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Department of Internal Medicine (L.J.H., J.v.d..H., P.M.v.K., W.W.d.H., M.W., D.S.-M., R.F., A.-J.v.d.L., S.W.J.L.), Section of Endocrinology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; Research Transplantation (C.B., G.W.), Novartis Pharma A.G., Basel, Switzerland CH-4002; Service d’Endocrinologie (A.B.), Center Hospitalier Universitaire de Liege, Domaine Universitaire du Sart-Tilman, Liege, Belgium 4000
Address all correspondence and requests for reprints to: Leo J. Hofland, Ph.D., Department of Internal Medicine, Section of Endocrinology, Room EE585, Erasmus MC, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: l.hofland{at}erasmusmc.nl.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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These observations initiated the development of novel stable SRIF analogs with a more universal sst binding profile. One of these new compounds, SOM230, was recently shown to reduce circulating IGF-I levels in rats by 75% after 126 d of continuous infusion. This effect was significantly more potent, compared with OCT, which suppressed IGF-I release under the same experimental condition by only 28% (12). In rats, the terminal elimination half-life was 23 h, which is approximately 11 times longer, compared with OCT (12). Finally, in both cynomolgus monkeys and beagle dogs, infusion of SOM230, and to a much lesser extent OCT (SMS 201–995), lowered IGF-I levels potently (13). Compared with OCT, SOM230 has a 30, 5, and 40 times higher binding affinity to sst1, sst3, and sst5 receptors, respectively, and 2.5 times lower affinity to sst2 (Ref. 12 and Table 1
). This universal binding profile of SOM230 to sst, in combination with the importance of sst2 and sst5 receptors in regulating GH secretion by pituitary adenoma cells, was the rationale for the present study to evaluate, for the first time, the effects of SOM230, OCT, and the native SRIF molecule SRIF-14 on hormone secretion by human GH-secreting pituitary adenomas. Moreover, recent evidence suggests that sst5 receptors are also involved in the regulation of prolactin (PRL) secretion by human prolactinoma cells (11, 14). Therefore, we compared the effects of OCT and SOM230 on PRL secretion by primary cultures of human prolactinomas. A correlation is made with the sst subtype expression patterns in the adenoma cells.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Pituitary tumor samples were obtained by transsphenoidal operation from nine patients with GH-secreting pituitary adenomas and from three patients with prolactinomas as described in detail previously (15). Diagnosis was made on the basis of clinical and biochemical characteristics of the patients, in combination with (immuno)histochemistry of the tumor samples (Table 2). All patients gave their informed consent for the use of tumor material for research purposes. Directly after obtaining the tissue, a piece of tissue was snap frozen on dry ice and stored at –80 C until analysis. The remaining tissue was used for cell culture.
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Quantitative PCR
Quantitative PCR was performed as described previously (16). Briefly, poly A+ mRNA was isolated using Dynabeads Oligo (dT)25 (Dynal AS, Oslo, Norway) from freshly isolated pituitary adenoma cell pellets containing 0.5–1.0 x 106 adenoma cells. Analysis of sst subtype mRNA levels in both tissue or freshly isolated cell pellets (n = 4) yielded comparable results (data not shown). cDNA was synthesized using the poly A+ mRNA, which was eluted from the beads in 40 µl H2O for 10 min at 65 C, using Oligo (dT)12–18 primer (Invitrogen, Breda, The Netherlands). One twentieth of the cDNA library was used for quantification of sst subtype mRNA levels. A quantitative PCR was performed by TaqMan Gold nuclease assay (Perkin-Elmer Corp., Foster City, CA) and the ABI PRISM 7700 sequence detection system (Perkin-Elmer) for real-time amplifications, according to manufacturer’s protocol. The assay was performed using 15 µl TaqMan Universal PCR master mix (Applied Biosystems, Capelle aan de ijssel, The Netherlands), 500 nM forward primer, 500 nM reverse primer, 100 nM probe and 10 µl cDNA template, in a total reaction volume of 25 µl. The reactions were carried out in a ABI 7700 sequence detector (Perkin-Elmer, Groningen, The Netherlands). After an initial heating at 95 C for 8 min, samples were subjected to 40 cycles of denaturation at 95 C for 15 sec and annealing for 1 min at 60 C. The primer and probe sequences that were used are indicated below. The detection of hypoxanthine-phosphoribosyl-transferase (hprt) mRNA served as a control and was used for normalization of the sst subtype mRNA levels.
The primer sequences that were used included the following: hprt forward, 5'-TGCTTTCCTTGGTCAGGCAGTAT-3'; hprt reverse, 5'-TCAAATCCAACAAAGTCTGGCTTATATC-3'; sst1 forward, 5'-TGAGTCAGCTGTCGGTCATC-3'; sst1 reverse, 5'-ACACTGTAGGCACGGCTCTT-3'; sst2 forward, 5'-TCGGCCAAGTGGAGGAGAC-3'; sst2 reverse, 5'-AGAGACTCCCCACACAGCCA-3'; sst3 forward, 5'-CTGGGTAACTCGCTGGTCATCTA-3'; sst3 reverse, 5'-AGCGCCAGGTTGAGGATGTA-3'; sst5 forward, 5'-CATCCTCTCCTACGCCAACAG-3'; and sst5 reverse, 5'-GGAAGCTCTGGCGGAAGTT-3'.
The probe sequences that were used included the following: hprt, 5'-FAM-CAAGCTTGCGACCTTGACCATCTTTGGA-TAMRA-3'; sst1, 5'-FAM-ACAGCTGCGCCAACCCCATC-TAMRA-3'; sst2, 5'-FAM-CCGGACGGCCAAGATGATCACC-TAMRA-3'; sst3, 5'-FAM-CGGCCAGCCCTTCAGTCACCAAC-TAMRA-3'; and sst5, 5'-FAM-CCCGTCCTCTACGGCTTCCTCTCTGA-TAMRA-3'.
Primers and probes were purchased from Biosource (Nivelles, Belgium).
The relative amount of sst subtype mRNA was determined using a standard curve generated from known amounts of human genomic DNA. For determination of the amount of hprt mRNA, a standard curve was generated of a pool of cDNAs from a human cell line known to express hprt. The linear range of amplification ranged between 4 log dilutions of genomic DNA or cDNA, respectively. The relative amount of sst subtype mRNA was calculated relative to the amount of hprt mRNA and is given in arbitrary units. Each sample was assayed in duplicate.
Cell dispersion and cell culture
Single-cell suspensions of the pituitary adenoma tissues were prepared by enzymatic dissociation with dispase as described in detail previously (15). For short-term incubation of monolayer cultures, the dissociated cells were plated in 48-well plates (Corning, Cambridge, MA) at a density of 105 cells per well per 1-ml culture medium. After 3–4 d the medium was changed and 72-h incubations without or with test substances were initiated. At the end of the incubation, the medium was removed and centrifuged for 5 min at 600 x g. The supernatant was collected and stored at –20 C until analysis. The choice for a 72-h incubation was made on the basis of previous studies, in which we demonstrated that exposure of GH-secreting pituitary adenoma cells for 4–96 h to octreotide showed a variable, but in all instances during longer incubations statistically significant inhibition of GH release, which paralleled the sensitivity of GH secretion to octreotide in vivo (17). For long-term incubation studies in Transwells (18), the isolated tumor cells were plated in Transwell-COL membranes (Corning) at a density of 105 cells/well. The Transwells were then placed into multiwell plates (24-well, Corning) containing 1 ml culture medium. After 72 h the Transwells were transferred to wells containing fresh medium (without or with test substances). Every 3–4 d the cells were placed into fresh medium and the incubation media were collected and stored at –20 C until determination of hormone concentrations.
The cells were cultured at 37 C in a CO2 incubator. The culture medium consisted of MEM supplemented with nonessential amino acids, sodium pyruvate (1 mmol/liter), 10% fetal calf serum, penicillin (1 x 105 U/liter), fungizone (0.5 mg/liter), L-glutamine (2 mmol/liter), and sodium bicarbonate (2.2 g/liter, pH 7.6). Media and supplements were obtained from Gibco Bio-cult Europe (Invitrogen, Breda, The Netherlands).
Unfortunately, generally not enough tumor material was obtained to test for each tumor the dose dependency of effects for the indicated drugs.
Hormone determinations
Human GH and PRL concentrations in the media and cell extracts were determined by a nonisotopic, automatic chemiluminescence immunoassay system (Immulite; Diagnostic Products Corp. Inc., Los Angeles, CA). Intra- and interassay coefficients of variation for GH and PRL were 6.0 and 5.7% and 6.2 and 6.4%, respectively. ACTH, LH, and FSH concentrations in the culture media were determined as well to exclude the presence of contaminating normal pituitary cells in the cultures. Human ACTH, LH, and FSH concentrations were determined by a nonisotopic, automatic chemiluminescence immunoassay system (Immulite, Diagnostic Products Corp. Inc.). Intra- and interassay coefficients of variation for ACTH, LH, and FSH were 5.6, 5.7, and 6.4% and 7.8, 12.3, and 7.5%, respectively. Except for the expected hormones GH and PRL, none of the other hormones were detectable (not shown).
Test substances
OCT (Sandostatin) and bromocriptine were obtained from Novartis Pharma A.G. (Basel, Switzerland). SOM230 was provided by Novartis Pharma A.G. Somatostatin-14 (SRIF-14) was purchased from Sigma Chemical Co. (St. Louis, MO).
Statistical analysis of the data
All data on hormone release are expressed in mean ± SE, n = 4 wells per treatment group. All data were analyzed by ANOVA to determine overall differences between treatment groups. When significant differences were found by ANOVA, a multiple comparison between treatment groups was made using the Newman-Keuls test. Correlation analysis was done by the use of the Spearman’s rank correlation test. Calculation of IC50 values for inhibition of hormone release were made using GraphPad Prism (San Diego, CA).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In seven of nine GH-secreting pituitary adenoma samples the sst subtype mRNA expression pattern was determined. Figure 1 shows that two adenomas expressed sst1 mRNA, three adenomas expressed sst3 mRNA and that all adenomas expressed sst2 and sst5 mRNAs. Expression of sst mRNAs was variable between adenoma samples. The difference between the lowest and the highest level measured, amounted to 7-, 8-, 3-, and 5-fold for sst1, sst2, sst3, and sst5, respectively. The sst subtype mRNA levels showed no statistical correlation (data not shown). The mean percentage in vivo GH suppression (range +18 and –91% suppression) between 2 and 8 h after the administration of a single sc dose of 100 µg OCT (patients 1, 2, 3, 5, 6, and 7) was positively correlated with sst2 mRNA expression levels (Fig. 2, left panel) but not with sst5 mRNA levels (Fig. 2, right panel).
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In most GH-secreting pituitary adenomas, the effect of 10 nM OCT, SOM230, or SRIF-14 on GH release was evaluated in parallel in vitro. Figure 3 shows that GH release was significantly suppressed by OCT in seven of nine cultures, by SOM230 in eight of nine cultures and by SRIF-14 in six of six cultures. In the majority of the adenomas, the percentage suppression using a maximally active concentration of the three compounds, was comparable. Only the adenoma cells of patient 7 showed a dissociated response to OCT on the one hand and to SOM230 and SRIF-14 on the other hand. In this adenoma culture, GH release was not inhibited by OCT, whereas both SOM230 and SRIF-14 induced a statistically significant suppression of GH release. In the respective patient, OCT (100 µg sc) did not suppress GH concentrations as well. As seen in Fig. 3, the response in terms of GH suppression was variable between the individual adenoma cultures. This variable responsiveness to OCT and SOM230 correlated well with the sst2 mRNA expression levels in the adenoma cells of the respective patients (Fig. 4, upper panel). Comparable to the patients responsiveness to OCT, sst5 mRNA expression showed no statistically significant correlation with the percentage of GH suppression by 10 nM OCT. Interestingly, the effects of 10 nM SOM230, which shows a more universal binding profile for sst receptors, including high-affinity binding to sst5, also showed no correlation with sst5 mRNA expression levels. This is demonstrated in Fig. 4 (lower panel).
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(right panel) shows the effects of the three compounds on GH release by the adenoma cells of patient 7, which did not respond to OCT. The adenoma cells of this patient had the lowest sst2 mRNA levels of all cases studied (Fig. 1
, upper right panel). As shown, GH release by the cells of this patient was inhibited in a dose-dependent manner by both SOM230 and SRIF-14. The IC50 values for the inhibition of GH release were 0.5 and 0.6 nM for SOM230 and SRIF-14, respectively. In the other adenoma cultures, both OCT and SRIF-14 were slightly more efficacious, in terms of IC50 values, compared with SOM230. Figure 5 (left panel) shows the mean dose response of OCT, SOM230, and SRIF-14 for the other cultures. Mean IC50 values were 0.02, 0.5, and 0.02 nM for OCT, SOM230, and SRIF-14, respectively.
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Because previous studies demonstrated the involvement of sst5 receptors in regulating PRL release, we also compared the effects of OCT and SOM230 on PRL release. Five adenoma cultures cosecreted PRL as well. OCT (10 nM) and SOM230 (10 nM) significantly inhibited PRL release in four of five and five of five cultures, respectively (Fig. 6). The percentage suppression was between 16 and 66% for OCT and between 38 and 74% for SOM230, indicating its higher efficacy. In four of five cultures (no. 1, 3, 8, and 9), SOM230 was significantly more potent with regard to its maximal suppressive effect on PRL release, when compared with OCT (P < 0.01).
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). Figure 7 shows that prolactinoma no.10 selectively expresses a high level of sst5 mRNA, whereas prolactinoma 11 expressed sst1 mRNA but very low sst5 mRNA. In agreement with the low affinity of OCT for sst5 and the very high affinity of SOM230 for this sst, 10 nM OCT did not significantly inhibit PRL release by the two prolactinoma cultures, whereas 10 nM SOM230 potently suppressed (–49%) PRL release by cells of adenoma 10 (high sst5) and slightly (–23%) by cells of prolactinoma no.11 (low sst5). Both adenoma cultures showed high sensitivity to 10 nM of the dopamine agonist bromocriptine (–73 and –89% inhibition in cultures 10 and 11, respectively). In one prolactinoma culture (no. 12) the long-term in vitro effects of OCT, SOM230, and bromocriptine were studied. Figure 8 shows that both SOM230 (10 nM) and bromocriptine (10 nM) suppressed PRL release by approximately 90% after 9 d of continuous incubation with the compounds. In this particular adenoma, OCT was only slightly effective (–30% after 9 d). Unfortunately, not enough tissue was obtained from this patient to study the sst subtype expression pattern.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In agreement with previous studies (3, 4, 5, 6, 7, 8, 9, 10), we found a variable expression of sst mRNAs, predominantly sst2 and sst5, in our series of GH-secreting pituitary adenomas. Only selected cases expressed sst1 and sst3 mRNAs, suggesting that these sst subtypes are probably of less importance in this type of pituitary adenoma. Moreover, in most adenomas, sst5 expression levels were relatively higher, compared with sst2 mRNA levels. On the other hand, the preoperative response of acromegalic patients to a single sc administration of 100 µg OCT was positively correlated with the sst2 mRNA, but not with sst5 mRNA levels, in the pituitary adenomas of the patients obtained via transsphenoidal surgery. These data demonstrate that the sst2 subtype is clearly the predominant receptor determining in vivo responsiveness to OCT in acromegalic patients.
In agreement with previous observations (10), sst2 mRNA levels were positively correlated with the in vitro GH suppression by this sst2 selective SRIF analog as well. Surprisingly, although SOM230 shows a very high affinity for sst5 receptors, no significant correlation was found between the in vitro GH suppression by a maximally active concentration of SOM230 and sst5 mRNA levels, whereas a positive correlation was found between the effects of SOM230 and sst2 mRNA levels. Although these data were unexpected, a previous study by Jaquet et al. (9) in fact already made the same observation using SRIF-14. In this study, sst2 mRNA but not sst5 mRNA levels in GH-secreting pituitary adenomas showed a positive correlation with in vitro GH suppression by 1 nmol/liter SRIF-14.
As suggested by Jaquet et al. (9), it is not known yet whether the observed sst mRNA levels directly correlate with sst protein levels. The importance of the sst2 subtype in regulating GH secretion by the majority of human GH-secreting pituitary adenomas is also evident by our observation that the potency of OCT in terms of IC50 values measured for the inhibition of GH release are slightly higher, compared with SOM230. Nevertheless, SOM230 shows a high efficacy to inhibit GH release, with an IC50 value in the low nanomolar range. In 89% of the cultures SOM230 significantly inhibited GH release. In this respect, OCT is slightly less efficacious, with a significant GH-suppressive effect in seven of nine cultures (78%). In one OCT-resistant culture, SOM230 inhibited GH release with an IC50 value comparable with that of SRIF-14 (IC50, 0.5 and 0.6 nM, respectively), confirming the importance of the sst5 receptor subtype in mediating GH release, when sst2 levels are low. However, although SOM230 has a slightly lower potency (IC50) for the inhibition of GH release in most cases, compared with OCT, its efficacy is higher, compared with OCT, in terms of the number of responders. Therefore, in addition to the sst2/sst5 bispecific compound BIM-23244, SOM230 also has the potential to achieve better control of GH hypersecretion in a larger number of acromegalic patients. Moreover, the very favorable elimination half-life of SOM230 (12) makes this compound an interesting candidate for clinical application as well.
Apart from regulating GH secretion, sst5 receptors play a regulatory role in normal and tumoral PRL secretion as well (2, 11, 14). A significant proportion of GH-secreting pituitary adenomas contain GH- and PRL-expressing cells, either as individual cells expressing GH or PRL or as mammosomatotroph cells expressing GH and PRL in the same cells (25). In agreement with these data, we observed cosecretion of GH and PRL in 56% of the cultures and showed that SOM230 has a potent inhibitory effect on PRL secretion in mixed GH-PRL-secreting pituitary adenomas and prolactinomas. In four of five mixed GH-PRL-secreting pituitary adenomas, SOM230 was significantly more potent, compared with OCT, in its maximal suppressive effect on PRL secretion. Recently it was shown that activation of sst1 by the sst1-selective agonist BIM-23296 caused a dose-dependent inhibitory effect in the nanomolar range on GH and PRL secretion by GH-secreting pituitary adenomas. In addition to lowering GH and PRL secretion, this SS-analog induced a decrease in cell viability as well (26). In our series we found that two of seven adenomas expressed sst1. In selected cases, therefore, sst1 may play a regulatory role on GH-secreting pituitary adenoma cell function as well.
In three dopamine (DA) agonist-sensitive prolactinomas, SOM230 was significantly more potent than OCT in lowering PRL secretion. In two of the prolactinomas, there was a clear relationship between the expression of sst5 mRNA in the adenoma cells and the percentage inhibition of PRL secretion by SOM230. In one prolactinoma culture, which expressed high levels of sst5 mRNA and no other sst mRNAs, PRL secretion was reduced to the same extent as that induced by bromocriptine. One other prolactinoma, which showed a significantly lower responsiveness to SOM230, had very low sst5 mRNA levels. The lower potency of OCT in reducing PRL secretion by prolactinomas seems related to the very low sst2 levels, as was demonstrated in a series of 10 prolactinomas by Jaquet et al. (14). These data further underline the role of sst5 in mediating its suppressive effect on PRL secretion. However, the potential clinical importance of these findings should be considered in view of the very high proportion of patients with prolactinomas responding to DA agonist treatment with a normalization of PRL levels and tumor shrinkage (27, 28). In addition, Jaquet et al. (14) previously showed that the effects of sst5 selective compounds on prolactinoma cells are superimposable at higher concentration to those of the DA agonists, but not additive, particularly in adenomas resistant to dopaminergic suppression of PRL release.
Whereas sst5 receptors may mediate antiproliferative effects (29), the role of this receptor in the control of pituitary adenoma cell proliferation is unclear. Indirect evidence for a role of sst5 in the regulation of human GH-secreting pituitary adenoma cell proliferation was obtained from the observation of a germ line mutation (Arg240Trp) in genomic DNA from pituitary adenoma and peripheral blood mononuclear cells of an acromegalic patient resistant to SRIF analog treatment and a higher proliferation rate of cells overexpressing this mutant sst5 receptor, compared with cells expressing wild-type sst5 (30). Whether activation of sst5 receptors expressed on human GH-secreting pituitary adenomas and prolactinomas also mediates an antiproliferative effect in these cell types remains to be elucidated, however.
Because somatostatin analogs inhibit the secretion of insulin, impaired glucose tolerance was observed after the acute administration of octreotide (31). Recently we observed similar glucose responses to the acute administration of SOM230 in vivo (32). However, SOM230 did not modify insulin secretion, suggesting another mechanism of action. The inhibitory effect of octreotide on insulin secretion is short-lived, and clinically important effects on carbohydrate metabolism during long-term therapy are not observed (33). Although the acute rise in glucose levels after SOM230 injection requires further attention, preclinical studies in cynomolgus monkeys showed that insulin, glucagon, and glucose levels remained unchanged after 7 d of high-dose infusion with SOM230 (13). In addition, 126 d treatment of rats with pharmacological doses of SOM230 did not modify plasma glucose levels (12). These data suggest that SOM230 is well tolerated in rats and monkeys with regard to glucose homeostasis.
In conclusion, the novel universal SRIF analog SOM230 is a potent inhibitor of GH and PRL secretion in GH-secreting pituitary adenomas. The higher number of cultures responding to SOM230, compared with OCT, suggests that SOM230 has the potential to increase the number of patients controlled biochemically, both via sst2 and sst5. In addition, SOM230 is more potent in its inhibitory effect on PRL secretion in mixed GH/PRL-secreting pituitary adenomas. In prolactinoma cultures, sst5 receptors mediate the potent inhibitory effects of SOM230 on PRL secretion. Because the majority of patients with prolactinomas are successfully treated using DA agonists, there may be a role for SOM230 in the treatment of prolactinoma patients, which are intolerant to DA agonists.
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Footnotes |
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Received August 4, 2003.
Accepted December 22, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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 E Thodou, G Kontogeorgos, D Theodossiou, and M Pateraki Mapping of somatostatin receptor types in GH or/and PRL producing pituitary adenomas. J. Clin. Pathol., March 1, 2006; 59(3): 274 - 279. [Abstract] [Full Text] [PDF]
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M C Zatelli, D Piccin, F Tagliati, A Bottoni, M R Ambrosio, A Margutti, M Scanarini, M Bondanelli, M D Culler, and E C d. Uberti Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro J. Mol. Endocrinol., October 1, 2005; 35(2): 333 - 341. [Abstract] [Full Text] [PDF]
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P Jaquet, G Gunz, A Saveanu, H Dufour, J Taylor, J Dong, S Kim, J-P Moreau, A Enjalbert, and M D Culler Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy Eur. J. Endocrinol., July 1, 2005; 153(1): 135 - 141. [Abstract] [Full Text] [PDF]
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L. J Hofland, J. van der Hoek, R. Feelders, M. O van Aken, P. M van Koetsveld, M. Waaijers, D. Sprij-Mooij, C. Bruns, G. Weckbecker, W. W de Herder, et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5 Eur. J. Endocrinol., April 1, 2005; 152(4): 645 - 654. [Abstract] [Full Text] [PDF]
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), OCT (
), and SRIF-14 (
) in cultured pituitary adenoma cells. The left panel represents the mean dose-dependent effects of SOM230 (n = 5; adenoma no. 2, 3, 4, 5, and 6), OCT (n = 4; adenoma no. 2, 3, 5, and 6), and SRIF-14 (n = 4; adenoma no. 2, 3, 5, and 6). The right panel shows the dose-dependent inhibitory effects of the compounds on GH release by cells patient 7.
