Yttrium-90 and Rhenium-188 Radiopharmaceuticals for Radionuclide Therapy

Another very promising form of radioreceptor therapy uses oestrogen
receptors (ERs) as the target structure on tumour cells. ERs are intranuclear
proteins that are expressed with high frequency in female breast and genital
tumours. ERs bind oestrogens with high affinity and specificity and mediate
an efficient concentration of the ligands in the cell nucleus. The ER hormone
complex binds to specific ‘responsive elements’ of the DNA. Expression of ERs
can be modulated reliably in biological models in vivo and in vitro. Because
labelling with a radionuclide does not alter the affinity and specificity of the
oestrogen for its receptor, oestrogen vehicles will carry radionuclides effectively
and selectively into the cell nucleus of ER positive tumour cells.
ER ligands can therefore be used as vehicle molecules for radionuclides
allowing radiation to be brought to that part of the cell, the DNA, which is
most radiation sensitive. Hormone receptors, in this case ERs, can then act as
a point of attack for cytotoxic radiopharmaceuticals with receptor affinity.
Radiohormone therapy of this kind would also be effective for the treatment
of genital carcinomas (e.g. ovarian cancer) where there is expression of sexual
steroid receptors but no hormonal regulation, and, therefore, no responsiveness
to conventional hormone therapy. Ideal radionuclides for this purpose would
be Auger electron emitters, as their radiotoxic action is released at focal points
within a very small space and can therefore be kept within the receptor positive
cells or affected cell nucleus. Almost every decay of an Auger emitter within
the DNA causes a double strand break and leads to irreparable and lethal cell
damage. Auger emitters in extranuclear or extracellular locations are much less
toxic [2.56–2.59].
2.3.5. Gene therapy approaches
In gene therapy approaches to targeted radionuclide therapy, the aim is to
provoke genetic modifications in tumour cells to induce or strengthen expression
of target structures on the tumour cells.
One example of this is the sodium iodide symporter (NIS), which is used
therapeutically in radioiodine therapy for active transport of radioactive iodine
into cells of the thyroid glands. If it were possible to provoke expression of NIS in
extrathyroidal tumour tissue, such as mammary tumours or prostate carcinomas,
then it would be possible to use radioiodine therapy against those tumours
as well. The NIS is usually only found in thyroid, saliva, tear and lactating
mammary glands. Limited therapeutic stimulation of NIS expression can be
achieved through administration of various pharmaceuticals (e.g. retinoic acids).
It is better to bring the NIS directly into the tumour tissue by artificial means.
One possibility is to transfect tumour cells with the plasmids responsible for NIS
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