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Novartis Pharma AG, Research Transplantation WSJ 386, CH-4002 Basel, Switzerland
Address all correspondence and requests for reprints to: Gisbert Weckbecker or Christian Bruns, Novartis Pharma AG, Research Transplantation WSJ 386, CH-4002 Basel, Switzerland. E-mail: gisbert.weckbecker{at}pharma.novartis.com or christian.bruns{at}pharma.novartis.com.
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Introduction |
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Materials and Methods |
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Materials
All materials were purchased from Sigma (St. Louis, MO); unless otherwise specified.
Binding studies
Binding assays were performed using membranes from Chinese hamster ovary cells (sst1–sst4) and African green monkey kidney cells (sst5) expressing the respective human SRIF receptor subtype, as described previously (8). Briefly, membranes were incubated for 1 h with the SRIF receptor ligand [125I]Tyr-11-SRIF-14 in the presence or absence of increasing concentrations of SRIF analogs. The incubation was stopped by rapid filtration through GF/C filters (Whatman, Maidstone, Kent, UK). Inhibition curves were analyzed and IC50 values calculated using a curve-fitting program. The average values of 3–7 individual binding experiments performed in triplicate are presented.
Growth hormone secretion in rats
Male Sprague Dawley (Ico:OFA-SD) rats were anesthetized with pentobarbital-sodium, and the compound was given sc. Blood was collected after decapitation, 1 h after injection. The duration of action was estimated on the basis of inhibition of basal GH secretion, 6 h after treatment. GH levels were measured by RIA. The half-maximal inhibitory dose (ID50) values for inhibition of hormone secretion were determined graphically (log-probit) for each experiment. The resulting ID50 values were averaged logarithmically. The RIA for rat GH (rGH) used National Institute of Arthritis and Metabolic Diseases-rGH Reference Preparation 1 as standard, monkey anti-rGH as antiserum (produced in house), and goat antimonkey IgG as second antibody. [125I]rGH was labeled and purified before assays.
IGF-I levels in rats
Male rats (LEW/Ola/Hsd; Harlan Sprague Dawley, Inc., Horst, The Netherlands), weighing 200–250 g, were used in this study. SMS 201–995 and SOM230 were dissolved in sterile water and put in Alzet osmotic 14-d pumps (model 2002; Charles River Laboratories, Inc., Saint-Aubin-les Elbeuf, France), delivering 0.5 µl/h. Concentrations were adjusted to the mean body weight, considering a certain weight gain during the experiment, to obtain average doses of 1 and 10 µg/kg/h. For control animals, osmotic pumps were filled with sterile water only. In a second experiment, infusion rates of 10 and 50 µg/kg/h were maintained for 56 d by replacing the model 2002 minipumps every 2 wk and adjusting drug concentrations in the reservoir to the actual body weight of the rats; in this study, Lewis rat recipients of aorta allografts were studied (effects of SOM230 on grafts will be reported elsewhere). Pumps were implanted sc, on the back, using a short anesthesia with isofluran (Forene; Abbott Laboratories, Cham, Switzerland). Blood samples were collected before osmotic pump implantation and on various days afterwards. Animals were anesthetized with isofluran, for collecting blood from the retrobulbar plexus. After the third and last sampling, animals were killed. Blood was collected in Eppendorf (Hamburg, Germany) tubes containing EDTA (WED-19; Milian SA, Geneva, Switzerland), then spun in an Eppendorf centrifuge model 5413 for 5 min, and plasma was separated and frozen for analysis of IGF-I levels. IGF-I was determined using the IGF-I Kit from Nichols Institute Diagnostics SA (Geneva, Switzerland).
Body weight, food, and water intake in rats
Male Sprague Dawley rats (OFA-SD, from BRL, Switzerland), weighing 240–250 g, were sc implanted on the back with minipumps (Alzet pump type 2ML2). The minipumps were prepared 1 d before the start of the study and put in NaCl 0.9% overnight for priming. The following groups (5 rats each) were formed: vehicle (distilled sterile water), SOM230 (10 µg/kg/h), and SMS 201–995 (10 µg/kg/h). Both compounds were dissolved in sterile distilled water. Sublingual blood samplings (1 ml) were performed on d -1, 1, 2, 3, 7, 10, and 14 of the experiment, into EDTA-coated tubes, which were kept at 4 C for maximally 1 h before hematological analysis using the H1 Technikon analyzer (Bayer Diagnostics, Zürich, Switzerland). Every second day, the animals were weighed; and each day, feed intake and drinking water were measured. Rats were fed NAFAG pellets (KLIBA NAFAG, Kaiseraugst, Switzerland) ad libitum.
Growth hormone and IGF-I levels in rhesus monkeys
On experimental days, male rhesus monkeys were placed in primate chairs after being fed with fruits only in the morning of the previous day. A catheter with an extension tube was placed in a saphenic vein so that infusions and blood samplings could be done without being noticed by the animals, who were monitored by a video camera.
Aqueous stock solutions of SOM230 and SMS 201–995 were diluted with NaCl 0.9% to administer doses of 0.1–10 µg/kg sc in a vol of 0.1 ml/kg. Four to 6 animals were treated with a given dose. The control group consisted of a total of 19 animals. After 3 basal samples collected at 15-min intervals, compounds were administered sc in the thigh.
During the entire duration of the experiment, an infusion of 5–10 ml/h isotonic saline, containing heparin sodium (80 mg/liter) (Biochemie GmbH, Kundl, Austria) was maintained. At each sampling time, 1.5 ml blood (twice the void volume of the catheter) was collected separately before taking the actual blood sample. The first sample was reinfused afterwards. The second sample was mixed with EDTA (Fluka Chemie GmbH, Buchs, Switzerland) and aprotinin (Trasylol; Bayer Diagnostics), resulting in final concentrations of 1.8 mg/ml and 1000 Kallikrein-inactivator units/ml, respectively. Plasma was prepared and used for hormone determination. The remaining red blood cells were reinfused upon termination of the experiment. For determination of GH, the following RIA was used: Crescormon from Kabi AB (Stockholm, Sweden) served as standard; rabbit anti-hGH, produced in house, was used as antiserum; goat antirabbit from Calbiochem was used as second antibody; and [125I]hGH served as labeled ligand. For determination of IGF-I, the IGF-I RIA Kit from Nichols Institute Diagnostics SA was used, which contains rabbit anti-IGF-I antiserum, goat antirabbit as second antibody, [125I]IGF-I, and a standard.
In the 30-h pilot experiment, SOM230 and SMS 201–995, dissolved in isotonic saline, were injected sc in rhesus monkeys (100 µg/kg) at 0, 6, and 24 h. Monkeys were placed in primate chairs until blood collection at 6.5 h after the first injection. The IGF-I plasma levels of the first three samples, taken before administration of compound, were averaged logarithmically (basal value), set to 100%, and used to express the log values, at the different time points, as percent of basal values.
Studies in cynomolgus monkeys
Male cynomolgus monkeys (4–6.5 yr old) from Siconbrec, the Philippines, were kept in single cages, the night before blood sampling, for maximally 24 h (otherwise, in pens), with free access to food and water. The drugs were dissolved in water at pH 5–6.5 and filled in minipumps (Alzet model 2ML2; Alza Corp., Palo Alto, CA) under sterile conditions. The pumps were primed in 0.9% NaCl at 37 C overnight. Minipumps were implanted in an sc pocket in the back, between the shoulders.
A cross-over study was performed with animals randomized to two groups (n = 3 each). In the first period, one group was treated with SMS 201–995 and the other with SOM230, for a total of 2 wk. In the second period, the treatment regimens were switched, so that six monkeys were used per treatment. Both periods comprised 1 wk of observation and measurement of basal GH levels (baseline), then 1 wk of treatment with the SRIF analogs delivered by minipump at 0.3 µg/kg/h, which was immediately followed by 1 wk of treatment at 1.0 µg/kg/h, and a subsequent recovery period of 2 wk with vehicle administration only. The baseline of period 1 (first part of the cross-over study) comprised eight values, and that of period 2 (second part of the cross-over study) comprised five values per monkey. To assess the drug effects on hormones, blood was collected on d 7 of the low- and high-dose infusion treatment, respectively, with bleedings at 0815 h and 1115 h, so that two values were obtained per monkey and dose level. Drug blood levels were monitored once weekly using a specific SOM230 ELISA assay.
IGF-I levels in beagle dogs
IGF-I levels were monitored in six male beagle dogs (9.1–14.0 kg body weight, 3–9 yr old). Before the start of the experiment, the dogs were fasted overnight. Osmotic minipumps, Alzet type 2ML1, delivering 10 µl/h during 7 d, were used. Compounds were dissolved in sterile water to give delivery rates of 1, 3, or 10 µg/kg/h, assuming a body weight of 10 kg. Compounds, doses, and vehicle were given in randomized sequence. Three to 5 d after implantation of the minipumps, blood was collected from the jugular vein and mixed with EDTA (tubes, COM-75; Milian SA). One day after the first bleeding, a second assessment of IGF-I levels was performed, and the two values (0 and 24 h) were both included in the calculations. For determination of IGF-I levels, plasma was frozen till analysis (IGF-I Kit from Nichols Institute Diagnostics SA). The RIA, developed for human IGF-I, fully cross-reacts with canine IGF-I, as demonstrated previously (20).
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), which were incorporated into a cyclohexapeptide template to give the new SRIF peptidomimetic SOM230 its unique properties.
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Effects of SOM230 on rGH and IGF-I plasma levels
To assess the ability of SOM230 to control GH levels in the intact animal, rats were injected with increasing sc doses of SOM230, and for comparison with SMS 201–995, and ID50 values were calculated. At 1 h post dose, the inhibitory effect of SOM230 (0.22 µg/kg, mean of three experiments) is slightly less pronounced than that of SMS 201–995 (0.13 µg/kg, mean of 22 experiments); however, when 6-h values are compared, the effect of SOM230 is 4-fold greater than that of SMS 201–995 (5.5 vs. 23.7 µg/kg, mean of two and six experiments, respectively), indicating an increased duration of action of SOM230.
Plasma IGF-I levels depend directly on GH action. However, unlike the rapid changes of GH in response to SRIF, IGF-I levels drop slowly, requiring long-term exposure to SRIF. Therefore, minipumps, delivering 1 or 10 µg/kg/h for 14 d, were implanted in rats. These regimens were found previously to induce marked-to-maximal endocrine effects in rats treated with SMS 201–995. Under these conditions, a dose-dependent suppression of plasma IGF-I levels was achieved with both SMS 201–995 and SOM230 (Fig. 2). There were, however, clear differences between the two SRIF analogs in both the extent and duration of the reduction of IGF-I levels. With SMS 201–995, the maximum inhibition was 51% (10 µg/kg/h infusion rate), with rapid loss of responsiveness after d 2 of the infusion regimen. The loss of SMS 201–995 efficacy was observed in both the high- and the low-dose treatment groups. By contrast, SOM230 induced a markedly more pronounced decrease in IGF-I levels (90% in the 10-µg/kg/h group), which was associated with an improved persistence of efficacy. In fact, IGF-I levels on d 14 in the low-dose SOM230 group were still decreased by 41%, compared with only 10% reduction under SMS 201–995 treatment.
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). For both compounds, the difference in the degree of IGF-I suppression achieved on d 14 was maintained throughout the entire experiment, indicating that the loss of responsiveness observed for SMS 201–995 in the first experiment (Fig. 2
) takes place during the first week of infusion therapy. Again, pronounced differences between the action of SOM230 and SMS 201–995 were observed, in that the high-dose regimen of SMS 201–995 was less active than the low-dose regimen; whereas for SOM230, a clear dose response with increasing efficacy, as a function of increasing infusion rates, was obtained. Accordingly, SMS 201–995 and SOM230, at an infusion rate of 50 µg/kg/h, decreased plasma IGF-I levels on d 56 (end of study), in relation to placebo controls, by 18% and 74%, respectively. The very pronounced difference between SOM230 and SMS 201–995 in inhibition of IGF-I was also reflected in the growth rate of treated rats.
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, control rats grew continuously, from 246 ± 4.4 g (SE) on d 0 to 313 ± 7.3 g on d 14. SMS 201–995 had only a marginal inhibitory effect on body weight gain. In contrast, the body weight of rats receiving SOM230 decreased slightly, from 254 ± 5.9 g on d 0 to 247 ± 7.3 g on d 2, and stayed at this level throughout the entire study period and was 246 ± 6.6 g on d 14. The parallel daily monitoring of feeding behavior indicated that SOM230 treatment apparently was not associated with a change in feed or water intake. The daily feed intake per rat amounted to 22.9 ± 0.51 g, 21.5 ± 0.53 g, and 22.7 ± 0.48 g in rats treated with vehicle, SOM230, and SMS 201–995 infusion, respectively. There was also no significant change in the amount of drinking water consumed daily. In the 56-d experiment mentioned above, there was also a complete and persistent block of rat body weight gain during the entire study period (data not shown), confirming the 14-d treatment findings mentioned above.
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Rhesus monkey plasma GH and IGF-I levels
The dose dependency of the GH-lowering effect of sc administered SOM230 in rhesus monkeys is shown in Fig. 5. At a dose of 0.1 µg/kg, SOM230 exhibited marginal inhibitory effects, which still allowed for GH peaks to occur. The higher doses of 1 and 10 µg/kg SOM230 completely prevented the formation of GH spikes and showed a clear-cut dose-dependent inhibitory effect. When SOM230 and SMS 201–995 were compared, the ID50 value for inhibition of GH was 0.5 and 0.4 µg/kg, respectively (mean of four to six monkeys, Fig. 5). The ID50 values were similar for SOM230 and SMS 201–995, as they are based on means of values obtained between 30 and 120 min after sc administration. However, it was observed that at a single dose of 1 µg/kg, plasma GH levels in the SMS 201–995 group rapidly rebounded, after 3–4 h, to values approximately 2-fold higher than baseline levels. In contrast, in monkeys treated with SOM230, plasma GH levels increased slowly after the initial inhibition and did not rise beyond the pretreatment concentrations.
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). Three injections of 100 µg/kg SOM230 or SMS 201–995 were given at 0, 6, and 24 h, and blood samples were collected for up to 30 h. Both analogs marginally suppressed IGF-I levels within the first 6 h. Though the second and third injection of SMS 201–995 failed to further lower IGF-I levels at these early time points, SOM230 decreased the levels (-53%) to approximately half of those observed with SMS 201–995 at 30 h.
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). The low dose of SOM230 (0.3 µg/kg/h) induced a reduction of GH levels from 16.3 ± 4.3 ng/ml to 3.8 ± 1.9 ng/ml on d 7 (P = 0.02 vs. baseline). Upon switching to the high-dose SOM230 infusion (1 µg/kg/h), there was a further decline in absolute GH plasma levels to 1.8 ± 0.8 ng/ml (P = 0.007 vs. baseline, Fig. 7). When the animals were infused with vehicle after SOM230 treatment, there was still a tendency for inhibition of GH, indicating its low duration of action. By contrast, SMS 201–995 induced a much less pronounced decline in GH plasma levels. Thus, there was a significant difference in the GH-lowering effect of SOM230 vs. SMS 201–995, and the effect of SOM230 was more prolonged after cessation of the treatment. The inhibitory effect on GH in the cynomolgus monkey was selective, in that plasma insulin, glucagon, and glucose levels remained unchanged on d 7 of the high-dose infusion period (data not shown), whereas IGF-I plasma levels dropped significantly (from 1402 ± 100 ng/ml to 896 ± 47 ng/ml) (P = 0.001, Student’s t test). SMS 201–995 did not induce a significant drop in IGF-I levels under these conditions. The plasma levels of SOM230 and SMS 201–995 on d 7 of the 1-wk infusion period with 1 µg/kg/h amounted to 12.5 ± 5 and 4.4 ± 1.8 ng/ml, respectively. Both compounds could not be detected on d 4 of the washout period.
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Though infusion of SMS 201–995 at 1, 3, and 10 µg/kg/h dose-dependently decreased plasma IGF-I levels (41.4, 29.4, and 19.3 ng/ml, respectively), the level of inhibition did not reach statistical significance because of the small number of animals investigated (n = 3–4). Based on these results, the dose of SOM230 selected for testing was 3 µg/kg/h. At this infusion rate, SOM230 significantly decreased plasma IGF-I levels, to 15.4 ng/ml (P = 0.04), and was at least 3-fold more efficacious than SMS 201–995.
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Discussion |
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SOM230 binds with high affinity to all human SRIF receptor subtypes except for sst4. Its high affinity for sst1, sst2, and in particular for sst5, which is 40-times higher than octreotide and even improved over SRIF, may be crucial for GH inhibition. Pituitary somatotrophs express predominantly sst2 and sst5; accordingly, drug combinations that contain both sst2- and sst5-selective SRIF analog agonists were shown to inhibit GH release more potently than single-agent treatment in pituitary adenoma cultures (24, 25). In a recent study by Savenu et al. (19), an important function of sst5 for GH regulation was proposed for human GH-secreting pituitary tumors only partially sensitive to the inhibitory action of octreotide. These tumors expressed high levels of sst5 and were inhibitable by both sst5-selective and sst2- and sst5-biselective SRIF analogs. Such studies would indicate a role for SOM230 in the treatment of acromegaly unresponsive or only partially responsive to octreotide or lanreotide. Subtype sst5 shows the greatest divergence between the human and the rat form (81% identity), which is accompanied by species differences in the binding affinity of SRIF analogs. If sst5 plays a key role in the pharmacology of SOM230 in rats, a different activity profile of SOM230 may be found in patients. Moreover, the affinity of SOM230 to sst5 suggests potential inhibitory effects on PRL secretion, given that Shimon et al. (25) found that sst5-selective agents inhibit PRL secretion from prolactinomas, whereas sst2-selective agonists were inactive.
Involvement of the sst1 SRIF receptor subtype in regulation of GH secretion has been demonstrated in a recent antisense study, both in vitro and in vivo (26). By binding to sst1, SOM230 may trigger a pathway in GH regulation that is not affected by octreotide or lanreotide. Whether the binding of SOM230 to sst3 can directly or indirectly affect plasma GH levels is currently unknown. Nevertheless, recent studies have characterized the role of sst3 in more detail, pointing to other potential uses of SOM230. The sst3 SRIF receptor subtype is suggested to inhibit gastric smooth-muscle cell relaxation (27) and induce cell apoptosis and reduced cell growth (28, 29). This subtype may also have a role in immunological responses, because human peripheral B- and T-lymphocytes express exclusively sst3 (3).
SOM230 very effectively inhibited growth hormone release in rats. The duration of GH suppression seems to be longer, compared with octreotide, the ID50 value of SOM230 for GH inhibition at 6 h post injection being 4-fold lower than octreotide, which may be explained not only by improved potency but also by a longer duration of action of SOM230 in vivo. Short-term studies in rhesus monkeys confirm the pronounced GH inhibition found in rats (Fig. 5). To address long-term effects of SOM230 on GH levels in monkeys, a minipump infusion study was carried out (Fig. 7) where SOM230 was infused at 0.3 and 1.0 µg/kg/h in the first and second week, respectively. The effect of SOM230 on GH levels was again very pronounced and superior to SMS 201–995, indicating that it exerts not only short-term (Fig. 5), but also chronic inhibitory effects on GH secretion, with a clear tendency for inhibition also in the washout phase. This observation in cynomolgus monkeys supports the notion of a long duration of action of SOM230 already detected in acute studies in rats. Plasma levels measured in the same experiment indicate higher levels of SOM230 than octreotide. Thus, the inhibitory effects seen in vivo may result from both improved pharmacodynamic and pharmacokinetic properties of SOM230.
One of the most intriguing pharmacological features of SOM230 is its potent and long-lasting suppression of plasma IGF-I. One to 3 d of treatment are required until the full IGF-I-lowering effect of SRIF analogs is achieved. Therefore, either continuous infusion regimens, using sc implanted minipumps (as in rats, cynomolgus monkeys, and dogs), or multiple injection regimens (as in the rhesus monkey) were used to study the inhibitory effects of SOM230, in parallel with octreotide, on plasma IGF-I levels. In the rat, SOM230 strongly decreases IGF-I plasma levels, the duration and the efficacy being markedly superior to the effects elicited by octreotide. In particular, SOM230 shows no signs of escape over a time period of up to 56 d (Fig. 3). This constant long-term inhibition (Fig. 3) follows an initial, even more potent, lowering of IGF-I levels within 2 d of infusion treatment, which is followed by a small loss of responsiveness within the first 14 d (Fig. 2). In beagle dogs, the pronounced IGF-I-lowering property of SOM230 could be confirmed, in that SOM230 is at least 3 times more potent than octreotide in decreasing plasma IGF-I levels. Moreover, in a pilot experiment with a small number of rhesus monkeys, three consecutive injections of SOM230 markedly decreased IGF-I plasma levels, from 24 h onwards, whereas octreotide was only marginally active acutely. In general, it should be noted that the lowering of IGF-I levels was observed under a variety of conditions, including various rat strains, different species, and a variety of regimens (single-agent treatment and combination therapy, short-term and long-term studies, injection, and infusion), demonstrating the robustness of the inhibitory effects of SOM230 on the GH/IGF-I axis.
Potential explanations for the marked IGF-I-lowering effects of SOM230, in comparison with octreotide, include: 1) the more pronounced inhibition of GH may result indirectly in a more pronounced lowering of plasma IGF-I levels; and 2) a postulated direct inhibitory effect of SOM230, independent of pituitary effects and exerted at the level of the liver and potentially other peripheral tissues. An antiproliferative and proapoptotic action of SOM230, mediated by sst3 and sst5, may play a role in its IGF-I-lowering effects (30).
GH and IGF-I are key regulators of body weight. Rats treated continuously with SOM230 failed to grow (without signs of overt toxicity), whereas octreotide led only to a marginal growth retardation (Fig. 4). It is tempting to speculate that the markedly decreased circulating IGF-I levels observed under SOM230 are the basis for impaired body growth. However, another possibility, which is outside the scope of the present studies, is an inhibitory effect of SOM230 on the local production of IGF-I. In fact, in liver IGF-I-null mice, the body growth rate is normal despite reduction of plasma IGF-I by 75%, indicating that circulating IGF-I alone had no discernible effect on postnatal body growth (31).
Based on the comprehensive preclinical characterization of SOM230, its potential indications include those for octreotide or lanreotide (namely, acromegaly and gastroenteropancreatic tumors). The use of octreotide and lanreotide for these indications is mainly based on their high affinity for sst2, which is an important SRIF receptor subtype because of its wide distribution and the mediation of endocrine and antiproliferative effects. SRIF receptor subtype sst2 also binds SOM230. By binding to sst2 and, in addition, to sst1, sst3, and sst5 with high affinity, SOM230 may exhibit a superior pharmacological profile that may translate into an improved therapeutic outcome of the treatment of acromegaly and possibly gastroenteropancreatic tumors.
Binding of a synthetic ligand to as many SRIF receptor subtypes as possible is expected to best mimic the activity profile of universal natural ligand SRIF. Whether such a profile of a synthetic SRIF analog will translate into a clinical advantage needs to be explored. The continued clinical use of natural SRIF (Stilamine), for various indications, points to a clinical role of universal SRIF mimetics. SOM230 could potentially overcome the therapeutic limitations of natural SRIF that are attributable to its lability. SOM230 is a small-molecular-mass SRIF analog (1047.2 Da) with good stability, water solubility, and physicochemical properties that are compatible with its formulation as a long-release form. Moreover, the potential clinical use of SOM230 requires an acceptable safety profile. So far, no prohibitive untoward side effects of SOM230 were observed in any of the small and large animal species undergoing pharmacological testing (data not shown). Significantly, continuous high-dose treatment, e.g. in rats, was well tolerated (Fig. 3).
In conclusion, SOM230 is a novel cyclohexapeptide with an almost universal high-affinity binding profile for four of the five SRIF receptor subtypes. SOM230 exerts potent and long-lasting inhibitory effects on the GH/IGF-I axis in rats, monkeys, and dogs and is currently being tested in phase I clinical trials.
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Acknowledgments |
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Footnotes |
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Abbreviations: ID50, Half-maximal inhibitory dose; Phg, phenylglycine; rGH, rat GH; SRIF, somatostatin; Tyr(Bzl), tyrosylbenzyl.
Received February 25, 2002.
Accepted for publication May 7, 2002.
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