Somatostatin Receptor-Based Scintigraphy and Antitumor Treatment—An 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.


    Introduction
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 Introduction
 References
 
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 (sst1–5) 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 0–17% 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, 50–80% 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 tumor’s 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 (Hodgkin’s disease, non-Hodgkin’s 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, {alpha}-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.


    References
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 Introduction
 References
 

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