Antitumor Steroids
449
Partial antiestrogens (OH-Tam and re-
lated SERMs), which maintain the HBD
in an open conformation, accumulate the
receptor within the nucleus in which
it progressively loses its ability to bind
estradiol. Blockade of the proteasomal
degradation of ER by these antagonists as-
sociated with maintenance of its synthesis
(see Sect. 3.4), explains this accumula-
tion process.
3.4
Ligand-induced Regulation of Estrogen
Receptor Level
Ligands strongly influence the turnover
rate of ER, by regulating its production
and ubiquitin-dependent proteolysis. Es-
trogens block ER synthesis (decrease of
ER mRNA level) while antiestrogens do
not. Maintenance of ER synthesis un-
der antiestrogen treatment may therefore
upregulate the receptor when its protea-
somal degradation is weak, as observed
with OH-Tam and related SERMs. Es-
trogens and pure antiestrogens induce a
strong and rapid ubiquitination of the
receptor,
leading
to
its
rapid
proteol-
ysis;
SERMs
are
largely
less
effective
in
this
regard.
As
a
consequence
of
these regulatory processes, estrogens, and
pure antiestrogens downregulate the re-
ceptor
while
SERMs
may
lead
to
its
accumulation.
The
ability
of
cycloheximide
and
puromycin
to
stabilize
the
activated
receptor within the cell nucleus suggests
the
induction
of
a
protein
favoring
its return into the cytoplasm where it
would
be
degraded.
This
concept
of
cytoplasmic degradation is supported by
the observation that cycloheximide and
puromycin fail to block the ER elimination
when it is provoked by pure antiestrogens,
which fail to stabilize the receptor within
the nucleus.
In fact, only 10% of ER molecules
should be saturated by a ligand to pro-
duce the proteasomal degradation of the
whole population. Moreover, receptors of
which the HBD has been blocked by a
covalent binding (i.e. tamoxifen aziridine)
are similarly eliminated. The mechanism
underlying this ampliFcation process is
not known. Secretion of unidentiFed hy-
drophobic compounds by early-stimulated
cells may play a role. Such compounds,
the
existence
of
which
has
been
de-
tected in conditioned media from ligand-
treated cells, may act by themselves or in
synergy with undetectable concentration
of ligands.
4
Antitumor Estrogens
ER content is extremely variable among
breast cancer. Median concentrations vary
among studies reaching a maximum of
100 fmoles mg
1
proteins, which corre-
spond roughly to 10 000 receptors per cell.
Only a limited number of cytotoxic drugs
would be able to exert signiFcant antitu-
more
f
fec
tw
i
thsuchalowconcen
tra
t
ion
of vectors. The high reactivity of alkylating
agents (1000 DNA interstrand cross-links
is lethal) led to their selection for the syn-
thesis of antitumor estrogens. Numerous
compounds were synthesized in the 1970s
and 1980s. However, as stated above, most
of them failed to display a sufFcient bind-
ing afFnity for ER, or any unambiguous
speciFcity of action, leading to a progres-
sive disinterest to this approach. Other
cytotoxic agents such as vinca alkaloids
and intercalating agents (like ellipticin
and daumomycin) also failed to show any
potential therapeutic interest. Note that
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