Somatostatin analogs and radiopeptides in cancer therapy

Abstract

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 [(111)In]-[diethylenetriamine pentaacetic acid (DTPA)-D-Phe(1)]-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 radionuclide...

Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers

“…Each organ was then weighed, and samples were analyzed for 111 In activity using a PerkinElmer (Packard) Cobra II gamma counter. Chelation of 111 In with DTPA and other chelating agents form very stable complexes that are commonly used for in vivo biodistribution studies of various therapeutic molecules and their delivery systems (45)(46)(47). The stability constant between DTPA and 111 In has been determined by others to be 1.5 ϫ 10 29 (48), and previous studies have shown that the [ 111 In]-DTPA ligand has a strong chelating effect on the radiometal in human serum (44).…”

Improved radiotracing of oxytocin receptor-expressing tumours using the new [111In]-DOTA-Lys8-deamino-vasotocin analogue

“…The observation that a variety of tumours overexpress natural peptide receptors has served as the molecular basis for the clinical use of radiolabelled peptides in peptide receptor radionuclide therapy (PRRT) (de Jong and Krenning, 2002), a strategy that has already proved to be successful in detecting and treating somatostatin receptor-positive tumours using radioactive somatostatin or its analogues (Froidevaux and Eberle, 2002). In these tumours, the heavy deposition of radioactive metals such as [ 111 In] and [ 90 Y], which leads to valuable radiodetection and radiotherapeutic effects, was achieved using the 1,4,7,10-tetraazacyclododecane-N,N 0 ,N 00 ,N 000 -tetraacetic acid (DOTA) chelating agent irreversibly bound to a free amino group of somatostatin or its analogues (Merlo et al, 1999).…”

Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

“…The 111 In-OctreScan was the first diagnostic radiopeptide approved by the FDA for scintigraphy of patients with neuroendocrine tumors (Okarvi, 2008). The recent introduction of the metal chelator DOTA (Figure 4) considerably improved the stability of the radioconjugates, allowing incorporation of a variety of radionuclides for applications from receptor-mediated radionuclide therapy to PET (Froidevaux, Eberle, 2002).…”

“…SSTR5 overexpression is also present in growth hormone (GH)-expressing pituitary adenoma and kidney cancer. SSTR4 is overexpressed in ovary cancer whereas SSTR1, SSTR2, SSTR3 and SSTR5, simultaneously, are all overexpressed in thyroid cancer (Reubi, 2003;Froidevaux, Eberle, 2002).…”