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Laboratory of Molecular Endocrinology, Le Centre Hospitalier de l’Université Laval Research Center and Laval University, Québec, G1V 4G2, Canada
Address all correspondence and requests for reprints to: Professor Fernand Labrie, MRC Group in Molecular Endocrinology, CHUL Research Center, 2705 Laurier Boulevard, Québec, G1V 4G2, Canada.
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Abstract |
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Tamoxifen, on the other hand, showed a stimulatory estrogenic-like
action on the mouse uterus in both intact and ovariectomized animals,
thus resulting in moderate to severe endometrial hyperplasia. These
morphological changes were accompanied by a marked stimulation of both
the estrogenic and androgenic 17ß-hydroxysteroid dehydrogenase as
well as 5
-reductase uterine activities. The histological atrophic
changes observed in the vagina after tamoxifen treatment were less
pronounced than those seen after treatment with EM-800. The agonistic
estrogen-like action of tamoxifen was also illustrated by the
suppression of serum LH levels in ovariectomized animals.
A marked stimulation of the ovarian stroma, accompanied by a significant reduction in folliculogenic activity, was observed after EM-800 or tamoxifen administration, although the interstitial ovarian hyperplasia was more pronounced after EM-800 treatment. While both antiestrogens blocked the developmental growth of the mammary gland, EM-800 showed more potent antiestrogenic activity than tamoxifen. The highly potent and specific antiestrogenic activity of EM-800 suggests that this compound could improve the therapy of breast cancer while avoiding the undesirable stimulation of the endometrium.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The therapeutic approaches for estrogen-sensitive breast cancer have focused on the use of antiestrogens, especially tamoxifen, that block the interaction of estrogens with their specific receptor in the mammary gland (10, 11, 12). Although tamoxifen has shown clear beneficial effects for the treatment of breast cancer, especially when given as an adjuvant to surgery (10, 13), this compound is known to possess mixed agonistic/antagonistic activities that are species-, cell-, and gene-specific (14, 15, 16, 17, 18, 19).
The need for compounds having pure antiestrogenic action and thus
lacking partial estrogenic action in the human mammary gland and
endometrium has led to the development of drugs, such as 7-alkyl
derivatives of estradiol, that possess pure and potent antiestrogenic
activity, both in vivo and in vitro (20, 21, 22, 23, 24, 25).
The present study compares the effects of long-term administration of tamoxifen in intact and ovariectomized mice, in comparison with those seen after treatment with EM-800, a new orally active pure antiestrogen developed in our laboratory. This orally active compound is the most potent and pure antiestrogen in human breast and uterine cancer cells (26, 27, 28, 29). We have also investigated possible alterations of the activity of steroidogenic enzymes, especially in the uterus, after administration of the two compounds.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemicals
EM-800
((+)-7-pivaloyloxy-3-(4'-pivaloyloxyphenyl)-4-methyl-2-(4''-(2'''-piperidinoethoxy)phenyl)-2H-benzopyran)
(Fig. 1
) was synthesized in the medicinal
chemistry division of our laboratory while tamoxifen was from Sigma
Chemical Co. (St. Louis, MO). EM-800 and tamoxifen, prepared in 4%
ethanol, 4% polyethylene glycol 600 (PEG-600), 1% gelatin, 0,9%
NaCl, were administered orally, once daily for 24 weeks, in a total
volume of 0.2 ml.
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EM-800 and tamoxifen were administered daily for 24 weeks orally (by gavage) using the vehicle 1% gelatin (wt/vol) and 4% (wt/vol) PEG-600. In ovariectomized animals, treatment was started 4 days after ovariectomy. Body wt was measured once a week. Control animals received the same volume of the vehicle. The animals were killed by decapitation under basal conditions in a longitudinal fashion.
Histology
The tissues (ovaries, uterus, and vagina) from each animal were
weighed, immersed in a solution of 10% buffered formalin for 48
h, routinely processed in a tissue processor, and embedded in paraffin,
as previously described (30). Sections of 5–6 µm were cut and
stained with hematoxylin-eosin. Examination of the tissue slides was
performed by light microscopy.
5-Reductase and 17ß-hydroxysteroid dehydrogenase (17ß-HSD)
assays
Tissues were homogenized with a Polytron PT-10 homogenizer
(Brinkman Instruments, Canada), at a setting of 8 for 10 sec, in 1.0 ml
phosphate buffer (20 mM KH2PO4,
0.25 M sucrose, 1 mM EDTA, pH 7.5) containing
protease inhibitors (1 mM phenylmethylsulfonyl fluoride and
5 mg/ml each of pepstatin A, antipain, and leupeptin) and then
centrifuged for 30 min at 1000 x g to remove cell
debris. Protein content of tissue homogenates was measured by the
method of Bradford using BSA as standard (31). Aliquots of homogenate
were incubated at 37 C in 0.5 ml phosphate buffer (12.5 mM
KH2PO4, 1 mM EDTA, pH 7.5)
containing 0.6 µM 14C-labeled substrates
obtained from New England Nuclear (Boston, MA):
[14C]testosterone (57.3 mCi/mmol),
[14C]estrone (E1) (51.7 mCi/mmol), and
[14C]androstenedione (4-dione) (53.9 mCi/mmol).
NADP+ was used as cofactor for 5-reductase while NADH
and NADPH were used as cofactors for the reductive form of 17ß-HSD,
and NAD+ and NADP+ were used as cofactors for
the oxidative form of 17ß-HSD. Cofactors were present at the final
concentration of 1 mM.
Duration of the assay was chosen to maintain the final conversion of the 14C-labeled substrate below 20%. The enzymatic reaction was stopped by chilling the incubation mixtures in an ice water slurry. After 3 ml diethyl ether were added and vortexed for 1 min, the tubes were centrifuged at 2000 x g for 10 min to separate the aqueous and organic phases and then placed in an ethanol-dry ice bath. The organic phase was decanted while the aqueous phase was extracted once more. The two organic phases were pooled and evaporated to dryness under a stream of nitrogen. Next, 20 µg each of unlabeled 4-dione, testosterone, progesterone, and 11-deoxy-cortisol were added as carriers to facilitate identification of the spots on the TLC plates. The residue obtained was suspended in 70 µl dichloromethane (CH2CL2) and chromatographed on 60 f254 silica gel plates with a mixture of toluene-acetone (4:1, vol/vol). Visualization of the carrier steroids was achieved by UV light, and autoradiography was then performed for 24 h. The spots corresponding to substrate and metabolites as revealed by autoradiography of the TLC plates were cut out and transferred into scintillation vials containing 0.5 ml ethanol and 10 ml scintillation fluid for radioactivity counting. Enzymatic activity was expressed as picomoles of product formed per mg protein/min.
RIAs
Serum LH was measured by double-antibody RIA using rat hormones
(LH-I-6 for iodination and LH-RP-2 as standard), and the rabbit
antiserum anti-rLH-S-8 generously supplied by the National Pituitary
Program (Baltimore, MD).
Statistical analysis
Statistical significance was measured according to the
multiple-range test of Duncan-Kramer (32). Data are expressed as
means ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). While EM-800
led to a 62% (P < 0.01) maximal inhibition of uterine
wt at the daily oral dose of 100 µg, the inhibition achieved with the
same dose of tamoxifen was only 24% (P < 0.01). On
vaginal wt, the 100 µg dose of EM-800 and tamoxifen gave inhibitions
of 68% and 48%, respectively (P < 0.01 for both
groups vs. intact control). Since a near-plateau was reached
at the daily 100 µg oral dose for both compounds, this dose was
chosen for the 6-month study.
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). In ovariectomized animals, treatment
with EM-800 decreased uterine wt below the value found in control
ovariectomized animals, namely from 64.0 ± 3.88 mg to 37.2
± 2.4 mg, respectively (P < 0.01) (Fig. 2). On the
other hand, as can be seen in the same figure, no statistically
significant inhibitory effect on uterine wt was observed after
treatment with tamoxifen in either intact or ovariectomized
animals.
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). More specifically, EM-800 caused a
58.3% decrease in vaginal wt in intact animals from 63.3 ± 3.89
mg to 26.4 ± 1.04 mg (P < 0.01). On the other
hand, in ovariectomized animals, treatment with EM-800 inhibited
vaginal wt to a value 32.9% below that found in control ovariectomized
mice, namely from 33.8 ± 1.15 mg in control mice to 22.7 ±
0.82 mg, P < 0.01. Tamoxifen, on the other hand,
decreased vaginal wt by 69.2% in intact mice (from 63.3 ± 3.89
to 19.5 ± 0.75 mg, P < 0.01) and by 35% (from
33.8 ± 1.15 to 22.0 ± 0.63 mg, P < 0.01),
in ovariectomized animals, respectively, in comparison with the
corresponding vehicle-treated controls (Fig. 3).
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At histopathological examination of the tissues, a moderate uterine
atrophy was observed 24 weeks after ovariectomy. These changes were
characterized by decreased endometrial and myometrial thickness as well
as by condensation of the endometrial stroma (Fig. 4B compared with 4A). The atrophic
glandular epithelial cells had an inactive appearance with a reduced
amount of cytoplasm and a cytoplasmic/nuclear ratio <1. The myometrium
in ovariectomized animals was composed of basophilic cells with a
decreased amount of cytoplasm. Treatment of intact animals with EM-800
at the daily dose of 100 µg, for 6 months, resulted in a moderate to
marked uterine atrophy that involved both the endometrial and
myometrial layers and was more pronounced than that observed in
ovariectomized-control animals. Such reduced thickness of both the
endometrial and myometrial layers was accompanied by a decrease in the
endometrial to myometrial volume ratio. The endometrial atrophy was
characterized by a reduced number of endometrial glands, which were
lined by atrophic glandular cells having a cytoplasmic/nuclear ratio
<1. On the other hand, the condensed stroma was composed of apparently
inactive stromal cells while, in some areas, a mild edema of the stroma
was observed. Myometrial cells of EM-800-treated animals had increased
basophilia and a decreased amount of cytoplasm.
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). A marked, often
cystic, dilatation of the endometrial glands was also observed. These
changes were accompanied by the accumulation of secretory, eosinophilic
material in the glandular and endometrial lumen as well as a regional
moderate edema of the endometrial stroma. A polypoid structure, as
well as an increased height of the luminal epithelium, was seen in
intact animals treated with tamoxifen (Fig. 5C). A moderate hypertrophy
and stratification of the glandular epithelium was also observed in
tamoxifen-treated intact animals, with the presence of mild focal
nuclear atypia, characterized by enlargement and pleomorphism of the
nuclei containing prominent nucleoli (Fig. 5, E and F). In the
myometrial layer, treatment with tamoxifen led to a mild to moderate
atrophy, this change being accompanied by a reduced amount of cytoplasm
in the myometrial cells, thus resulting in decreased myometrial
thickness (Fig. 5C).
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, when EM-800 was administered to ovariectomized
animals at the daily dose of 100 µg, a moderate to marked uterine
atrophy was observed which, interestingly, was greater than that
achieved after ovariectomy. On the contrary, treatment of
ovariectomized female mice with tamoxifen, at the same dose, caused the
appearance of a cystic endometrial hyperplasia analogous to that seen
in intact animals treated with the same dose of tamoxifen. An increased
endometrial thickness was also observed (Fig. 5, D and F).
A severe vaginal atrophy was found 6 months after ovariectomy, the
vaginal epithelium being composed of only one to three layers of
atrophic germinal epithelial cells (Figs. 6B and 7B). After treatment with EM-800,
a severe vaginal atrophy was seen in intact animals analogous to that
seen in ovariectomized controls. These changes were characterized by a
marked decrease in the thickness of the vaginal epithelium, which was
composed of only one to three layers of germinal epithelial cells (Fig. 6C). In ovariectomized animals treated with EM-800, the observed
vaginal atrophy illustrated by one to three layers of germinal
epithelial cells did not differ from that seen in ovariectomized
controls (Fig. 6, panels D and B, respectively).
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). Similarly, in ovariectomized animals
treated with the same dose of tamoxifen, the vaginal epithelium
consisted of three to five layers of epithelial cells (Fig. 7D).
Interestingly, a more severe atrophy of the vaginum characterized by
one to three epithelial layers of atrophic germinal cells was observed
after ovariectomy and treatment with EM-800 of intact and
ovariectomized animals (Figs. 7B and 6D, respectively).
Treatment with 100 µg EM-800, for 6 months, resulted in a moderate
hypertrophy as well as in a moderate to marked hyperplasia of the
interstitial cells of the ovarian stroma. The interstitial cells were
enlarged and contained abundant, pale eosinophilic and finely grandular
cytoplasm with a centrally located or laterally displaced nucleus (Fig. 8D1). These cells were arranged in nests,
causing expansion of the volume of the stromal ovarian tissue.
Concomitantly, a significant reduction in folliculogenic activity was
seen. The above indicated change was accompanied by a moderate to
marked decrease in the number of developing follicles and corpora
lutea, while a mild to moderate increase in the number of
atretic-anovulatory follicles was also present (Fig. 8B). After
treatment with tamoxifen, a moderate to marked decrease in the number
of developing follicles and corpora lutea was seen. This effect was
accompanied by the presence of multiple foci of moderate interstitial
cell hypertrophy (Fig. 8C). Similar to the changes observed after
EM-800 treatment, the interstitial cells contained abundant
eosinophilic and finely granular cytoplasm (Fig. 8D2).
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and 10C). In addition, no additional effects on
the mammary gland histomorphology were observed after EM-800 (Fig. 9D) or tamoxifen (Fig. 10D) administration in ovariectomized
animals, the mammary gland showing atrophic changes identical to those
seen in ovariectomized controls (Figs. 9B and 10B).
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, a
significant stimulation of reductive estrogenic 17ß-HSD activity,
responsible for the conversion of estrone to estradiol, was observed
after tamoxifen administration in both intact (from 1.67 ± 0.09
to 6.30 ± 0.72 pmol/mg/min, P < 0.01) and
ovariectomized (from 1.08 ± 0.22 to 7.31 ± 0.67
pmol/mg/min, P < 0.01), animals compared with intact
and ovariectomized controls, respectively. On the contrary, it can be
seen that the 24-week treatment with EM-800 had no significant effect
on the rate of conversion of estrone to estradiol in uterine homogenate
obtained from either both intact or ovariectomized-treated animals.
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that when
[14C]androstenedione was used as substrate, treatment
with tamoxifen caused a highly significant increase in uterine
androgenic reductive 17ß-HSD activity, in both intact (from 3.09
± 0.44 to 6.44 pmol/mg/min, P < 0.01) and
ovariectomized animals (from 4.20 ± 1 to 8.44 ± 1.13
pmol/mg/min, P < 0.01). EM-800 administration, on the
other hand, caused no statistically significant change in uterine
androgenic reductive 17ß-HSD activity in both intact and
ovariectomized mice (Fig 12).
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-reductase, which catalyzes the conversion of testosterone to
dihydrotestosterone (from 0.40 ± 0.05 to 1.62 ± 0.22
pmol/mg/min, P < 0.01), while no significant change in
uterine 5-reductase was observed after tamoxifen treatment in intact
animals. EM-800 had no significant effect in either intact or
ovariectomized animals on this parameter (Fig. 13).
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)
while no significant effect of EM-800 was observed on serum LH levels
in ovariectomized animals where serum LH was increased 30-fold compared
with intact animals. On the other hand, tamoxifen administration
resulted in a highly significant suppression of serum LH levels in both
intact and ovariectomized animals (from 0.22 ± 0.04 to 0.13
ng/ml, P < 0.01; and from 6.37 ± 1.21 to
0.75 ± 0.03 ng/ml in intact and ovariectomized animals,
respectively, P < 0.01) (Fig. 14).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interestingly, the uterine wt measured after EM-800 treatment of ovariectomized animals was smaller than that found after ovariectomy alone. Moreover, the histopathological changes reflected the changes in uterine wt. Thus, the marked EM-800-induced uterine atrophy, involving both the endometrial and myometrial layers, was accompanied by an apparently inactive endometrium. The atrophic endometrium was composed of a few atrophic glands and a low cuboidal glandular and luminal epithelium, with a cytoplasmic-nuclear ratio lower than 1. It is also noteworthy that the endometrial atrophy achieved with EM-800 in ovariectomized animals was significantly greater than that observed 6 months after castration alone. This dramatic inhibition of uterine morphology achieved with EM-800 appears to be superior to that reported for other recently developed, specific antiestrogens (20) and certainly very different from that of tamoxifen.
In fact, no significant reduction in uterine wt was observed after 24
weeks of treatment of intact animals with tamoxifen, while uterine wt
in ovariectomized animals treated with tamoxifen was not significantly
different from that of control ovariectomized rats. In fact, a marked
stimulation of the endometrial layer was observed in both intact and
ovariectomized animals treated with tamoxifen. This stimulatory effect
of tamoxifen on the endometrium was characterized by severe cystic
endometrial hyperplasia, luminal fluid retention, and hypertrophy of
the luminal and glandular epithelium with focal cellular atypia. Most
of the histological changes observed in the endometrium after tamoxifen
treatment represent typical estrogenic-like uterotrophic effects
accompanying increased circulating estrogen levels (38). Such changes,
as illustrated in Fig 5, are also seen after estradiol treatment in
laboratory animals (39, 40, 41).
Although evidence for an estrogenic action of tamoxifen in the human myometrium has been reported (42, 43), we have not observed such an action in the rat myometrium in the present study. On the contrary, treatment of intact animals with tamoxifen resulted in an atrophic myometrium, while no additional effects were seen in the myometrium of ovariectomized animals that received this antiestrogen compared with ovariectomized control animals.
The stimulatory effect of tamoxifen on the uterus, due to its partial estrogenic activity, has been described previously in rats and mice (39, 40, 41, 44, 45, 46, 47, 48) as well as in women (35, 42, 49, 50, 51, 52). A preferential activity of tamoxifen for the glandular uterine epithelium has also been demonstrated, when compared with other antiestrogens, which are also partial agonists for the estrogen receptor (39).
Both EM-800 and tamoxifen treatments led to a decrease in vaginal wt in intact and ovariectomized treated animals, an effect that was significantly greater than the effect of ovariectomy alone. Despite this global inhibition of vaginal wt, the vaginal epithelium was less atrophic after tamoxifen treatment, compared with intact animals treated with EM-800 in whom a severe vaginal atrophy, identical to that seen after ovariectomy, was observed. Due to the relatively small volume of the vaginal epithelial cells of the mucosa, the inhibition by tamoxifen of the volume of the underlying muscular and stromal layer led to an overall inhibition of vaginal wt in ovariectomized animals treated for 6 months with tamoxifen compared with ovariectomy alone. On the other hand, many studies have reported that tamoxifen administration leads to increased maturation and estrogenization of the vaginal mucosa in rats and mice as well as in postmenopausal women (48, 53, 54, 55, 56, 57, 58).
EM-800 treatment led to a significant increase in ovarian wt, which was associated with a corresponding hypertrophy and hyperplasia of the interstitial cells, thus leading to a marked expansion of the interstitial stroma. These changes were accompanied by a significant reduction in folliculogenic activity, suppression of ovulation, absence of new corpora lutea, and development of cystic atretic follicles.
Stromal cell hyperplasia often accompanies ovarian atrophic changes including lack of normally developing follicles and absence of corpora lutea, these two changes being signs of inhibited ovulation and loss of normal ovarian cyclicity (59). On the other hand, the elevation in serum LH levels from 0.22 ± 0.04 to 1.17 ± 0.32 (P < 0.01) in intact animals treated with EM-800 is likely to account, at least in part, for the hyperstimulation of the ovarian stroma seen after treatment with EM-800. In addition, analogous histological ovarian changes have been described by Korach (60) in transgenic estrogen receptor knockout mice having a high circulating level of gonadotropins. An elevation of serum LH levels and an inhibition of ovulation have also been reported by Dukes et al. (61) after treatment with other pure antiestrogens, although at a lower magnitude and after a shorter duration of treatment.
Estrogens are well known to exert a global inhibitory effect at the hypothalamo-pituitary level in the rat (62). It is noteworthy that although serum LH increased in intact animals treated with EM-800, the levels achieved were much lower than those measured after ovariectomy. Since EM-800 achieves a complete blockade of uterine and vaginal wt, one explanation for the relatively smaller increase in serum LH could be the partial access of EM-800 at the hypothalamic site of control of LHRH secretion in the rat. Access to the feedback mechanisms controlling LHRH secretion is limited by the blood-brain barrier, and marked species differences are known to exist.
Analogous, but of lower magnitude, histological changes indicative of suppression of ovulation and ovarian stromal hypertrophy, were seen after tamoxifen treatment. A significant decrease in ovarian wt was also observed in the animals treated with tamoxifen. It is noteworthy that after treatment with tamoxifen, the expansion of the ovarian stroma was mainly due to interstitial cell hypertrophy, and neither significant hyperplasia nor a large number of cystic follicles were seen, as observed in animals treated with EM-800. In addition, the suppression of serum LH levels with tamoxifen administration clearly demonstrates its estrogenic activity at the hypothalamo-pituitary level, as opposed to the pure antiestrogenic activity of EM-800 illustrated by the increases in both serum LH levels and ovarian wt.
Each sex steroid-sensitive tissue, depending upon the type(s) as well as the relative activities of the steroidogenic enzymes expressed locally, can regulate and modulate the formation, metabolism, and action of steroid hormones, according to local requirements, in a tissue-specific manner (63, 64). Thus, compounds having antiestrogenic and/or estrogenic action can potentially modulate the activities of the steroidogenic enzymes. Such an action could provide an additional mechanism for controlling the estrogenic response in target tissues. In this context, the enzyme 17ß-HSD, responsible for the interconversion of estradiol to estrone, is likely to play an important role in the physiology of the uterus, vagina, and mammary gland (63, 65, 66, 67).
A significant increase in the uterine reductive estrogenic as well as
androgenic 17ß-HSD activities, with a subsequent expected increase in
the formation of estradiol and testosterone from estrone and
androstenedione, respectively, was observed in the uterus of both
intact and ovariectomized animals treated with tamoxifen. In addition,
a significant increase in 5-reductase activity, responsible for the
formation of dihydrotestosterone from testosterone, was observed in
ovariectomized animals treated with tamoxifen. The biological
consequences of such effects remain to be determined. In the present
study, although the tissue content of active steroids and their
metabolites have not been measured, the possibility exists that changes
in intracellular levels of androgens and/or estrogens could be
responsible up to an unknown extent for the uterotrophic effects of
tamoxifen observed in our study in intact animals. On the other hand,
treatment with EM-800 did not have any effect on the activities of
17ß-HSD or 5-reductase in uterine tissues of both ovariectomized
and intact animals treated with this compound.
With respect to the effects on the mammary gland, the two antiestrogens completely inhibited the growth and tubuloalveolar development of the mouse mammary gland. Full development of the mouse mammary gland occurs at the age of 3 months in the mouse, whereas treatment of the animals used in our study started at approximately 2 months. Although tamoxifen administration has been shown to promote the growth of the mammary gland in the immature female rat (68), no such action has been observed under the experimental conditions used in our study in the mouse.
The present data demonstrate the highly potent and pure antiestrogenic activity of EM-800. When compared with tamoxifen, the improved inhibition of estrogen action was observed on all the estrogen-sensitive parameters studied in the mouse, namely the uterus, vagina, mammary gland, and hypothalamo-pituitary-ovarian feedback system. The pure antiestrogenic activity of EM-800, which leads to a more complete blockade of estrogen action in all the estrogen target tissues examined, suggests that this compound could offer the possibility of a more efficient treatment of breast cancer as well as of other estrogen-sensitive conditions, such as endometriosis, leiomyomata, and benign breast disease as well as other estrogen-responsive conditions in men and women.
Received April 17, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5-steroids in the ZR-75–1 human breast cancer cell
line. Cancer Res 46:4933–4937-dihydrotestosterone and antiestrogen N,
n-butyl-N-methyl-11-(16'-chloro-3', 17ß-dihydroxy-estra-1', 3',
5'-(10')triene-7'-yl)undecanamide in human breast cancer ZR-75–1
cells. Cancer Res 51:2797–2802This article has been cited by other articles:
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 F. Labrie, P. Champagne, C. Labrie, J. Roy, J. Laverdiere, L. Provencher, M. Potvin, Y. Drolet, M. Pollak, L. Panasci, et al. Activity and Safety of the Antiestrogen EM-800, the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant Breast Cancer J. Clin. Oncol., March 1, 2004; 22(5): 864 - 871. [Abstract] [Full Text] [PDF]
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