems unlikely that women will be
at risk. It is still not clear if the mechanism of formation
of uterine tumours is through genetic mechanisms, analogous
to those seen in the rat liver, or as a result of the oestrogen
agonist actions of tamoxifen. A resolution to this question
would be of considerable importance in the ultimate use of tamoxifen
or particular analogues of tamoxifen in the clinical setting.
There is evidence from the largest clinical trial on the chemopreventive
use of tamoxifen in women (
6) that this drug provides considerable
benefit in reducing the incidence of breast cancer. Tamoxifen
is a genotoxic carcinogen in the rat yet in humans it is unlikely
that this will be the cause of limitations in the widespread
use of this drug. As such it raises interesting issues in the
licensing of rodent genocarcinogens for use in a clinical situation.
Based on an understanding of its mechanism of toxicity and its
proven benefit in the clinic, populations of women at high risk
of developing breast cancer may be able to benefit from second
or third generation designer oestrogens that provide similar
therapeutic benefits to tamoxifen with different toxicological
profiles. These may ultimately prove to be of considerable value
as chemopreventive drugs.
|
Notes
|
|---|
Email:
iw6{at}le.ac.uk 
|
References
|
|---|
-
Powles,T.J. and Hickish,T. (1995) Tamoxifen therapy and carcinogenic risk. J. Natl Cancer Inst., 87, 1343–1345.[Free Full Text]
-
Clarke,M., Collins,R., Davies,C., Godwin,J., Gray,R., Peto,R. and EBCTCG Secretariat (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet, 351, 1451–1467.[ISI][Medline]
-
Poirier,D., Auger,S., Merand,Y., Simard,J. and Labrie,F. (1994) Synthesis and antiestrogenic activity of diaryl thioether derivatives. J. Med. Chem., 37, 1115–1125.[ISI][Medline]
-
IARC (1996) Tamoxifen. In Some Pharmaceutical Drugs. IARC, Lyon, pp. 253 –365.
-
Early Breast Cancer Trialist' Collaborative Group (1992) Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet, 339, 1–15.[ISI][Medline]
-
Fisher,B., Costantino,J.P., Wickerham,D.L. et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl Cancer Inst., 90, 1371–1388.[Abstract/Free Full Text]
-
Powles,T., Eeles,R., Ashley,S., Easton,D., Chang,J., Dowsett,M., Tidy,A., Viggers,J. and Davey,J. (1998) Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet, 352, 98–101.[ISI][Medline]
-
Veronesi,U., Maisonneuve,P., Costa,A., Sacchini,V., Maltoni,C., Robertson,C., Rotmensz,N. and Boyle,P. (1998) Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Lancet, 352, 93–97.[ISI][Medline]
-
Blackwood,M.A. and Weber,B.L. (1998) BRCA1 and BRCA2: from molecular genetics to clinical medicine. J. Clin. Oncol., 16, 1969–1977.[Abstract]
-
Fornander,T., Cedermark,B., Mattsson,A. et al. (1989) Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet, 1, 117–119.[ISI][Medline]
-
Rutqvist,L.E., Johansson,H., Signomklao,T., Johansson,U., Fornander,T. and Wilking,N. (1995) Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J. Natl Cancer Inst., 87, 645–651.[Abstract/Free Full Text]
-
Curtis,R.E., Boice,J.D.Jr, Shriner,D.A., Hankey,B.F. and Fraumeni,J.F.Jr (1996) Second cancers after adjuvant tamoxifen therapy for breast cancer. J. Natl Cancer Inst., 88, 832–834.
-
Jordan,V.C. (1998) Designer estrogens. Sci. Am., 279, 36–43.
-
Greaves,P., Goonetilleke,R., Nunn,G., Topham,J. and Orton,T. (1993) Two-year carcinogenicity study of tamoxifen in Alderly Park Wistar-derived rats. Cancer Res., 53, 3919–3924.[Abstract/Free Full Text]
-
Williams,G.M., Iatropoulos,M.J., Djordjevic,M.V. and Kaltenberg,O.P. (1993) The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis, 14, 315–317.[Abstract/Free Full Text]
-
Hard,G.C., Iatropoulos,M.J., Jordan,K., Radi,L., Kaltenberg,O.P., Imondi,A.R. and Williams,G.M. (1993) Major differences in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Cr1:CD(BR) rats. Cancer Res., 53, 4534–4541.[Abstract/Free Full Text]
-
Hirsimaki,P., Hirsimaki,Y., Nieminen,L. and Payne,B.J. (1993) Tamoxifen induces hepatocellular carcinoma in rat liver: a 1-year study with two antiestrogens. Arch. Toxicol., 67, 49–54.[ISI][Medline]
-
Tucker,M.J., Adams,H.K. and Patterson,J.S. (1984) Tamoxifen. In Laurence,D.R., McLean,A.E.M. and Weatherall,M. (eds) Safety Testing of New Drugs. Academic Press, New York, NY, pp. 125–161.
-
Martin,E.A., Carthew,P., White,I.N.H., Heydon,R.T., Gaskell,M., Mauthe,R.J., Turteltaub,K.W. and Smith,L.L. (1997) Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen. Carcinogenesis, 18, 2209–2215.[Abstract/Free Full Text]
-
Carthew,P., Martin,E.A., White,I.N.H., De Matteis,F., Edwards,R.E., Dorman,B.M., Heydon,R.T. and Smith,L.L. (1995) Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital. Cancer Res., 55, 544–547.[Abstract/Free Full Text]
-
Dragan,Y.P., Fahey,S., Street,K., Vaughan,J., Jordan,V.C. and Pitot,H.C. (1994) Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats. Breast Cancer Res. Treat., 31, 11–25.[ISI][Medline]
-
Carthew,P., Edwards,R.E. and Nolan,B.M. (1997) Depletion of hepatocyte nuclear estrogen receptor expression is associated with promotion of tamoxifen induced GST-P foci to tumours in rat liver. Carcinogenesis, 18, 1109–1112.[Abstract/Free Full Text]
-
Newbold,R.R., Jefferson,W.N., PadillaBurgos,E. and Bullock,B.C. (1997) Uterine carcinoma in mice treated neonatally with tamoxifen. Carcinogenesis, 18, 2293–2298.[Abstract/Free Full Text]
-
Han,X. and Liehr,J.G. (1992) Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res., 52, 1360–1363.[Abstract/Free Full Text]
-
White,I.N.H., De Matteis,F., Davies,A., Smith,L.L., Crofton Sleigh,C., Venitt,S., Hewer,A. and Phillips,D.H. (1992) Genotoxic potential of tamoxifen and analogues in female Fischer F344/N rats, DBA/2 and C57Bl/6 mice and in human MCL-5 cells. Carcinogenesis, 13, 2197–2203.[Abstract/Free Full Text]
-
Martin,E.A., Heydon,R., Brown,K., Lim,C.K., White,I.N.H. and Smith,L.L. (1998) Evaluation of tamoxifen and -hydroxytamoxifen 32P-postlabelled DNA adducts by the development of a novel automated on-line solid-phase extraction HPLC method. Carcinogenesis, 19, 1061–1069.[Abstract/Free Full Text]
-
Carthew,P., Rich,K.J., Martin,E.A., De Matteis,F., Lim,C.K., Manson,M.M., Festing,M., White,I.N.H. and Smith,L.L. (1995) DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation. Carcinogenesis, 16, 1299–1304.[Abstract/Free Full Text]
-
Li,D., Dragan,Y., Jordan,V.C., Wang,M. and Pitot,H.C. (1997) Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney and uterus. Cancer Res., 57, 1438–1441.[Abstract/Free Full Text]
-
Montandon,F. and Williams,G.M. (1994) Comparison of DNA reactivity of the polyphenylethylene hormonal agents diethylstilbestrol, tamoxifen and toremifene in rat and hamster liver. Arch. Toxicol., 68, 272–275.[ISI][Medline]
-
Pace,P., Jarman,M., Phillips,D., Hewer,A., Bliss,J. and Coombes,R.C. (1997) Idoxifene is equipotent to tamoxifen in inhibiting mammary carcinogenesis but forms lower levels of hepatic DNA adducts. Br. J. Cancer, 76, 700–704.[ISI][Medline]
-
Dahme,E. and Rattel,B. (1994) Unlike tamoxifen, droloxifene produces no hepatic tumors in the rat. Onkologie, 17, 6–16.
-
White,I.N.H., Martin,E.A., Vogel,J.S., Mauthe,R.J., Turteltaub,K.W. and Smith,L.L. (1997) Comparison of the binding of [14C]radiolabelled tamoxifen or toremifene to rat DNA using accelerator mass spectrometry. Chem. Biol. Interact., 106, 149–160.[ISI][Medline]
-
Randerath,K., Bi,J., Mabon,N., Sriram,P. and Moorthy,B. (1994) Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol. Carcinogenesis, 15, 797–800.[Abstract/Free Full Text]
-
Davies,R., Oreffo,V.I.C., Bayliss,S., Dinh,P.-A., Lilley,K.S., White,I.N.H., Smith,L.L. and Styles,J.A. (1996) Mutational spectra of tamoxifen-induced mutations in the livers of lacI transgenic rats. Environ. Mol. Mutagen., 28, 430–433.[ISI][Medline]
-
Davies,R., Oreffo,V.I.C., Martin,E.A., Festing,M., White,I.N.H., Smith,L.L. and Styles,J.A. (1997) Tamoxifen causes gene mutations in the livers of lambda/lacI transgenic rats. Cancer Res., 57, 1288–1293.[Abstract/Free Full Text]
-
Vancutsem,P.M., Lazarus,P. and Williams,G.M. (1994) Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen. Cancer Res., 54, 3864–3867.[Abstract/Free Full Text]
-
Hsu,I.C., Meetcalf,R.A., Sun,T., Welsh,J.A., Wang,N.J. and Harris,C.C. (1991) Mutational hot spot in the p53 gene in human hepatocellular carcinomas. Nature, 350, 427–428.[Medline]
-
Bressac,B., Khalid,S., Wands,J. and Ozturk,M. (1991) G to T mutations of p53 gene in hepatocellular carcinomas from Southern Africa. Nature, 350, 429–432.[Medline]
-
Welsh,J.A., Moberger,B., Fornander,T. et al. (1997) Tamoxifen has a characteristic mutation spectrum in human endometrial cancers. Proc. Am. Soc. Cancer Res., 38, 450.
-
Kuwashima,Y., Kurosumi,M., Kobayashi,Y., Tanuma,J., Suemasu,K., Higashi,Y., Kasamatsu,T., Shiromizu,K. and Kishi,K. (1998) Random nuclear p53 overexpression pattern in tamoxifen-mediated endometrial carcinoma. Int. J. Gynecol. Pathol., 17, 135–139.[ISI][Medline]
-
Lim,C.K., Yuan,Z., Lamb,J.H., White,I.N.H., De Matteis,F. and Smith,L.L. (1994) A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes. Carcinogenesis, 15, 589–593.[Abstract/Free Full Text]
-
Reunitz,P.C., Bagley,J.R. and Pape,C.W. (1984) Some chemical and biochemical aspects of liver microsomal metabolism of tamoxifen. Drug Metab. Dispos., 12, 478–483.[Abstract]
-
Jones,R.M., Yuan,Z.X., Lamb,J.H. and Lim,C.K. (1996) On-line high-performance liquid chromatographic–electrospray ionization mass spectrometric method for the study of tamoxifen metabolism. J. Chromatogr., 722A, 249–255.
-
Boocock,D.J., Maggs,J.L., White,I.N.H. and Park,B.K. (1999) -Hydroxytamoxifen, a genotoxic metabolite of tamoxifen in the rat: identification and quantification in vivo and in vitro. Carcinogenesis, 20, 153–160.[Abstract/Free Full Text]
-
Jacolot,F., Simon,I., Dreano,Y., Beaune,P., Riche,C. and Berthou,F. (1991) Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. Biochem. Pharmacol., 41, 1911–1919.[ISI][Medline]
-
Berthou,F., Dreano,Y., Belloc,C., Kangas,L., Gautier,J.C. and Beaune,P. (1994) Involvement of cytochrome P450 3A enzyme family in the major metabolic pathways of toremifene in human liver microsomes. Biochem. Pharmacol., 47, 1883–1895.[ISI][Medline]
-
Dehal,S.S. and Kupfer,D. (1997) CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res., 57, 3402–3406.[Abstract/Free Full Text]
-
Crewe,H.K., Ellis,S.W., Lennard,M.S. and Tucker,G.T. (1997) Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem. Pharmacol., 53, 171–178.[ISI][Medline]
-
Styles,J.A., Davies,A., Lim,C.K., De Matteis,F., Stanley,L.A., White,I.N.H., Yuan,Z.X. and Smith,L.L. (1994) Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis, 15, 5–9.[Abstract/Free Full Text]
-
Mani,C., Pearce,R., Parkinson,A. and Kupfer,D. (1994) Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes. Carcinogenesis, 15, 2715–2720.[Abstract/Free Full Text]
-
White,I.N.H., De Matteis,F., Gibbs,A.H., Lim,C.K., Wolf,C.R., Henderson,C. and Smith,L.L. (1995) Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved. Biochem. Pharmacol., 49, 1035–1042.[ISI][Medline]
-
Birnboim,H.C. (1985) DNA clastogenic activity of diethylstilbestrol. Biochem. Pharmacol., 34, 3251–3257.[ISI][Medline]
-
Phillips,D.H., Carmichael,P.L., Hewer,A., Cole,K.J. and Poon,G.K. (1995) -Hydroxytamoxifen, a metabolite of tamoxifen with exceptionally high DNA binding activity in rat hepatocytes. Cancer Res., 54, 5518–5522.[Abstract/Free Full Text]
-
Potter,G.A., McCague,R. and Jarman,M. (1994) A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism. Carcinogenesis, 15, 439–442.[Abstract/Free Full Text]
-
Poon,G.K., Walter,B., Lonning,P.E., Horton,M.N. and McCague,R. (1995) Identification of tamoxifen metabolites in human HEP G2 cell line, human liver homogenate and patients on long-term therapy for breast cancer. Drug Metab. Dispos., 23, 377–382.[Abstract]
-
Phillips,D.H., Potter,G.A., Horton,M.N., Hewer,A., Crofton Sleigh,C., Jarman,M. and Venitt,S. (1994) Reduced genotoxicity of [D5-ethyl]-tamoxifen implicates -hydroxylation of the ethyl group as a major pathway of tamoxifen activation to a liver carcinogen. Carcinogenesis, 15, 1487–1492.[Abstract/Free Full Text]
-
Davis,W., Venitt,S. and Phillips,D.H. (1998) The metabolic activation of tamoxifen and alpha-hydroxytamoxifen to DNA-binding species in rat hepatocytes proceeds via sulphation. Carcinogenesis, 19, 861–866.[Abstract/Free Full Text]
-
Osborne,M.R., Hewer,A., Hardcastle,I.R., Carmichael,P.L. and Phillips, D.H. (1996) Identification of the major tamoxifen–deoxyguanosine adduct formed in the liver DNA of rats treated with tamoxifen. Cancer Res., 56, 66–71.[Abstract/Free Full Text]
-
Dasaradhi,L. and Shibutani,S. (1997) Identification of tamoxifen–DNA adducts formed by -sulfate tamoxifen and -acetoxytamoxifen. Chem. Res. Toxicol., 10, 189–196.[ISI][Medline]
-
Osborne,M.R., Hardcastle,I.R. and Phillips,D.H. (1997) Minor products of reaction of DNA with -acetoxytamoxifen. Carcinogenesis, 18, 539–543.[Abstract/Free Full Text]
-
Shibutani,S., Dasaradhi,L., Terashima,I., Banoglu,E. and Duffel,M.W. (1998) Alpha-hydroxytamoxifen is a substrate of hydroxysteroid (alcohol) sulfotransferase, resulting in tamoxifen DNA adducts. Cancer Res., 58, 647–653.[Abstract/Free Full Text]
-
Dipple,A. (1995) DNA adducts of chemical carcinogens. Carcinogenesis, 16, 437–441.[Free Full Text]
-
Lim,C.K., Yuan,Z.X., Jones,R.M., White,I.N.H. and Smith,L.L. (1998) Identification and mechanism of formation of potentially genotoxic metabolites of tamoxifen: study by LC-MS/MS. J. Pharm. Biomed. Anal., 15, 1335–1342.
-
Moorthy,B., Sriram,P., Pathak,D.N., Bodell,W.J. and Randerath,K. (1996) Tamoxifen metabolic activation: comparison of DNA adducts formed by microsomal and chemical activation of tamoxifen and 4-hydroxytamoxifen with DNA adducts formed in vivo. Cancer Res., 56, 53–57.[Abstract/Free Full Text]
-
Davies,A.M., Martin,E.A., Jones,R.M., Lim,C.K., Smith,L.L. and White,I.N.H. (1995) Peroxidase activation of tamoxifen and toremifene resulting in DNA damage and covalently bound protein adducts. Carcinogenesis, 16, 539–545.[Abstract/Free Full Text]
-
Davies,A.M., Malone,M.E., Martin,E.A., Jones,R.M., Jukes,R., Lim,C.K., Smith,L.L. and White,I.N.H. (1997) Peroxidase activation of 4-hydroxytamoxifen to free radicals detected by EPR spectroscopy. Free Radic. Biol. Med., 22, 423–431.[ISI][Medline]
-
Dehal,S.S. and Kupfer,D. (1996) Evidence that the catechol 3,4-dihydroxytamoxifen is a proximate intermediate to the reactive species binding covalently to proteins. Cancer Res., 56, 1283–1290.[Abstract/Free Full Text]
-
Martin,E.A., Rich,K., White,I.N.H., Woods,K.L., Powles,T.J. and Smith,L.L. (1995) 32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis, 16, 1651–1654.[Abstract/Free Full Text]
-
Phillips,D.H., Hewer,A., Grover,P.L., Poon,G.K. and Carmichael,P.L. (1996) Tamoxifen does not form detectable DNA adducts in white blood cells of breast cancer patients. Carcinogenesis, 17, 1149–1152.[Abstract/Free Full Text]
-
Shibutani,S., Shaw,P.M., Suzuki,N., Dasaradhi,L., Duffel,M.W. and Terashima,I. (1998) Sulfation of -hydroxytamoxifen catalyzed by human hydroxysteroid sulfotransferase results in tamoxifen–DNA adducts. Carcinogenesis, 19, 2007–2011.[Abstract/Free Full Text]
-
Carmichael,P.L., Ugwumadu,A.H.N., Neven,P., Hewer,A.J., Poon,G.K. and Phillips,D.H. (1996) Lack of genotoxicity of tamoxifen in human endometrium. Cancer Res., 56, 1475–1479.[Abstract/Free Full Text]
-
Carmichael,P.L., Neven,P., Sardar,S. et al. (1998) A lack of evidence for the genotoxicity of tamoxifen and toremifene in the human endometrium. Eur. J. Cancer, 34, P106.
-
Hemminki,K., Rajaniemi,H., Lindahl,B. and Moberger,B. (1996) Tamoxifen-induced DNA adducts in endometrial samples from breast cancer patients. Cancer Res., 56, 4374–4377.[Abstract/Free Full Text]
-
Fisher,B., Costantino,J.P., Redmond,C.K., Fisher,E.R., Wickerham,D.L., Cronin,W.M. and NSABP Contributors (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J. Natl Cancer Inst., 86, 527–537.[Abstract/Free Full Text]
-
White,I.N.H., Gibbs,A.H., Jones,A.M., Lim,C.K., Al-Azzawi,F. and Smith,L.L. (1997) Comparison of the potential of microsomal fraction from human and rat reproductive tracts to activate tamoxifen. Proc. Am. Soc. Cancer Res., 38, 337
-
Styles,J.A., Davies,A., Davies,R., White,I.N.H. and Smith,L.L. (1997) Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells). Carcinogenesis, 18, 303–313.[Abstract/Free Full Text]
-
Sargent,L.M., Dragan,Y.P., Sattler,C. et al. (1996) Induction of hepatic aneuploidy in vivo by tamoxifen, toremifene and idoxifene in female Sprague–Dawley rats. Carcinogenesis, 17, 1051–1056. [Erratum, Carcinogenesis (1996), 17, 1393.]
-
Pathak,D.N. and Bodell,W.J. (1994) DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems. Carcinogenesis, 15, 529–532.[Abstract/Free Full Text]
-
Wakeling,A.E. and Bowler,J. (1992) ICI 182 780, a new antioestrogen with clinical potential. J. Steroid Biochem. Mol. Biol., 43, 173–177.[ISI][Medline]
-
Wakeling,A.E. (1993) Are breast tumours resistant to tamoxifen also resistant to pure antioestrogens? J. Steroid Biochem. Mol. Biol., 47, 107–114.[ISI][Medline]
-
Wakeling,A.E. (1995) Tissue-specific actions of antioestrogens. Mutat. Res. Fundam. Mol. Mech. Mutagen., 333, 45–49.
-
Martel,C., Labrie,C., Belanger,A., Gauthier,S., Merand,Y., Li,X., Provencher,L., Candas,B. and Labrie,F. (1998) Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse. Endocrinology, 139, 2486–2492.[Abstract/Free Full Text]
-
Howell,A., DeFriend,D.J., Robertson,J.F.R., Blamey,R.W., Anderson,L., Anderson,E., Sutcliffe,F.A. and Walton,P. (1996) Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182 780 in women with advanced breast cancer. Br. J. Cancer, 74, 300–308.[ISI][Medline]
-
Robertson,J.F.R., Howell,A., DeFriend,D.J., Blamey,R.W., Walton,P. and De Friend,D.J. (1997) Duration of remission to ICI 182 780 compared to megestrol acetate in tamoxifen resistant breast cancer. Breast, 6, 186–189.
-
Delmas,P.D., Bjarnason,N.H., Mitlak,B.H., Ravoux,A.C., Shah,A.S., Huster,W.J., Draper,M., Christiansen,C. and Ravoux,A.-C. (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. N. Engl. J. Med., 337, 1641–1647.[Abstract/Free Full Text]
-
Jordan,V.C. (1998) Antiestrogenic action of raloxifene and tamoxifen: today and tomorrow. J. Natl Cancer Inst., 90, 967–971.[Free Full Text]
-
Frolik,C.A., Bryant,H.U., Black,E.C., Magee,D.E. and Chandrasekhar,S. (1996) Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: effects of raloxifene hcl, tamoxifen, estrogen and alendronate. Bone, 18, 621–627.[Medline]
-
Boss,S.M., Huster,W.J., Neild,J.A., Glant,M.D., Eisenhut,C.C. and Draper,M.W. (1997) Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am. J. Obstet. Gynecol., 177, 1458–1464.[ISI][Medline]
-
Ashby,J., Odum,J. and Foster,J.R. (1997) Activity of raloxifene in immature and ovariectomized rat uterotrophic assays. Regul. Toxicol. Pharmacol., 25, 226–231.[ISI][Medline]
-
Yang,N.N., Venugopalan,M., Hardikar,S. and Glasebrook,A. (1996) Identification of an estrogen response element activated by metabolites of 17ß-estradiol and raloxifene. Science, 273, 1222–1225.[Abstract]
-
Brzozowski,A.M., Pike,A.C.W., Dauter,Z. et al. (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature, 389, 753–758.[Medline]
-
Levenson,A.S. and Jordan,V.C. (1998) The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptor. Cancer Res., 58, 1872–1875.[Abstract/Free Full Text]
-
Barkhem,T., Carlsson,B., Nilsson,Y., Enmark,E., Gustafsson,J.A., Nilsson,S. and Gustafsson,J.-A. (1998) Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol., 54, 105–112.[Abstract/Free Full Text]
-
Paech,K., Webb,P., Kuiper,G.G.J.M., Nilsson,S., Gustafsson,J.Å., Kushner, P.J., Scanlan,T.S. and Gustafsson,J.-A. (1997) Differential ligand activation of estrogen receptors er alpha and er beta at ap1 sites. Science, 277, 1508–1510.[Abstract/Free Full Text]
-
Martin,E.A., Gaskell,M., White,I.N.H. et al. (1998) Analysis of tamoxifen–DNA adducts in humans and rats by accelerator mass spectrometry. Mutagenesis, 13, 528, abstract 29.
Received February 2, 1999;
revised March 17, 1999;
accepted March 17, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
|
|
 
V. P. Tryndyak, L. Muskhelishvili, O. Kovalchuk, R. Rodriguez-Juarez, B. Montgomery, M. I. Churchwell, S. A. Ross, F. A. Beland, and I. P. Pogribny
Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis
Carcinogenesis,
August 1, 2006;
27(8):
1713 - 1720.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
