Systemic Radiation Therapy Using Receptor Specific Radioligands: Experience with 111In-Pentetreotide
ABSTRACT & COMMENTARY
Synopsis: In this report, 111In-pentetreotide (a somatostatin analogue specific for the somatostatin-2 receptor conjugated to an Auger electron-emitting element) was injected at a single dose, twice a month to patients with advanced tumors. Subjective and objective responses were observed in some of the patients, particularly those with carcinoid tumors. These anti-tumor responses could have been the result of direct cancer cell cytotoxicity or impaired tumor angiogenesis, as tumor vessels have previously been demonstrated to have increased somatostatin receptor as well. The optimally effective and maximum tolerated dose for 111In-pentetreotide are yet to be established.
Source: McCarthy KE, et al. Cancer J Sci Am 1998;4: 94-102.
Fourteen patients with advanced cancers that expressed somatostatin receptors (as determined by 111In-pentetreotide scan) received two monthly 180 mCi intravenous injections of 111In-pentetreotide. Of these, clinical benefit (improvement in performance status, less pain, etc.) was observed in six, and objective partial responses, determined radiographically, occurred in two. However, tumor necrosis, as estimated by changes in Housefield units on CT scan of tumor images, occurred in six. The most striking results were observed in those patients with gastroenteropancreatic neuroendocrine tumors. Low level, treatment-related toxicity was experienced in most patients. Two patients experienced grade 3 myelotoxicity, and six had grade 1 or 2 hemoglobin toxicity (NCI Common Toxicity Criteria). McCarthy and colleagues conclude that 111In-pentetreotide is both well-tolerated and effective therapy in some subjects with somatostatin receptor-expressing tumors. Future efforts will be required to determine the maximum tolerated dose and appropriate schedule.
COMMENTARY
Somatostatin, a 14 amino acid cyclic peptide, is an important regulator of peptide synthesis, secretion, and growth in cells that possess specific somatostatin receptors. Somatostatin analogues (e.g., octreotide, lanreotide, and pentetreotide) have been developed to offer various pharmacological advantages, particularly a longer serum half-life (estimated to be less than a minute for the native peptide). These analogues have specific amino acid sequences that are necessary for receptor binding. Five specific somatostatin receptors have been identified (sst 1-5), and, when bound to ligand, these receptors activate G-protein dependent signal transduction pathways, including tyrosine phophatase, adenylate cyclase, and protein kinase C.
Certain endocrine and neuroendocrine tumors possess high densities of somatostatin receptors,1-3 and radiolabeled ligands have been used clinically for scintographic evaluation of patients. Recently, somatostatin receptor 2 (sst 2) has been shown to be specifically upregulated in peritumoral blood vessels as well.4 Furthermore, a number of non-endocrine tumors have been shown to possess large numbers of somatostatin receptors. Investigators have now shown that somatostatin and its analogues inhibit tumor growth in vitro and in vivo by direct action on tumor cells and/or tumor vasculature.5-7
In contrast to 131I, which emits high energy gamma particles, radioactive elements that emit low energy (Auger) electrons (such as 90Yt, 111In, or 125I) may be more likely to be effective for receptor-specific in situ therapy. Auger electrons provide high energy emissions but over only a very small distance. Thus, to be effective, they must enter the tumor cell and, ideally, the nucleus. The requirement for cell penetration has been demonstrated by McCarthy et al by comparing cytotoxicity of 125I-octreotide in tumor cells with high density receptor vs. tumor cells with little or no receptor. Receptor positive cells were found to be susceptible to cytotoxicity from the labeled peptide in a dose-dependent fashion, whereas receptor negative cells were unaffected.8
The current study is an important first step in the development of this new approach. McCarthy et al demonstrated that the radioligand was both safe at the selected dose, and effective in a number of cases. Of course, as with most preliminary reports, the findings raise as many questions as they answer. The specificity of the response must be assessed. The threshold level of receptor density required to achieve the desired response must be determined. It is also possible that tumors other than carcinoids will be responsive. Whether the radioligand penetrates solid tumors must be analyzed. The therapeutic ratio must also be measured. What differential between tumor cell and normal cell receptor expression will be necessary to avoid toxicity? The demonstration of somatostatin receptor in peritumoral vessels is also of potential importance. Could this approach be developed for a more generalized assault on tumor vessels?
Certainly, there is enough in this preliminary report to stimulate additional and intensive research in this area.
References
1. Reubi JC, et al. Int J Cancer 1994;56:681-688.
2. Reubi JC, et al. J Steroid Biochem Mol Biol 1994;43: 27-35.
3. Reubi JC, et al. J Clin Endocrinol Metab 1984;59: 1148-1151.
4. Reubi JC, et al. Metabolism 1996;45(suppl 1):39-41.
5. Prevost G, et al. Endocrinology 1991;129:323-329.
6. Dansei R, et al. Clin Cancer Res 1997;3:263-272.
7. Weckbecker G, et al. Cancer Res 1995;54:6334-6337.
8. Meyers MO, et al. J Surg Res (In press).
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