Mechanisms of Antineoplastic Action of Somatostatin Analogs

Abstract

Abstract. Over the past decade, impressive antineoplastic activity of somatostatin analogs has been demonstrated in many tumor models. More recent research has provided information regarding mechanisms underlying the antiproliferative and apoptosis-inducing actions of these compounds. These include both 'direct' mechanisms that are sequellae of binding of somatostatin analogs to somatostatin receptors present on neoplastic cells and 'indirect' mechanisms related to effects of somatostatin analogs on the host. The upregulation of intracellular tyrosine phosphatase activity triggered by binding of ligands to the type II somatostatin receptor has received considerable attention as a direct mechanism, not only because this activity is the converse of the tyrosine kinase activity associated with many peptide mitogen receptors, but also because the type II somatostatin receptor is frequently expressed by common human neoplasms, including breast cancer. The potential importance of indirect mechanisms of action of somatostatin analogs, such as alterations in host insulin-like growth factor physiology, is emphasized by the in vivo antineoplastic activity of these compounds against somatostatin receptor-negative neoplasms. Clinical efficacy and a favorable toxicity profile of somatostatin analogs in the treatment of relatively uncommon conditions such as acromegaly and neuroendocrine tumors have already been demonstrated. Preclinical data now are sufficient to justify controlled clinical trials in breast, prostate, and pancreatic cancer. The development of monthly depot formulations will facilitate the clinical evaluation of somatostatin analogs for these and other indications.

Enhanced inhibitive effects of combination of rofecoxib and octreotide on the growth of human gastric cancer

“…It reminds us of the early evidence that somatostatin analogues could inhibit the proliferation of somatostatin receptor-negative neoplasm. 9 These results suggest that octreotide may indirectly affect tumor growth through inhibition of release of some peptides or growth factors such as insulin, EGF and IGF-1, which promote tumor proliferation. 26 Although octreotide could inhibit the growth of gastric adenocarcinoma, the inhibition rate (60.6%) for gastric xenografts treated by octreotide alone 8 was also much lower than the result of rofecoxib plus octreotide in vivo with the same animal model, drug doses and schedules.…”

“…6,7 Various studies have demonstrated that the growth of normal cells and malignant tumor may be regulated by gut peptides. 8,9 In the stomach, besides the known inhibitory function of somatostatin (SST) on acid secretion, it has been suggested that the analogues of SST could be candidates for arresting the growth of gastric adenocarcinoma. Previous data from the literature have shown that the mean tumor volume in nude mice treated with octreotide, an analogue of SST, was significantly lower than that of control group with an inhibitory rate of 60.6%.…”

“…6,10 The antineoplastic action of octreotide is thought to be mediated through the receptors for SST that may trigger the MAPK pathways. 11,12 Cellular proliferation is achieved through entry of cells from G 0 into the active cell cycle, whereas progression through the cell cycle is controlled by a spectrum of regulatory proteins. COX-2 or SST may modulate expression of a cascade of genes that control cell proliferation at different site of intracellular pathway.…”

Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238

“…Because somatostatin receptors are widely distributed in the gastrointestinal tract and other tissues, 11,22,29 concerns were raised that therapy with radionuclide somatostatin analogues or AN-238 may produce some side effects. However, in early studies with radiolabeled somatostatin analogues, no or only low-grade toxicity was observed in patients at doses resulting in objective responses.…”

Antitumor effects of somatostatin

“…Page 4 of 22 A c c e p t e d M a n u s c r i p t 4 Somatostatin analogs show antineoplastic activity in a variety of experimental models in vivo and in vitro (Schally 1988;Pollak,Schally 1998;Weckbecker et al, 1993) . They inhibit the growth of various cancer cell lines, such as those of gastric, lung, colorectal, prostatic, ovarian, kidney, brain or thyroid origin (Keri et al, 1996;Weckbecker et al, 1993;Froidevaux, Eberle 2002;.…”