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Biological activity and receptor binding characteristics to various human tumors of acetylated somatostatin analogs
J Pinski1, S Milovanovic, T Yano
1Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146.
Abstract:
Several somatostatin analogs with recently synthesized acetylated N terminus were assayed in vivo for their effects on sodium pentobarbital-stimulated growth hormone (GH) levels in fed male rats and gastrin-releasing peptide (14-27)-stimulated gastrin levels in fasted male rats. The binding characteristics of these analogs to somatostatin receptors were also examined in various human tumors and normal tissues. The analog RC-101-I, injected at a dose of 0.1 micrograms/100 g body wt, significantly suppressed GH release (P less than 0.01) for at least 2 hr. Analog RC-160-II caused the longest inhibition of GH release, greater than that induced by nonacetylated parent analog RC-160, with GH levels showing significant suppression (P less than 0.01) for more than 3 hr. Analogs RC-160-II and RC-101-I and RC-160, injected at a dose of 1.0 micrograms/100 g body wt, significantly (P less than 0.01) suppressed gastrin-releasing peptide (14-27)-stimulated serum gastrin. Analog RC-101-I was active in this test at a dose of 0.1 micrograms/100 g body wt. RC-160-II showed significant binding to somatostatin-14 receptors in all investigated tissues (human colon, human colon cancer, breast cancer, human pancreas and pancreatic cancer, human prostate and prostate cancer, and rat cerebral cortex), but there were marked variations in binding affinities among various normal and cancerous tissues. The highest affinity was found in membranes of colon cancer (Ka = 18.4 nM-1) and breast cancer (Ka = 12.46 nM-1). The binding affinity of RC-160-II to somatostatin receptors in membranes of the breast cancer was similar to that of RC-160. RC-101-I showed higher binding affinity to somatostatin-14 receptors than RC-160 in human breast, pancreatic, and prostate cancer. With the exception of breast cancer tissue, the binding affinity of RC-101-I was significantly lower than that of RC-160-II in membranes of all investigated tissues. It can be concluded that acetylated somatostatin analogs RC-101-I and RC-160-II possess prolonged and enhanced biological activities in suppressing serum GH and gastrin in rats. Significant variations in binding affinities for these analogs in different tissues and various tumors suggest that differences may exist between somatostatin receptors in normal versus malignant tissues. This raises the possibility that some of these analogs could be used more selectively in the treatment of various neoplasms.
Insights
Newly synthesized acetylated somatostatin analogs, RC-101-I and RC-160-II, effectively suppress growth hormone (GH) and gastrin release in rats. These analogs exhibit varied binding affinities to somatostatin receptors in normal and cancerous tissues, suggesting potential for targeted cancer therapies.
Area of Science:
- Endocrinology
- Pharmacology
- Oncology
Background:
- Somatostatin analogs are investigated for therapeutic potential.
- Acetylated N-terminus analogs represent a new class of somatostatin derivatives.
- Understanding their in vivo activity and receptor binding is crucial.
Purpose of the Study:
- To evaluate the in vivo efficacy of novel acetylated somatostatin analogs.
- To assess the binding characteristics of these analogs to somatostatin receptors.
- To explore potential therapeutic applications in neoplasms.
Main Methods:
- In vivo assays in rats to measure growth hormone (GH) and gastrin levels.
- Assessment of somatostatin receptor binding in human tumor and normal tissues.
- Dose-response evaluations for analog activity.
Main Results:
- RC-101-I and RC-160-II significantly suppressed GH and gastrin release in rats.
- RC-160-II demonstrated prolonged inhibition of GH release.
- Analogs showed varied binding affinities to somatostatin receptors across different tissues, with higher affinity in colon and breast cancer.
Conclusions:
- Acetylated somatostatin analogs RC-101-I and RC-160-II possess enhanced and prolonged biological activity.
- Differential binding affinities suggest potential for selective targeting of somatostatin receptors in tumors.
- These analogs may hold promise for the treatment of various neoplasms.