Experimental and clinical studies with somatostatin analogue octreotide in small cell lung cancer

Abstract

Summary We have detected somatostatin receptors (SSR) by autoradiography in 3/4 established small cell lung cancer (SCLC) cell lines but not in two non-SCLC cell lines. The growth of 1/3 SSR positive SCLC cell lines was significantly inhibited by the long-acting somatostatin analogue octreotide statin) 10-9M. We treated 20 SCLC patients with octreotide 250 gg three times daily for I week prechemotherapy (six patients) or at relapse after chemotherapy (14). Octreotide was well tolerated, and serum insulin-like growth factor-I levels were suppressed to 62±7% of pre-treatment levels. However there was no evidence of anti-tumour activity measured by tumour bulk or serum levels of neuron-specific enolase. In one patient metastatic skin nodules were shown to be SSR positive before and at the end of 2 weeks octreotide. Despite this the patient had progressive disease, and tumour cells obtained by fine needle aspirate before and after treatment showed no growth inhibition when cultured with octreotide immediately or following establishment as a cell line. In summary we saw little correlation between SSR expression and growth inhibition by octreotide, either in vitro or clinically.Somatostatins are a family of 14-and 28-residue neuropeptides which regulate peptide secretion from the pituitary, gut and pancreas (Bloom & Polak, 1987;Frohman & Krieger, 1987). Somatostatin receptors (SSR) are expressed by these so-called 'SS target tissues', and by tumours arising from them including pituitary adenomas and pancreatic insulinomas (Reubi et al., 1982;1984). Natural SS-14 is of limited therapeutic use here because of its short plasma half-life (3 min) and diverse action (Moreau & DeFeudis, 1987;Schally, 1988). Systematic structure/activity studies have led to the development of potent octapeptide SS analogues with prolonged and selective activity. One of these, octreotide (SMS 201-995, Sandostatin) has pharmacological effects in vivo for up to 9 h and is 45-70 times more potent than SS-14 at inhibiting growth hormone release (Plewe et al., 1987;Schally, 1988). In patients with acromegaly, carcinoid syndrome, insulinomas and other gastroenteropancreatic tumours, octreotide produces clinical improvement in parallel with suppression of inappropriate peptide secretion, and in some cases reduction in tumour bulk Wood et al., 1985;Kvols et al., 1986;Lamberts et al., 1987;Comi, 1989;Maton, 1989). Octreotide and other octapeptide SS analogues have also shown experimental evidence of antiproliferative activity in some common solid tumours, including cancers of the breast, exocrine pancreas, colon and prostate (Setyono-Han et al., 1987;Schally, 1988;Parmar et al., 1989;Weber et al., 1989). Growth inhibition here could be mediated directly, via SSR which have been detected on breast, pancreas and prostate cancers (Reubi et al., 1987;Setyono-Han et al., 1987;Srkalovic et al., 1990), or indirectly via suppression of local or circulating levels of growth factors (Schally, 1988).There is some evidence that SS may play a role in growth regulat...

Novel cross talk between MEK and S6K2 in FGF-2 induced proliferation of SCLC cells

“…Multiple Ca 2+ -mobilizing neuropeptides have been identi®ed as autocrine/paracrine growth factors for SCLC (Bunn et al, 1990;Seckl and Rozengurt, 1998;Sethi and Rozengurt, 1991). In contrast, apart from stem cell factor (Hibi et al, 1991;Krystal et al, 1996;Seckl et al, 1994), hepatocyte growth factor (Seckl et al, 1994) and insulin-like growth factor (Macaulay et al, 1990), polypeptide growth factors have not been thought to play a major role in driving SCLC cell proliferation. Strikingly, although ®broblast growth factor-2 (FGF-2) is abundantly expressed in adult human lungs (CordonCardo et al, 1990), there have been no previous reports examining the biological e ects of this polypeptide growth factor in SCLC.…”

Activated G Protein-coupled Receptor Induces Tyrosine Phosphorylation of STAT3 and Agonist-selective Serine Phosphorylation via Sustained Stimulation of Mitogen-activated Protein Kinase

“…Numerous reports have demonstrated the expression of a high density of somatostatin receptors on a variety of human cancer cells (4,8). The antiproliferative action of either somatostatin or its more metabolically stable analog octreotide, however, does not correlate with this expression, having inhibitory actions on pancreatic (9) and breast tumors (1) but eliciting no effect on the growth of small cell lung (10) and colon tumors (11). Growth-promoting effects of somatostatin have also been described in vitro on human pancreatic carcinoid (12) and epidermoid carcinoma cells (13), whereas in rat mesangial cells, somatostatin stimulates proliferation in the absence of serum but inhibits the growth of proliferating cells (14).…”

Production of immunoreactive insulin-like growth factor-I (IGF-I) and IGF-I binding proteins by human lung tumours

“…The detection of elevated immunoreactive insulin-like growth factor-I (IGF-I) in human lung tumours (Minuto et al, 1986;Macaulay et al, 1988a) together with the observed secretion of immunoreactive IGF-I by selected small cell lung cancer (SCLC) cell lines in vitro (Jacques et al, 1988) raises the possibility that IGF-I may be a clinically valuable serological tumour marker in patients with lung tumours. However, in a recent study of 42 untreated patients with histologically confimed SCLC, evidence of elevated IGF-I levels was obtained in two patients only (Macaulay et al, 1988b).…”

“…No evidence of increased serum IGF-I levels was obtained in a cohort of 52 lung cancer patients having SCLC and NSCLC histologies. In contrast, serum levels of low molecular weight BPs were markedly elevated in the majority of lung cancer patients.The detection of elevated immunoreactive insulin-like growth factor-I (IGF-I) in human lung tumours (Minuto et al, 1986;Macaulay et al, 1988a) Healthy adult male and female non-smokers (n = 32), and male and female normal smokers (n = 31) were included in the study as controls. The age range for controls was 23-81 years and for lung cancer patients 39-79 years.…”

“…The detection of elevated immunoreactive insulin-like growth factor-I (IGF-I) in human lung tumours (Minuto et al, 1986;Macaulay et al, 1988a) Healthy adult male and female non-smokers (n = 32), and male and female normal smokers (n = 31) were included in the study as controls. The age range for controls was 23-81 years and for lung cancer patients 39-79 years.…”