| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
of a New Clinically Relevant Antiestrogen (GW7604) Related to Tamoxifen1
Department of Surgery (D.J.B.), The Robert H. Lurie Comprehensive Cancer Center (R.C.D., H.L., J.M.S., V.C.J.), Northwestern University Medical School, Chicago, Illinois 60611; and Signal Pharmaceutical (J.W.Z.), San Diego, California 92121
Address all correspondence and requests for reprints to: V. Craig Jordan, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Olson Pavilion 8258, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: vcjordan{at}northwestern.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10-11–10-6 M), but 4-OHT was weakly estrogen-like at low concentrations (10-11–10-10 M). Compounds (10-7 M) blocked the growth promoting action of estradiol (10-10 M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P < 0.05).
An assay system was used that can classify compounds into
tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay
depends on the activation of the transforming growth factor 
(TGF) gene in situ by wild-type or D351Y mutant ER
stably transfected into MDA-MB-231 cells (MacGregor-Schafer et
al., Cancer Res, 1999, 59:4308–4313). GW7604 inhibited both
estradiol (10-9 M) and 4-OHT
(10-8, 10-7
M) induction of TGF in a concentration related manner
(10-9–10-6
M). GW7604 and raloxifene stimulated TGF with the D351Y
ER. In contrast, ICI 182,780 (10-6
M) did not initiate TGF and blocked the induction of
TGF with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells.
Using computer-assisted molecular models of ER complexes, we found that
the antiestrogenic side chain of 4-OHT weakly interacted with the
surface amino acid 351 (aspartate), but the carboxylic acid of GW7604
caused a strong repulsion of aspartate 351. We propose that GW7604 is
less estrogen-like than 4-OHT, because it disrupts the surface charge
around aa351 required for coactivator docking in the 4-OHT:ER
complex. This charge is restored in the D351Y ER, thus converting
GW7604 from an antiestrogen to an estrogen-like molecule.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The clinical pharmacology of nonsteroidal antiestrogens is complex and
cannot be described as simple blockade of estrogen action, and the
compounds are now referred to as selective ER modulators (SERMs) to
describe the site-specific effects. New SERMs are being investigated
for multiple applications as treatments or preventives for breast
cancer, osteoporosis, and coronary heart disease (8).
Raloxifene is already used clinically to treat and prevent osteoporosis
(9), but raloxifene is also being tested to determine
whether it will reduce the risk of coronary heart disease in high risk
women and also against tamoxifen to determine its worth as a breast
cancer preventive (10). The clinical success of tamoxifen
and raloxifene has encouraged the search for novel SERMs for
applications as multifunctional drugs. The tamoxifen derivative GW5683
is unique because, unlike other nonsteroidal antiestrogens, it
possesses a carboxylic acid side chain and not a tertiary nitrogen
group (Fig 1
). GW5638 is an antiestrogen
with reportedly less estrogenic than tamoxifen in the rat uterus but
which maintains agonist activity in bone (11, 12). GW5638
is a prodrug that is converted to its active metabolite, GW7604,
similar to the way tamoxifen is converted to the metabolite
4-hydroxytamoxifen (4-OHT) (13, 14, 15). GW7604 is therefore
used in cell culture systems to study mechanisms of action at the ER in
much the same way as 4-OHT is used in studies of tamoxifen in
vitro. GW7604 is particularly interesting for several reasons: it
has a unique structure as an antiestrogen, and it has been suggested to
destroy ER (16) in a manner similar to that of pure
antiestrogens (17). Clearly the actions of GW5638 in
vivo classify it as a SERM (11), so an evaluation of
the mechanism of action of GW7604 merits consideration.
|
A D351Y mutant ER was identified in a tamoxifen-stimulated MCF-7 breast
tumor grown in athymic mice (22). The complementary DNA
(cDNA) for D351Y ER was stably transfected into ER negative breast
cancer cells MDA-MB-231 (23) and the estrogenic and
antiestrogenic actions of ligands, compared with breast cancer cells
stably transfected with cDNA for wild-type ER (24) at a
transforming growth factor (TGF) gene target in situ.
Interestingly, raloxifene behaved as an antiestrogen that suppressed
AF-1 and AF-2 with wild-type ER but D351Y ER caused a partial
reactivation of estrogen-like function (25). In contrast,
4-OHT stimulated TGF gene expression with both wild-type and D351Y
ER (26).
As a prelude to the testing of GW5638 in laboratory models of tamoxifen-stimulated breast and endometrial cancer, we have compared and contrasted the actions of GW7604 and 4-OHT on the growth of estrogen-responsive MCF-7 breast and ECC-1 endometrial carcinoma cell lines in culture. Wijayaratne and co-workers (16) previously noted dramatic decreases in ER protein in MCF-7 cells, by Western blotting, and suggested that GW7604 may have some properties related to pure antiestrogens such as ICI182,780. We have reexamined this action of GW7604 on ER in both breast and endometrial cells and used our antiestrogen classification assay (27) to describe a potential mechanism of action for GW7604. In the absence of crystallographic data, we have employed ligand docking with the 4-OHT:ER complex to complement our study. The computer-assisted lowest-energy calculations are based on the interaction of amino acids in the immediate vicinity of the antiestrogenic carboxylic acid side chain. In this way, we propose a potential molecular mechanism of action for GW7604 that supports our classification of this novel SERM.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
MCF-7 cells (originally obtained from Dr. Dean Edwards, now at the University of Colorado, in 1985) were maintained in phenol red containing RPMI 1640 supplemented with 10% FBS, 2 mM glutamine, 6 ng/ml bovine insulin, 100 U/ml penicillin, 100 µg/ml streptomycin, and nonessential amino acids. MCF-7 cells were maintained in phenol red-free RPMI 1640 at least 48 h before each experiment.
ECC-1 human endometrial cells (obtained from Dr. Miles Brown, Dana Farber Cancer Center, Boston) were maintained in phenol red containing DMEM supplemented with 10% FBS, 2 mM glutamine, 6ng/ml bovine insulin, 100 U/ml penicillin, 100 µg/ml streptomycin, and nonessential amino acids. ECC-1 cells were grown in phenol red-free DMEM at least 48 h before each experiment. All cells were passaged twice per week with 0.5% trypsin (1:10 dilution). Cells were grown in a 37-C incubator with 5% carbon dioxide.
E2 was obtained from Sigma Chemicals
(St. Louis, MO), 4-OHT and ICI182,780 were generous gifts from Dr. Alan
Wakeling (Astra USA, Inc. Zeneca Pharmaceuticals, Manesfield, UK), GW 7604 was a generous gift
from Dr. Timothy Willson (GlaxoWellcome Inc.,
Durham, NC), and raloxifene (formerly known as keoxifene) was a
generous gift from Eli Lilly & Co. (Indianapolis, IN).
Structures of the compounds are shown in Fig. 1
.
Human breast cell (MCF-7) and endometrial cell (ECC-1)
proliferation assay
Cells were seeded at 15,000 per well in 24-well plates, on day
0, in estrogen-free maintenance medium. The cells were treated on days
1, 3, and 5 with test media containing E2 and
antiestrogens at the indicated concentrations. All of the compounds
were dissolved in 100% ethanol and added to the medium at a 1:1000
dilution. Dose response curves were prepared for GW7604, 4-OHT,
and E2 between
10-11–10-7
M alone. Combinations with E2
(10-10 M) were
used to determine antiestrogen action. On day 6, cells were sonicated
and assayed for DNA content, as described previously (28),
using a fluorometer.
Western blot analysis
Cells were seeded into T-75-cm2 tissue
culture flasks. Cells were exposed to ligands in culture media
containing 10% stripped FBS, for 24 h, and nuclear extracts were
prepared as described previously (29). Cells were
trypsinized and pelleted. The pellet was resuspended in protein
extraction buffer [0.45 M NaCl, 1 mM MgCl2,
0.2 mM phenylmethylsulfonyl fluoride, 0.5 mM
dithiothreitol, 25% gycerol, and 20 mM HEPES (pH 7.7)]
and then was respun. The extracts were collected and stored at -80 C.
Protein concentration was measured using the Protein Assay kit
(Bio-Rad Laboratories, Inc., Hercules, CA). Total protein
(100 µg) was analyzed by SDS-PAGE. Proteins were transferred to
nitrocellulose membrane and probed with monoclonal antibody AER311
(Neomarkers, Fremont, CA), raised against the human ER, and
ß-actin antibody AC-15 (Sigma) was used to
standardize loading. Complexes were detected using ECL
(Amersham Pharmacia Biotech, Piscataway, NJ). The membrane
was wrapped in plastic and exposed to X-OMAT film (Eastman Kodak Co., Rochester, NY).
Northern blot analysis
The assay of compounds for estrogenic and antiestrogenic
activity at the TGF gene was described previously (27).
Concentration response experiments, in at least triplicate, were
conducted with compounds as indicated in Results. Analysis
of TGF messenger RNA (mRNA) expression was assessed by Northern
blots as described previously (30). Cells were treated
with ligand for 24 h, and total RNA was extracted using TRIZOL
reagent (Life Technologies, Inc., Rockville, MD). Twenty
micrograms of total RNA were separated by electrophoresis in denaturing
agarose gel (2.2 M formaldehyde and 1% agarose),
and transferred to a nylon filter by capillary blotting, and
cross-linked by UV irradiation. The blot was hybridized, and the probe
was prepared with 50 ng cDNA fragments randomly labeled with
[32p]deoxycycidine triphosphate. A human TGF
cDNA probe, derived by EcoRI digestion of a
TGF-containing plasmid, was a generous gift from Dr. R. Derynck,
(Genentech, Inc., San Francisco, CA). The membrane was
washed successively with 1x SSC (150 mM sodium
chloride/15 mm sodium citrate, pH. 7.0) buffer and 0.1% SDS solution
for 30 min at 60 C, 0.5x SSC buffer/0.1% SDS solution for 30 min, and
0.1x SSC buffer/0.1% SDS solution for two 15-min periods at 60 C. The
blot was exposed to Eastman Kodak Co. X-OMAT film for
autoradiography, in a cassette with double Quanta III intensifying
screens, at -80 C, for 24–48 h.
Molecular modeling
A structural model of dimeric human ER bound to 4-OHT was
constructed from 3ERT.pdb (21) using crystallographic
symmetry operations. After removing all water molecules except the
ordered water forming a hydrogen bond with the O4 of 4-OHT, the model
was minimized in the consistent valance force field using Discover
(Molecular Simulations Inc., San Diego, CA). The small molecule GW7604
was constructed using tamoxifen found in 3ERT as template, and the
compound was then minimized in consistent valance force field using
Discover. For docking, GW7604 was placed in the active site, using
4-OHT as a guide, and the compound hydroxyl was restrained to be within
4.0Å of both the order water molecule and Glu 353, using a quadratic
force term. Docking was performed using Affinity, and results were
visualized using Insight 9.72 (Molecular Stimulations, Inc., San
Diego, CA).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
) were extremely sensitive to the
proliferative effects of E2, but GW7604 did not
increase the proliferation of endometrial cancer cells above control
(no treatment). In contrast, 4-OHT showed a concentration-related
increase in the proliferation of endometrial cancer cells. The
magnitude of the estrogen-like response of 4-OHT was increased at low
concentrations, compared with GW7604, but was not as dramatic as the
E2 response (Fig. 2A). We also demonstrated that,
at high concentrations
(10-7 M), the
antiestrogens inhibited the E2-stimulated
(10-10 M)
proliferation of endometrial cancer (ECC-1) cells (Fig. 2B) and breast
cancer (MCF-7) cells (Fig. 2C).
|
) that E2
decreases the transcription of ER in MCF-7 cells with decreased protein
levels (Fig. 3A) (29). Interestingly, 4-OHT increased ER
in MCF-7 cells but only at the protein level. It is widely accepted
that pure antiestrogen ICI182,780 degrades ER protein although having
no effect on ER mRNA (17, 29). Because GW7604 has
previously been found to decrease ER protein (16), we
tested the effects of GW7604 on ER protein levels in our cell lines and
compared the results with the effect of ICI 182, 780. In Fig. 3A, Western blot analysis shows ER protein levels in MCF-7 and ECC-1 cells
after treatment with E2, 4-OHT, raloxifene, and
ICI182,780. GW7604 did not appreciably decrease the level of ER
protein in either cell population, compared with the decrease observed
with the pure antiestrogen ICI 182,780. These data were repeated at
least three times for MCF-7 cells, and the changes in ER protein were
quantified. Of the antiestrogens, only ICI 182,780 produced a
significant (P < 0.05) decrease in ER protein levels,
compared with untreated cells (Fig. 3B). ER mRNA was determined, and
only E2 caused an expected decrease in MCF-7
cells (Fig. 3C). The ER mRNA was also decreased in ECC1 cells by
E2 treatment but was unaffected by the
antiestrogens (Fig. 3C).
|
gene mRNA in
cells transfected with wild-type ER (Fig. 4, A and B). This was in marked contrast
to the effect of E2
(10-9 M) and
4-OHT (10-7
M), both of which activated the TGF gene in cells with
wild-type ER (Fig. 4, A and B). Most importantly, increasing
concentrations of GW7604 blocked gene activation of TGF by two
concentrations (10-8 and
10-7 M) of
4-OHT (Fig. 4B). As would be predicted if competition occurs at the ER,
GW7604 was more effective against the lower concentration
(10-8 M)
4-OHT. We then investigated the interaction of GW7604 with
E2 by comparing and contrasting the actions of
the compound in wild-type and D351Y ER-containing cells. We confirmed
that GW7604:wild-type ER complexes were antiestrogenic at the TGF
gene; increasing the concentrations of GW7604
(10-8–10-6
M) blocked E2
(10-9
M)-induced increases in TGF mRNA (Fig. 5, A and B). However, cells stably
transfected with the cDNA for the mutant ER D351Y increased TGF mRNA
in a concentration-related manner (Fig. 5, A and B). Nevertheless, the
increases observed with GW7604 did not reach statistical significance
in this series of experiments. We have previously reported that
nonsteroidal antiestrogens whose side chain interacts with aa351 in the
wild-type ER can become estrogen-like if aspartate is switched to
tyrosine (25, 27). The nonsteroidal antiestrogens in this
category that bind to the ER in this manner are related to raloxifene
(27).
|
|
gene activation in freshly thawed stock cells
stably transfected with cDNAs for wild-type or D351Y ER. The results
(Fig. 6, A and B) demonstrated that
GW7604 interacts with the ER at aa351. GW7604, unlike 4-OHT, did not
stimulate TGF mRNA via wild-type ER, but both D351Y ER:GW7604 and
raloxifene complexes activated the TGF gene. ICI 182,780, the pure
antiestrogen, did not activate the TGF gene with either wild-type or
D351Y ER alone (Figs. 6B and 7B) and
acted as an inhibitor of TGF gene induction if used in combination
with E2, 4-OHT, raloxifene, or GW7604 in cells
transfected with D351Y ER (Fig. 7, A and B). These data illustrate the
unique properties of ICI182,780 and the difference from the
nonsteroidal compound GW7604.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
)
has reduced estrogen-like actions at the TGF gene and can block both
E2 and 4-OHT induction of TGF mRNA. We
conclude, from the data presented (Figs. 6 and 7), that GW7604 is a
compound that could be classified as a raloxifene-like compound but
cannot be classified as a pure antiestrogen (Figs. 3 and 7).
We have advanced that idea the 4-OHT and GW7604 have an interaction
with aa351 (aspartate) by examining the external surface of the
complexes. The x-ray crystallography of the 4-OHT ER complex (ligand
binding domain) demonstrates that the protein envelopes the
antiestrogen, but helix 12 (shown in blue in Fig. 8A) is unable to position itself over the
top of the ligand because the side chain of 4-OHT is in the vicinity of
asp351. Shiau and co-workers (21) have used x-ray
crystallography to show that Helix 12 is now occupying the GRIP1
binding site, thereby silencing AF-2 activation. However, the fact that
4-OHT ER complexes are estrogen-like at the TGF gene, in the context
of the MDA-MB-231 breast cancer cell, suggests that other coactivators
of estrogen action must bind at novel sites on the complex. This
hypothesis was first proposed by Norris et al.
(31), who found that coactivators required for gene
activation of E2 or 4-OHT:ER complexes bind at
different sites on their respective complexes. We suggest that the
putative coactivator that binds to the 4-OHT ER complex and causes gene
transcription may bind to the area around the aspartate at aa351. The
exposed negative charge from aspartate in the 4-OHT ER complex would be
available to interact with an LXXLL area on the binding site of a
putative coactivator.
|
gene. Raloxifene and
4-OHT are both antiestrogens, and they block E2
action at the TGF gene with the D351G ER (32). In the
current study, we suggest that GW7604 does not neutralize or shield the
charge on the aspartate of wild-type ER but causes a repulsion of the
aspartate at aa351 (Fig. 8, A and B). In Fig. 8B, we show the
three-dimensional structures of both 4-OHT and GW7604, to illustrate
directly the differences in interaction with relevant amino acids. We
suggest that the repositioning of the surface charge around aa351 (Fig. 8A, right) is responsible for the reduced estrogenicity of
GW7604, because it cannot now bind to the appropriate coactivator
molecule for gene transcription. This conclusion supports the recent
report by Wijayaratne and co-workers (16), which
demonstrated general differences in the surfaces of GW 7604 ER
complexes and 4-OHT:ER complexes using a phage display technique.
However, the authors could not define a precise area on the surface of
the ER. We suggest that the most likely area for coactivator
interaction will involve aa351. Based on our accumulated experimental
evidence (25, 26, 27, 32), it is possible to summarize our
observations to propose a working model for the estrogen-like action of
several SERMs.
We suggest that the precise positioning of the surface aa351 aspartate
is critical for the assembly of a transcription complex at the TGF
gene. The side chain of raloxifene shields the aspartate completely, to
prevent gene activation (25); but the gene can be
reactivated with a larger charged amino acid substitution at 351, such
as tyrosine (25). The interaction of the side chain of
4-OHT with aspartate 351 is inadequate (21), and the
remaining charge can enhance TGF gene activation (26).
Removal of the charge at aa351 by substituting glycine retains
antiestrogenic activity but silences estrogen-like properties for the
4-OHT ER complex (32). Changing the amino acid from
glycine to tyrosine restores the charge at 351 and restores the
estrogen-like properties of the 4-OHT ER complex (26). The
observation that GW7604 also silences the ER complex implies that the
relocation of aspartate 351 on the surface (Fig. 8) creates an
inappropriate surface charge that prevents coactivator binding and, as
a result, prevents activation of the TGF gene. The replacement of
aspartate for tyrosine in D351Y ER must, therefore, permit some
coactivator binding to cause weak TGF gene transcription with GW7604
(Fig. 6).
Our second observation is that GW7604 is less estrogen-like than 4-OHT
in the ECC-1 endometrial cancer cell proliferation assay. In this
study, ECC-1 cells and MCF-7 cells were used to confirm the
antiproliferative action of GW7604 (11). Dauvois et
al. (33) used MCF-7 cells to establish that the
steroidal pure antiestrogen ICI182,780 would cause destruction
of ER. We subsequently confirmed these findings using ICI182,780
(29) and noted that ER mRNA is maintained, although
protein is lost. Although the profiles of GW7604 in some assays
resemble that of pure antiestrogens, GW7604 is distinct from steroidal
antagonists such as ICI182,780, because it does not appreciably degrade
ER protein levels in breast or uterine cells (Fig. 3). These data
support the general conclusion of the SERM classification assay.
The observation that GW7604 is a raloxifene-like compound at ER is
consistent with the previous findings that, like raloxifene (34, 35), the prodrug GW5638 maintains bone density in the rat but
blocks estrogen action in the uterus (12, 13). However,
the present and previous (16) mechanistic studies do
indicate that GW7604 produces a distinctly different external surface
of the ER than either tamoxifen or raloxifene. We support the view that
the molecular mechanism of action of GW7604 makes it different from
compounds reported previously (16). The finding that
GW7604 has low potential to stimulate the proliferation of endometrial
cancer cells is excellent preliminary data to suggest that, unlike
tamoxifen (3, 5), the prodrug GW5638 might not increase
the incidence of endometrial cancer in patients. GW5638 is being
advanced to the next stage of development by testing in animal models
of human drug resistance to tamoxifen (36, 37, 38) to garner
appropriate preclinical data before clinical testing is initiated.
|
Footnotes |
|---|
Received July 11, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  C. Delfour, P. Roger, C. Bret, M.-L. Berthe, P. Rochaix, N. Kalfa, P. Raynaud, F. Bibeau, T. Maudelonde, and N. Boulle RCL2, a New Fixative, Preserves Morphology and Nucleic Acid Integrity in Paraffin-Embedded Breast Carcinoma and Microdissected Breast Tumor Cells J. Mol. Diagn., May 1, 2006; 8(2): 157 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Pinzone, H. Stevenson, J. S. Strobl, and P. E. Berg Molecular and Cellular Determinants of Estrogen Receptor {alpha} Expression Mol. Cell. Biol., June 1, 2004; 24(11): 4605 - 4612. [Full Text] [PDF]
|
|
|
|
 |
|
 E. V. Jensen and V. C. Jordan The Estrogen Receptor: A Model for Molecular Medicine Clin. Cancer Res., June 1, 2003; 9(6): 1980 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Levenson, K. M. Svoboda, K. M. Pease, S. A. Kaiser, B. Chen, L. A. Simons, B. D. Jovanovic, P. A. Dyck, and V. C. Jordan Gene Expression Profiles with Activation of the Estrogen Receptor {alpha}-Selective Estrogen Receptor Modulator Complex in Breast Cancer Cells Expressing Wild-Type Estrogen Receptor Cancer Res., August 1, 2002; 62(15): 4419 - 4426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Dardes, R. M. O'Regan, C. Gajdos, S. P. Robinson, D. Bentrem, A. De Los Reyes, and V. C. Jordan Effects of a New Clinically Relevant Antiestrogen (GW5638) Related to Tamoxifen on Breast and Endometrial Cancer Growth in Vivo Clin. Cancer Res., June 1, 2002; 8(6): 1995 - 2001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, W.-C. Park, D. J. Bentrem, K. P. McKian, A. D. L. Reyes, J. A. Loweth, J. M. Schafer, J. W. Zapf, and V. C. Jordan Structure-Function Relationships of the Raloxifene-Estrogen Receptor-alpha Complex for Regulating Transforming Growth Factor-alpha Expression in Breast Cancer Cells J. Biol. Chem., March 8, 2002; 277(11): 9189 - 9198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Dardes, D. Bentrem, R. M. O'Regan, J. M. Schafer, and V. C. Jordan Effects of the New Selective Estrogen Receptor Modulator LY353381.HCl (Arzoxifene) on Human Endometrial Cancer Growth in Athymic Mice Clin. Cancer Res., December 1, 2001; 7(12): 4149 - 4155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan, S. Gapstur, and M. Morrow Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease J Natl Cancer Inst, October 3, 2001; 93(19): 1449 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Goldhirsch, J. H. Glick, R. D. Gelber, A. S. Coates, and H.-J. Senn Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer J. Clin. Oncol., September 15, 2001; 19(18): 3817 - 3827. [Full Text] [PDF]
|
|
|
|
|
|
V. C. Jordan, J. M. Schafer, A. S. Levenson, H. Liu, K. M. Pease, L. A. Simons, and J. W. Zapf Molecular Classification of Estrogens Cancer Res., September 1, 2001; 61(18): 6619 - 6623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Jordan Selective Estrogen Receptor Modulation: A Personal Perspective Cancer Res., August 1, 2001; 61(15): 5683 - 5687. [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, E.-S. Lee, A. D. L. Reyes, J. W. Zapf, and V. C. Jordan Silencing and Reactivation of the Selective Estrogen Receptor Modulator-Estrogen Receptor {{alpha}} Complex Cancer Res., May 1, 2001; 61(9): 3632 - 3639. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
