Somatostatin Analogs for Cancer Treatment and Diagnosis: An Overview

Abstract

Due to the limited efficacy and considerable toxicity of conventional chemotherapy, novel cytotoxic agents and innovative noncytotoxic approaches to cancer treatment are being developed. Amongst the various hormonal agents, increasing attention is being directed to somatostatin analogs. This is largely due to the demonstration of antineoplastic activity of these compounds in a variety of experimental models in vitro and in vivo and to the elucidation of some aspects of the molecular mechanisms underlying their antineoplastic activity. On the other hand, clinical experience with somatostatin analogs in the treatment of conditions like acromegaly and GEP tumors has shown that they are well tolerated compared to other antineoplastic therapies currently in use. As a consequence, there is much ongoing clinical research to determine whether or not results from experimental studies will translate into clinically useful antineoplastic activity. Besides being used in cancer treatment and palliation, radiolabelled somatostatin analogs are employed for the localization of primary and metastatic tumors expressing somatostatin receptors. The so-called ‘somatostatin receptor scintigraphy’ is indeed the most important clinical diagnostic investigation for patients with suspected neuroendocrine tumors. Targeted radiotherapy, which is being evaluated in clinical trials, represents an obvious extension of somatostatin scintigraphy. Since the short half-life of native somatostatin makes continuous intravenous infusion mandatory, several long-acting analogs have been synthesized. Amongst the hundreds of peptides synthesized, octreotide (which binds mainly to SSTR-2 and SSTR-5 receptor subtypes) has been the most extensively investigated. A thorough analysis of the pharmacological activities and therapeutic efficacy of the native somatostatin and the synthetic analogs (octreotide, lanreotide and vapreotide) reveals that the biological actions of these peptides are not always identical. These differences appear to be related to the different affinities of the natural hormone and synthetic derivatives for the different receptor subtypes. For all the three peptides long-lasting formulations have been developed to provide patients with the convenience of once or twice a month administration and to ensure stable drug serum concentrations between injections. Radiolabelled derivatives of octreotide, lanreotide and vapreotide have been synthesized and used as radiopharmaceuticals for somatostatin receptor scintigraphy and somatostatin receptor-targeted radiotherapy. The safety profile of synthetic somatostatin analogs is well established. Most adverse reactions to these peptides are merely a consequence of their pharmacological activity and consist mainly of gastrointestinal complaints, cholelithiasis and effects on glucose metabolism. They are often of little clinical relevance, thus making somatostatin analogs safe drugs for long-term use. While immediate release preparations are the drugs of choice in the short term, long-acting formulati...

Synthesis and evaluation of biodegradable PCL/PEG nanoparticles for neuroendocrine tumor targeted delivery of somatostatin analog

“…Some recently discovered carcinogenic and noncarcinogenic agents such as certain dietary substances, natural hormones and synthetic compounds have been proposed to stop or reverse the process of carcinogenesis to alleviate the limited efficacy and considerable toxicity of conventional chemotherapy (Morse et al, 1993), in which increasing attention has been paid to somatostatin and its analogs that have been reported to exert antineoplastic effects in a wide range of tumor types such as carcinoid, osteosarcoma, leukemia, and cancers of thyroid, breast, lung, liver, pancreas, colon, as well as gastric carcinomas (Scarpignato et al, 2001;Ain et al, 1997;Marschke et al, 1999;Setyono et al, 1987;Shan et al, 2003;Gencosmanoglu et al, 2002;Lee et al, 2002;Giannetti et al, 2000;Yuen et al, 2002;Gou et al, 2011b). Poly(ε-caprolactone) (PCL), biodegradable polyesters, is most commonly used for pharmaceutical applications.…”

PET and SPECT Imaging of Tumor Biology: New Approaches Towards Oncology Drug Discovery and Development

“…Somatostatin has a short plasma half-life (approximately 2 min) making it unsuitable for radioligand development [63]. The discovery of the short octapeptide somatostatin analog, octreotide, which displays a superior pharmacological profile, played a major role in the development of radioligands for somatostatin receptor imaging [64].…”

Somatostatin and cancer: Applying endocrinology to oncology

“…First, scintigraphy with radiolabeled somatostatin analogs like 111 In-DTPA-octreotide enables in vivo imaging of tumors and metastases. 25,26 Second, because SSTR binding results in internalization of the SSTR-ligand complex, somatostatin based treatments can be targeted to provide increased potency against the malignant cell while decreasing generalized toxicity. Clinical trials are underway of somatostatin analogs hybridized to cytotoxic agents and radionuclides.…”

“…Clinical trials are underway of somatostatin analogs hybridized to cytotoxic agents and radionuclides. 26,27 Although somatostatin and its analogs hold promise as new agents in cancer treatment, there are limitations. 28,29 As demonstrated in the paper by Hu et al, octreotide failed to inhibit growth and induce apoptosis in the gastric cells that poorly expressed SSTR-3, and SSTR-3 expression dropped with increasing malignancy.…”