Somatostatin analogs and radiopeptides in cancer therapy
Authors: Froidevaux Sylvie , Eberle Alex N. 
Published: October 2002

Since the discovery of somatostatin (sst) in 1973, numerous chemical and biological studies have been carried out to develop sst analogs with enhanced resistance to proteases and prolonged activity. Three highly potent sst analogs—octreotide, lanreotide, and vapreotide—are now available in the clinic, and demonstrate efficacy in the treatment of tumors of the pituitary and the gastroenteropancreatic tract. The most striking effect is the control of hormone hypersecretion associated with these tumors. Available data on growth suppression in patients indicate a limited antiproliferative action, tumor shrinkage is observed in 10–20% patients, and tumor stabilization in about half of the patients for duration of 8–16 months. Eventually, however, all patients escape from sst analog therapy with regard to both hormone hypersecretion and tumor growth, the only exception being observed in acromegalic patients who do not experience tachyphylaxis even after more than 10 years of daily octreotide injection. The mechanism underlying the escape phenomenon is not yet clarified. Regarding the molecular mechanisms involved in sst antineoplastic activity, both indirect and direct effects via specific somatostatin receptors (SSTRs) expressed in the target cells have be described. Direct action may result from blockade of mitogenic growth signal or induction of apoptosis following interaction with SSTRs. Indirect effects may be the result of reduced or inhibited secretion of growth‐promoting hormones and growth factors that stimulate the growth of various types of cancer; also, inhibition of angiogenesis or influence on the immune system are important factors. Five SSTR subtypes have been identified so far, which are variably expressed in a variety of tumors such as gastroenteropancreatic (GEP) tumors, pituitary tumors, and carcinoid tumors. Although all five SSTR subtypes are linked to adenylate cyclase, they are now known to affect multiple other cellular signaling systems and hence they differentially participate in the regulation of the various cellular processes. The finding of several laboratories that SSTR‐expressing tumors frequently contain two or more SSTR subtypes, and the recent discovery that SSTR subtypes might form homo/heterodimers to create a novel receptor with different functional characteristics, expand the array of selective SSTR activation pathways and subsequent intracellular signaling cascades. This may lead to improved clinical protocols that take into account possible synergistic interactions between the SSTR subtypes present on the same cancer cell. Radiolabeled sst analogs, such as [111In]‐[diethylenetriamine pentaacetic acid (DTPA)‐D‐Phe1]‐octreotide (OcreoScan), have proved to be very useful for tumor scintigraphy and internal radiotherapy of SSTR overexpressing tumors. The recent introduction of the metal chelator DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) considerably improved the stability of the radioconjugates, making possible the incorporation of a variety of radionuclides, such as 90Y for receptor‐mediated radionuclide therapy or 68Ga for positron emission tomography (PET). Another promising area is the development of sst conjugates incorporating cytotoxic anticancer drugs. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 161–183, 2002