Abstract
The use of a somatostatin analogue (SMS 201-995) has greatly facilitated the treatment of patients with the midgut carcinoid syndrome. Clinical studies have shown that SMS reduces the peripheral levels of tumour-produced serotonin (5-HT) and tachykinins, e.g. neuropeptide K (NPK), basally and after pentagastrin provocation. Some studies have indicated an inhibitory effect of SMS on tumour cell growth as well. In the present study we have investigated the effects of SMS on four different human midgut carcinoid tumours maintained in long term culture. Media levels of 5-HT and NPK-LI in tumour cell cultures decreased rapidly during incubation with SMS (10(-8)-10(-10) M) in all four tumours studied without evidence for tachyphylaxis (up to 6 weeks observation period). SMS treatment (10(-8) M) during 4 days reduced the media concentrations of 5-HT by 56%, while the intracellular contents of 5-HT were decreased by 27% indicating dual inhibitory effects on synthesis and secretion of 5-HT from tumour cells. The DNA contents of cultures were not affected by SMS (10(-8) M or 10(-10) M) treatment for 4 or 14 days. When tumour cell cultures were challenged with isoprenaline (IP) (10(-6) M) no reduction of the IP induced release of 5-HT could be detected after pretreatment of tumour cell cultures with SMS (10(-8) M) for 1 h, 4 h or 4 days. These studies provide evidence for a direct action of the somatostatin analogue on midgut carcinoid tumour cells, reducing both synthesis and secretion of hormones from tumour cells. This effect appears not to be related to inhibition of tumour cell growth. The inhibition of 5-HT secretion from tumour cells by SMS seems to operate via a second messenger system different from the one mediating the beta-adrenoceptor stimulated release of 5-HT.
Highlights
In order to investigate the effects of the somatostatin analogue on isolated tumour cells, we have studied growth and secretion of 5-HT and neuropeptide K (NPK) from cultured human midgut carcinoid tumour cells subjected to octreotide treatment
During experiments medium concentrations of 5-HT and/or NPK-like immunoreactivity (NPK-LI) were followed at regular intervals and compared with control cultures in standard medium
Bauer et al (1982) synthesised an analogue (SMS 201-995) of the conformationally stable part of somatostatin, which was highly resistant to degradation and selective in its inhibition of growth hormone secretion
Summary
Clinical provocation with pentagastrinA provocation test using PG (0.6 jg kg- ' i.v.) was used (Ahlman et al, 1985; Oberg et al, 1989). Ditions and 1, 3, and 5 min after injection of PG. The provoked release of 5-HT was expressed as the ratio between the highest level after injection and the mean basal level of 5-HT Cell cultures of the four tumours (cases I- IV) were incubated with SMS 201-995 (Sandoz, Basel, Switzerland) after 4-6 weeks of primary culture. During experiments medium concentrations of 5-HT and/or NPK-LI were followed at regular intervals and compared with control cultures in standard medium. Six experimental protocols were used: Protocol I Tumour cell cultures (case I) were incubated with two different concentrations of SMS (10°- M or 10-8 M) during a 2-week period and allowed to recover for 3 weeks (Figure 2). Protocol 2 Tumour cell cultures (case II) were incubated with SMS 10"M for 2 weeks, followed by SMS 10-9M for
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