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Evaluation of receptors for somatostatin in various tumors using different analogs
G Srkalovic1, R Z Cai, A V Schally
1Endocrine, Polypeptide, and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana.
Abstract:
The binding characteristics of several somatostatin (SS-14) analogs developed in our laboratory were examined in various human and animal tumors and normal tissues. In rat cerebral cortex and human breast cancer membranes the interaction of SS-14 with its binding sites was rapid, specific, saturable, linear with protein concentrations, and dependent on time and temperature. Analysis of kinetic and equilibrium experimental data showed that the interaction of [125I-Tyr11]SS-14 with the binding sites in all normal and tumoral tissue specimens was consistent with the presence of a single class of noncooperative binding sites. Superactive octapeptide analogs of somatostatin-containing hexapeptide sequences Cys-Phe-D-Trp-Lys-Thr-Cys or Cys-Tyr-D-Trp-Lys-Val-Cys showed significant binding affinities to SS-14 receptors. Among these analogs, D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 (RC-98-I) showed the highest binding affinity to normal human pancreatic tissue and human pancreatic adenocarcinoma. In contrast, Sandostatin (SMS 201-995) bound only to normal pancreas, not to human pancreatic cancers. Analog RC-98-I also showed a high binding to human and rat prostate cancers. In human epithelial ovarian cancers and an arrhenoblastoma, analogs D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2 (RC-95-I), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) appeared to be the most potent in displacing labeled SS-14. Analogs Ac-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 (RC-101-I) as well as RC-121, RC-160, and RC-95-I, but not SMS-201-995, showed high binding affinity in human breast cancers. In specimens of human meningioma the highest binding was found with analogs RC-121, RC-95-I, and RC-101-I. Since marked variations in binding affinities were noted for several analogs in the tissues of origin and the tumors, this suggest that differences may exist between somatostatin receptors not only in normal vs. cancerous tissues, but also among various tumors. Our findings also imply that some analogs could be therapeutically superior to others in the treatment of certain tumors.
Insights
New somatostatin analogs show varied binding affinities to receptors in normal and cancerous tissues. Some analogs exhibit higher binding to specific tumors, suggesting potential for targeted cancer therapies.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Somatostatin (SS-14) plays a crucial role in regulating various physiological processes.
- The development of somatostatin analogs aims to harness their therapeutic potential, particularly in cancer treatment.
- Understanding the binding characteristics of these analogs is essential for optimizing their efficacy.
Purpose of the Study:
- To investigate the binding affinities of novel somatostatin analogs to somatostatin receptors in diverse human and animal tumors and normal tissues.
- To compare the binding profiles of these analogs with Sandostatin (SMS 201-995).
- To identify analogs with selective binding properties for potential therapeutic applications in specific cancers.
Main Methods:
- Radioligand binding assays were performed using labeled somatostatin ([125I-Tyr11]SS-14) and various tissue preparations (membranes from rat cerebral cortex, human breast cancer, normal pancreas, pancreatic adenocarcinoma, prostate cancer, ovarian cancer, meningioma).
- Kinetic and equilibrium binding data were analyzed to characterize the interaction of somatostatin analogs with binding sites.
- The ability of different somatostatin analogs, including octapeptide derivatives, to displace labeled SS-14 was assessed.
Main Results:
- Somatostatin analogs demonstrated specific, saturable, and time/temperature-dependent binding to SS-14 receptors.
- Most analogs exhibited a single class of noncooperative binding sites.
- RC-98-I showed high binding affinity to normal pancreatic tissue and pancreatic adenocarcinoma, while Sandostatin did not bind to pancreatic cancers.
- Several analogs (RC-95-I, RC-121, RC-160, RC-101-I) displayed potent binding to ovarian and breast cancers, and meningiomas, with varied affinities.
- Significant variations in binding affinities were observed among different normal tissues and tumor types, suggesting heterogeneity of somatostatin receptors.
Conclusions:
- The binding characteristics of somatostatin analogs vary significantly across different normal tissues and tumor types.
- This receptor heterogeneity suggests that specific analogs may be therapeutically superior for treating certain cancers.
- Novel analogs like RC-98-I, RC-95-I, RC-121, RC-160, and RC-101-I show promise for targeted therapies, outperforming Sandostatin in certain cancer models.