Antitumor Steroids
Steroid Hormones
Lipophilic hormones (lipid-soluble) which derive from cholesterol and act through
association with their cognate receptors (speciFc nuclear receptors for each class of
hormones, i.e. estrogens, androgens, progestins, gluco- and mineralocorticoids).
Nuclear Receptor
Large family of ligand-dependent transcription factors (peptides able to modulate the
expression of genes).
Modality to selectively deliver a compound to a given cell type or tissue to produce a
biological effect only at his level.
Steroid hormones once secreted are trans-
ported through the blood by proteins
such as albumin or sex hormone bind-
ing globulin to be delivered to speciFc
receptors located in various tissues, in-
cluding tumors. Hence, steroid hormones
appear as attractive vectors that might be
used to achieve a selective targeting of
anti-neoplastic drugs, at least in hormone-
dependent cancer, which contains high
amounts of receptors (i.e. breast, prostate
etc.). While association of these drugs with
receptors is obviously of major impor-
tance, their binding ability to transport
proteins may also play a role (i.e. albu-
min localize at the tumor due to enhanced
vascular permeability).
Such a concept is obviously not new.
High doses of steroid hormones are in-
deed routinely used for the treatment of
various endocrine disorders. Synthetic an-
tagonists aimed to speciFcally block the
action of their receptors or/and metabolic
enzymes have also been in clinical prac-
tice since a long time. With speciFc regard
to neoplasia, antiestrogens, antiprogestins,
as well as aromatase inhibitors (enzymes
that convert androgens to estrogens) are
drugs of prominent importance for the
treatment of breast cancer. Therapeutic ef-
fectiveness as well as mechanism of action
of such compounds has been the subject of
a large number of reviews and will there-
fore not be addressed here. Potential utility
of steroidal derivatives aimed to selectively
kill tumor cells (i.e. ‘‘antitumor steroids’’)
will solely be analyzed.
In fact, during the last 30 years, sev-
eral investigators prepared a large number
of steroids bearing cytotoxic molecules
(e.g. alkylating agents, nitrosoureas,
platinum complexes, intercalating agents,
etc.). Unfortunately, such syntheses led al-
most always to drugs devoid of therapeutic
interest primarily due to the fact that their
cytotoxic groups were not linked in appro-
priate positions onto the steroids, leading
to a drastic loss of the binding afFnity of the
latter for their cognate receptors with con-
comitant decrease of cellular uptake. More-
over, for the few compounds that overpass
this limiting step, speciFc killing of tumor
cells was rarely observed in cell culture
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