Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase.

Abstract

Several analogues of somatostatin were examined in the Mia PaCa-2 human pancreatic cancer cell line for their ability to promote tyrosine phosphatase activity affecting the receptors for the epidermal growth factor. The inhibition of growth of the Mia PaCa-2 cells in culture was also evaluated to determine the mechanism of action of somatostatin analogues and their relative effectiveness in inhibiting cancer growth. Of the analogues tested D-Phe-Cys-Tyr-D-Trp-LysVal-Cys-Trp-NH2 (RC-160) caused the greatest stimulation of tyrosine phosphatase activity. Analogue D-Phe-Cys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 (RC-121) had less effect but was more potent than somatostatin-14. Analogue D-Phe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr(ol) (SMS 201-995) produced no significant dephosphorylation. The analogues displayed the same order of activity in assays on growth inhibition of Mia PaCa-2 cells in cultures. Analogue (SMS-201-995) caused virtually no tyrosine phosphatase stimulation or growth inhibition in this cancer cell line, although it possesses a much higher antisecretory activity than somatostatin-14 in normal tissues. These observations indicate that somatostatin and some of its analogues can act as growth inhibitors in cancer cells through the activation of tyrosine phosphatase. These data reinforce the view that somatostatin analogue RC-160 and related compounds could be used for treatment of pancreatic cancer.

Human pancreatic cancer cell lines do not express receptors for somatostatin

“…These hormones have been shown to have trophic effects on the growth of normal pancreas and also on pancreatic tumours (Johnson, 1981;Schally et al, 1986). It has therefore been proposed that somatostatin may be capable of inhibiting pancreatic tumour growth indirectly via the suppression of secretion of pancreatic trophic hormones and/or by direct effects on the tumour itself Liebow et al, 1989). Redding et al (1984) described the inhibition of both rat and hamster experimental pancreatic cancer growth by the administration of somatostatin-14.…”

“…Singh and colleagues (1991) have since shown that one of these xenografts expressed specific binding sites for somatostatin. It has been claimed that in vitro, somatostatin-14, and its analogue RC-160, reverse the growth-potentiating effects of epidermial growth factor (EGF) on the human pancreatic carcinoma cell line MiaPaCa-2 (Liebow et al, 1986) through the promotion of tyrosine phosphatase activity (Liebow et al, 1989). For somatostatin to impair directly the growth of pancreatic cancer the cells should therefore express receptors for the peptide.…”

Radioiodinated somatostatin analogue RC-160: preparation, biological activity, in vivo application in rats and comparison with [123I-Tyr3]octreotide

“…However, discrepancies with octreotide have been described, especially with regard to binding to a number of human cancers, like those of the breast, ovary, exocrine pancreas, prostate and colon [14][15][16][17][18]21 ]. Therefore, radioiodinated RC-160 might be an important radiopharmaceutical, having potential advantages over radioiodinated octreotide for the in vivo detection of the aforementioned somatostatin receptorpositive tumours.…”

“…Radioiodinated [Tyr3]octreotide is frequently used for the in vitro determination of the presence of somatostatin receptors [13]. Recently, several reports have been published on the in vitro binding to somatostatin receptors of another somatostatin analogue, the octapeptide RC-160 [14][15][16]. It has been reported that RC-160 has a higher affinity than octreotide for the somatostatin receptor in human breast, ovarian, exocrine pancreatic, prostatic and colonic cancers [14][15][16].…”

“…Recently, several reports have been published on the in vitro binding to somatostatin receptors of another somatostatin analogue, the octapeptide RC-160 [14][15][16]. It has been reported that RC-160 has a higher affinity than octreotide for the somatostatin receptor in human breast, ovarian, exocrine pancreatic, prostatic and colonic cancers [14][15][16]. A phase 1 clinical trial with RC-160 in patients with advanced exocrine pancreatic cancer is being performed, and it appears that RC-160 is well tolerated at doses up to 1500 gg/day [17,18].…”