Somatostatin Receptor-Based Scintigraphy and Antitumor TreatmentAn Expanding Vista?
Robert T. Jensen
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases
Digestive Diseases Branch
Bethesda, Maryland 20892-1804
Address correspondence and requests for reprints to: Dr. Robert T. Jensen, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Digestive Diseases Branch, Building 10, Room 9C-103, 10 Center Drive, MSC 1804, Bethesda, Maryland 20892-1804.
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Introduction
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The synthetic somatostatin analogues, octreotide
in the United States and octreotide and lanreotide in a number of
European countries, are approved for the treatment of various ectopic
hormone excess states (carcinoid syndrome, pancreatic endocrine tumor
syndromes, acromegaly) (1). Studies by Reubi and others
(1, 2) demonstrated the endocrine tumors causing these
disorders as well as a number of other endocrine tumors (medullary
thyroid cancer, pituitary adenomas, pheochromocytomas) overexpress
somatostatin receptors. This finding was used to develop radiolabeled
somatostatin analogues (i.e.
[111In-DTPA-DPhe1]octreotide
in the United States) that could be used to image these tumors
[somatostatin receptor scintigraphy (SRS)] (1, 3).
Subsequent studies have demonstrated SRS is the most sensitive method
to localize the primary and metastatic disease in patients with all
pancreatic endocrine tumors and carcinoids, except insulinoma, which
frequently have low densities of somatostatin receptors (4, 5). The localization of these tumors by SRS is due to
interaction of the radiolabeled analogues with specific cell surface
somatostatin receptors. Five subtypes of somatostatin receptors
(sst15) are described, each of which is a
member of the G protein-coupled seven transmembrane superfamily, and
almost all neuroendocrine tumors (carcinoids, pancreatic endocrine
tumors) possess at least one subtype, frequently multiple subtypes
(6). Both octreotide and lanreotide have high affinity for
sst2 and sst5, lower
affinity for sst3 and very low affinity for
sst1 and sst4
(6). Studies demonstrate radiolabeled analogues of
octreotide are rapidly internalized and the radiolabeled peptides can
remain present in the cells for prolonged periods and can become
translocated to the nucleus (1, 7, 8). These observations
have led to the possibility of using stable somatostatin analogues
coupled to various cytotoxic agents as a form of anticancer treatment.
Radiotherapy using high doses of
[111In-DTPA-DPhe1]octreotide,
which emits auger and conversion electrons as well as
90yttrium-labeled somatostatin analogues coupled
by a DOTA chelator (1,4,7,10-tetra-azacyclododecane-N,
N'N''N'''), which can emit
ß-particles and give high radiation doses of greater penetrance, have
been reported to inhibit tumor growth in both animal studies and in
preliminary human studies (9, 10, 11, 12). In one recent study in
patients with advanced progressive neuroendocrine tumors, 8 of 21
patients had tumor stabilization, and in an additional 30% a decrease
in tumor size occurred with high doses of
[111In-DTPA0]octreotide
(9, 13). In addition, somatostatin analogues coupled to
doxorubicin (AN-162), 2-pyrrolino-doxorubicin (AN-238), or paclitaxel
have been shown to be cytotoxic to tumor cells and tumors (14, 15). Lastly, a large number of experimental studies in isolated
cells, animal models (1, 16), and recent human studies
demonstrate somatostatin analogues, themselves, have potent antigrowth
effects (1, 13) on tumors. In general, in malignant
neuroendocrine tumors, numerous studies have demonstrated somatostatin
analogues have a poor tumoricidal effect, decreasing tumor size in only
017% of patients in various studies (13). However, both
octreotide and lanreotide have a potent tumoristatic effect, preventing
additional growth in neuroendocrine tumors that were progressing before
treatment, resulting in tumor stabilization (13). In
various studies, 5080% of patients with progressive metastatic
neuroendocrine tumors treated with somatostatin analogues demonstrated
tumor stabilization (13). Somatostatin analogues induce
increased apoptosis in malignant neuroendocrine tumors both in patients
and in implanted tumors in nude mice (17); however,
whether this is the mechanism of its tumoristatic effect in these
tumors remains unclear. The studies reviewed above demonstrate that the
presence of somatostatin receptors, often in high density on
neuroendocrine tumors, is proving useful for their localization and
allowing the development of various novel receptor-mediated antitumor
treatment modalities.
The rapid communication by Halmos et al. (18),
in this issue of the journal, as well as numerous other recent studies
(1, 3, 11, 15, 16, 19, 20) raise the possibility that the
presence of somatostatin receptors on other more common nonendocrine
tumors may be used, also, for the tumors localization or for
antitumor treatment. Studies demonstrate that most human tumors
originating from somatostatin target tissues have conserved
somatostatin receptors that are often expressed at high density
(2). Increased densities of somatostatin receptors are
found in various tumors of the central nervous system (meningiomas,
astrocytomas, gliomas), some malignant lymphoid tumors (Hodgkins
disease, non-Hodgkins disease), and in a proportion of cancers of the
prostate, breast, kidney, liver, and lung (1, 2, 3, 11, 15, 16, 19). Halmos et al. (18) report the
presence of high-affinity somatostatin receptors on 76% of human
epithelial ovarian cancers by binding studies and messenger RNA of at
least one somatostatin receptor subtype present in 88% of these
tumors. Whether the density of somatostatin receptors in these tumors
will be sufficient for these tumors to be localized by SRS, to respond
to the antiproliferative actions of somatostatin analogues or to be
useful for somatostatin receptor-targeted antitumor treatments is, at
present, unknown. Recent studies show lymphomas, central nervous system
tumors, some prostate cancers, and some breast cancers can be imaged
using SRS (1, 3, 21). Furthermore, somatostatin analogues
were shown to have antiproliferative effects on breast, gastric,
colorectal, prostate, thyroid and lung tumors (1, 19), and
cytotoxic somatostatin analogues to inhibit growth of human breast
cancer, prostate cancer, renal cell carcinomas, and human glioblastomas
(16). The advanced forms of many of these tumors have a
poor prognosis, and existing treatments are inadequate. For example, in
ovarian cancer that was studied by Halmos et al.
(18), 1 woman in 100 will die from this tumor. The results
reviewed above raise the possibility that the use of somatostatin
receptors for tumor localization and directing antitumor treatment may
be much wider than its current established uses in neuroendocrine
tumors.
It is important to realize that although the development of
receptor-based localization and antitumor strategies with the
somatostatin receptor may be the most advanced in application because
of the extensive experience on neuroendocrine tumors, the somatostatin
receptors are not the only G protein-coupled receptor that may be
useful for this approach (15, 19). Imaging of tumors using
receptors for the mammalian bombesin peptide, gastrin-releasing
peptide, vasoactive intestinal peptide, substance P, gastrin,
cholecystokinin,
-MSH and neurotensin are all described (19, 20). In some cases, cytotoxic analogues of ligands for these
receptors have antiproliferative effects on various tumor cells
in vitro and tumors in animals (15, 19).
Whether cytotoxic analogues of ligands for these receptors will have
useful clinical effects in vivo in human tumors is, at
present, unknown, but their development represents a potentially novel
approach to target cytotoxic therapies to the tumor cells in
vivo.
Received August 9, 2000.
Accepted August 10, 2000.
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