The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance

Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors.Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment.This may be related to a differential expression of somatostatin receptor subtypes among tumors.In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important con-sequences for visualizing, as well as for therapy, of receptorpostive tumors using radioisotope-or chemotherapeuticcompound-coupled somatostatin analogs.This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio-and chemotherapy.Herein, the development and potential role of novel somatostatin analogs is discussed.(Endocrine Reviews 24: 28 -47, 2003) I. General Introduction A. SS and sst subtypes B. SS receptor subtype expression in normal and tumorous human tissues C. Agonist-induced internalization of sst subtypes II.Consequences of sst Internalization for sst-Targeted Radiotherapy or Chemotherapy of sst-Positive Tumors A. Preclinical evidence for internalization of radiolabeled SS-analogs B. SS receptor-targeted radiotherapy C. SS receptor-targeted chemotherapy: preclinical evidence III.Tachyphylaxis and Resistance to SS A. Introduction B. Tachyphylaxis of pathological hormone secretion C. Escape from antiproliferative effects D. Mechanisms of tachyphylaxis and resistance E. New developments F. Conclusions IV.