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Original Studies |
Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique (A.S., G.G., A.E., P.J.), and Laboratoire de Transfert d’Oncologie Biologique-Assistance Publique-Hôpitaux de Marseilles (L.O., F.F.), Institut Fédératif Jean Roche, Faculté de Médecine Nord, 13916 Marseilles, France; Service de Neurochirurgie, Centre Hospitalier de Marseilles, Hôpital de la Timone (H.D.), 13005 Marseilles, France; Service d’Endocrinologie de Toulouse (P.C.), 31403 Toulouse, France; and Biomeasure, Inc. (M.D.C., J.P.M.), Milford, Massachusetts 01757
Address all correspondence and requests for reprints to: Dr. Philippe Jaquet, Interactions Cellulaires Neuroendocriniennes-Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, boulevard Pierre Dramard, 13916 Marseilles Cedex 20, France.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study we used in vivo data to select a series of tumors from acromegalic patients considered either full octreotide responders or partial responders. In these cases a portion of the tumor tissue obtained after transsphenoidal surgery was analyzed in terms of SSTR2 and SSTR5 messenger ribonucleic acid (mRNA) expression. The remainder of the tumor tissue was used for cell culture experiments in which the GH- and PRL-suppressive effects of SRIF-14 and of different SRIF analogs that are selective for the SSTR2-, SSTR5-, and SSTR2- plus -5 subtypes were analyzed. The main objectives in the present work were to characterize the quantitative mRNA expression of GH tumors from octreotide poorly responders and to extend in this group the preliminary observations (7, 8) showing a better suppressive effect on GH suppression of somatostatin analogs preferential for both SSTR2 and SSTR5 subtypes.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study was undertaken after obtaining informed
consent from each patient. Ten acromegalic patients (seven women and
three men), aged 26–62 yr, presenting with macroadenoma were studied.
Their endocrine status and the neuroradiological characterization of
the pituitary adenomas were documented before treatment. Basal GH
levels were the mean of three random samples obtained between
0800–0900 h. The basal IGF-I value was evaluated under fasting
conditions between 0800–0900 h. Magnetic resonance imaging revealed
adenomas with a maximal 11- to 42-mm diameter. SRIF agonist sensitivity
was assessed by an acute test using a single 200-µg injection of
octreotide (Sandostatin, Novartis, Basel, Switzerland).
Sensitivity to somatostatin analogs was expressed as the percent
decrease in GH from the basal value to the mean GH values 2–6 h after
octreotide injection. According to the test results, five patients were
considered full octreotide responders (mean GH suppression, 79 ±
7%), whereas the other five cases were considered partial octreotide
responders (mean GH suppression, 33 ± 6%). All patients
underwent transsphenoidal surgery. The clinical endocrine and tumoral
status of each patient is summarized in Table 1
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GH and PRL were measured using commercial immunoradiometric kits (Immunotech, Marseilles, France). Normal GH values ranged from 0.2–2.4 µg/L; normal PRL values ranged from 1–24 µg/L in women and from 1–17 µg/L in men. After an ethanol-acid extraction, the plasma IGF-I assay was performed using the IGF-I RIA kit from Nichols Institute Diagnostics (San Juan Capistrano, CA). The normal ranges, according to sex and age, were established by our laboratory.
Detection of SSTRs
Total RNA was extracted from 30–60 mg tissue from each tumor using the SV total RNA isolation system (Promega Corp., Lyon, France). The RNA samples were subsequently treated with 30 U ribonuclease-free deoxyribonuclease I (Roche, Mannheim, Germany). Total RNA was reverse transcribed into complementary DNA using 1 µg hexamers (Pharmacia Biotech, Orsay, France) and Moloney murine leukemia virus reverse transcriptase, as described by the manufacturer.
The 5'-exonuclease (Taq Man) assay, which produces a direct proportional readout for the progression of PCR reactions, was used to quantify the SSTRs mRNA (10). The details of reaction conditions, the primers used, and the quantification calculation for SSTR2 and SSTR5 mRNA were described previously (8). The results were expressed as picograms of SSTR per pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Cell culture studies
A portion of each tumor obtained at surgery was dissociated by mechanical and enzymatic methods. Depending on the tumor, 4–90 x 106 isolated cells were obtained. Tumor cells were initially cultured in DMEM supplemented with 10% FCS for 3 days. On day 3, the cells were washed and plated in multiwell culture dishes (Costar 3524, Brumath, France) coated with extracellular matrix from bovine endothelial corneal cells as previously described (11) at a density of 2 x 104 cells/well. When they were attached to the matrix on days 5–8, depending on the culture, the medium was removed and replaced with DMEM supplemented with 2% FCS, antibiotics, transferrin, and selenium as previously described (11). The effects of various doses of SRIF-14; octreotide; a SSTR2-preferential compound, BIM-23197; a SSTR5-preferential compound BIM-23268; and the SSTR2- and SSTR5-selective compound, BIM-23244, on the inhibition of GH and PRL release were measured over an 8-h period between days 5–8 of culture. Each drug concentration was tested in quadruplicate.
Products
SRIF-14 was purchased from Sigma (Saint-Quentin
Fallavier, France). Octreotide was supplied by Novartis (Basel,
Switzerland). The BIM compounds were provided by Biomeasure, Inc.
(Milford, MA). The human SSTR affinities (IC50;
nanomoles per L) of each compound, determined by radioligand receptor
binding assays to membranes from transfected CHO-K1 cells expressing
the different human SSTR subtypes, are summarized in Table 2. The native SRIF and SRIF analogs were
dissolved in 0.01 mol/L acetic acid containing 0.1% purified serum
albumin (Life Technologies, Inc., Cergy-Pontoise, France).
The drugs were stored at -80 C as
10-3 mol/L solutions. For
each experiment, fresh working solutions were prepared from a new
aliquot.
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The results are presented as the mean ± SEM. Statistical significance between two unpaired groups was determined by the Mann-Whitney test. To measure the strength of association between the pairs of variables without specifying dependencies, Spearman order correlations were used. P < 0.05 was considered significant for all tests.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The degree of GH inhibition by SRIF-14 in vitro and the
levels of SSTR2 mRNA expression have been previously shown to be highly
correlated (8). In the present series the degree of GH
inhibition in patients, as evaluated by acute octreotide test, was also
highly correlated to the level of SSTR2 mRNA expression
(P < 0.009; Table 1
).
In five adenomas (A1–A5) highly sensitive to octreotide, the mean
SSTR2 expression was 222 ± 61 pg/pg GAPDH. When the same analysis
was made in four of five (A7–A10) adenomas from partial octreotide
responders, the mean SSTR2 mRNA expression was much lower (25 ±
12 pg/pg GAPDH). As shown in Fig. 1, the
five adenomas from octreotide-responsive patients expressed SSTR5 mRNA
at an equivalent level (SSTR2/SSTR5 mRNA ratio, 0.9 ± 0.3). In
contrast, adenomas from the four partial octreotide responders with low
SSTR2 mRNA expression expressed high levels of SSTR5 mRNA (2271 ±
1197 pg/pg GAPDH). Thus, these data establish two patterns of mRNA
expression in the GH-secreting tumors. The octreotide-sensitive
adenomas equally express both SSTR2 and SSTR5 mRNA, whereas in the
adenomas that were poorly responsive to octreotide, the loss of SSTR2
mRNA contrasted with a 30-fold higher expression of SSTR5
vs. SSTR2 mRNA.
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)In this series of experiments, the dose-response inhibition of GH release was examined with 10-13–10-8 mol/L concentrations of SRIF-14; the SSTR2-preferential compound, BIM-23197; and the SSTR5 preferential compound, BIM-23268. Among the 10 adenoma cell cultures, 2 patterns of responses to SSTR2- and SSTR5-preferential analogs were observed. In cultures from the 5 octreotide-sensitive tumors (A1–A5), the SSTR2-preferential compound, BIM-23197, produced a maximal 41 ± 7% mean GH suppression at a 0.1 nmol/L concentration, with an EC50 of 3 ± 2 pmol/L. A similar dose-response inhibition of GH release was obtained with SRIF-14. In contrast, the SSTR5-preferential compound, BIM-23268, produced a maximal inhibition of GH release only at 10 nmol/L (EC50 = 800 ± 350 pmol/L). This discrepancy between the results obtained with BIM-23197 and BIM-23268 can be explained on the basis of the binding affinities of BIM-23268, which is preferential for SSTR5, but at high concentrations behaves as a weak SSTR2 agonist. Thus, in the tumor cells from full octreotide responders, the GH-suppressive effect of somatostatin was mediated through only the SSTR2 subtype. In the second class of GH-secreting tumors that were partially responsive to octreotide (A6–A10), maximal GH suppression was equally achieved by SRIF-14 and the SSTR5-preferential agonist, BIM-23268. In these 5 adenoma cell cultures, BIM-23197 was slightly less potent than BIM-23268 (maximal GH suppression, 31 ± 5% and 38 ± 7%, respectively). The EC50 values achieved with BIM-23268 and BIM-23197 were 25 ± 13 and 47 ± 18 pmol/L, respectively. These data indicate that in tumor cells that are partially responsive to octreotide, the GH-suppressive effect of SRIF is mediated through both the SSTR5 and SSTR2 subtypes.
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In the five octreotide-sensitive tumors in which the
GH-suppressive effect of SRIF was mediated through the SSTR2 subtype,
the effects of the SSTR2- plus SSTR5-selective analog, BIM-23244, and
octreotide on GH secretion were examined using
10-3–10-8
mol/L of each compound. The dose-response inhibition curves of GH
release induced by BIM-23244 and octreotide were parallel
(EC50 = 3 ± 3 and 55 ± 15 pmol/L,
respectively). At nanomolar concentrations, the mean maximal GH
suppressions induced by BIM-23244 and octreotide were 44 ± 5%
and 36 ± 7%, respectively. These results show that when the
GH-suppressive effect is mediated through the SSTR2 subtype, native
SRIF and BIM-23244 are similarly efficacious in suppressing GH
secretion. As expected from the binding affinities for SSTR2 (Table 2),
BIM-23244 was slightly more potent than octreotide.
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Comparison between BIM-23244 and the combination of SSTR2- and
SSTR5-preferential agonists (Fig. 4)
In the five cell cultures from adenomas equally sensitive to the SSTR2- and SSTR5- preferential agonists (octreotide partial responders), the dose-response inhibition of GH release by BIM-23244 was compared with that induced by a combination of the SSTR2 preferential agonist, BIM-23197, and the SSTR5 preferential agonist, BIM-23268, at equimolar doses. Similar maximal levels of GH suppression (44 ± 5%) were achieved by BIM-23244 and the combination of BIM-23197 and BIM-23268. The dose-response inhibitions of GH release induced by the two treatments were parallel. As expected from their respective IC50 values for both the SSTR2 and SSTR5 subtypes, the combination of BIM-23197 and BIM-23268 was slightly more potent in suppressing GH secretion than the biselective agonist BIM-23244.
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In five tumor cell cultures (A1, A2, A7, A9, and A10), both PRL
and GH were secreted into the culture medium. A dose-response
inhibition of PRL secretion by SRIF-14 and by the different SRIF
analogs was observed in all tumors, with a significant maximal
inhibition of PRL release. As shown in Fig. 5A, the dose-related
inhibition of PRL release was similarly achieved with increasing
concentrations of SRIF-14 and the SSTR5-preferring compound, BIM-23268.
The SSTR2-preferring compound, BIM-23197, was partially effective in
suppressing PRL suppression (mean maximal PRL inhibition, 34 ±
5% vs. 52 ± 6%, respectively, for BIM-23197 and
BIM-23268). Compared with octreotide, the biselective analog,
BIM-23244, was more effective in suppressing PRL secretion (Fig. 5B).
The mean maximal PRL suppressions at 10 nmol/L BIM-23244 and octreotide
were 51 ± 5% and 34 ± 7%, respectively (P
= 0.045). These results in mixed GH-/PRL-secreting tumors indicate a
better PRL-suppressive effect of either the SSTR5-preferring compound
or the bispecific SSTR2 and SSTR5 compound compared with the agonists
preferential for SSTR2 alone.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From our data, two classes of tumors emerged among the GH-secreting adenomas. The first was a series of tumors characterized by high sensitivity to SRIF-14 and SSTR2-preferential agonists. These tumors presented the highest level of SSTR2 mRNA expression and had the highest GH-suppressive effect with octreotide. Why, despite equivalent SSTR5 mRNA expression, the SSTR5 preferential analog did not suppress GH release in such tumors remains unknown. In the second class of tumors, the level of SSTR2 mRNA was low, and octreotide produced only partial inhibition of GH release. SRIF-14 was nevertheless able to suppress GH release, with a maximal suppressive effect similar to that of the first class of tumors, but at a 10-fold higher concentration. The presence of high levels of SSTR5 mRNA was associated with a potent suppressive effect of BIM-23268 on GH release, more efficacious than that of the SSTR2 analogs. In these tumors, the bispecific SSTR2 and SSTR5 compound, BIM-23244, induced a suppression of GH release identical to that achieved by native SRIF. These data suggest that in tumors deficient in the SSTR2 subtype presenting with a high SSTR5/SSTR2 ratio there may be a rescue through the SSTR5 subtype that mediates the suppression of GH release.
Such changes in the intensity of GH suppression as a function of the specificity of the SRIF agonists are in keeping with recent experimental data demonstrating ligand- induced SSTR subtype dimerization in CHO-K1 transfected cells (26). This study showed that the ligands (SRIF or SRIF agonist) could produce a homo- or heterodimerization of the SSTR receptor subtypes. Such a ligand-induced dimerization process resulted in increased binding affinity and modified SSTR functionality. Furthermore the ability of the ligands to homodimerize SSTR5 was highly dependent on the quantity of SSTR5 transfected into CHO-K1 cells. In our GH-secreting tumors presenting with high expression of SSTR2 mRNA, it could be that octreotide as well as ligands with high affinity to SSTR2 are inducing preferential SSTR2 homodimerization, mediating profound GH suppression in the picomolar range of these agonists. In the octreotide partially sensitive tumors, such a SSTR2 homodimerization could not be fully effective due to poor SSTR2 expression. In these cases, SSTR5 expressed at high levels could transduce GH inhibition by SRIF agonists with high affinity to SSTR5. Whether the SSTR5 preferential compounds act through homodimerization of SSTR5 subtypes or through SSTR5-SSTR2 receptor subtype heterodimerization remains speculative. Therefore, in octreotide partial responders in which the SSTR2 receptor is poorly efficient, the SSTR5-mediated pathway could compensate and transduce the inhibition of GH release in the presence of SSTR5 preferential compounds. The better efficacy of bipreferential SSTR2 and SSTR5, such as BIM-23244 and SRIF-14, compared with that of octreotide could support the hypothesis of a more efficient induced GH inhibition through SSTR5-SSTR2 heterodimerization.
In conclusion, the bispecific SRIF agonist, BIM-23244, targeting SSTR2 and SSTR5, was demonstrated to induce a greater GH- and PRL-suppressive effect in tumors considered partial octreotide responders. Such data, although significant in our cell culture studies, have to be extended by in vivo studies. Indeed, such an SSTR2- and SSTR5-bispecific agonist may also act upon other target cells bearing the SSTR5 subtype. Recent data (27) showed a preferential localization of SSTR1 and SSTR5 on pancreatic ß-cells as well as a preferential inhibition of insulin release by the SSTR5 preferential compound, BIM-23268 (28, 29). It is thus mandatory, particularly in acromegalic patients, to assess in vivo the inhibition of insulin secretion that can be produced by administration of a SSTR2- and SSTR5-bispecific agonist.
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Acknowledgments |
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Footnotes |
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Received July 18, 2000.
Revised September 13, 2000.
Accepted September 14, 2000.
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P. U. Freda Somatostatin Analogs in Acromegaly J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3013 - 3018. [Full Text] [PDF]
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D. C. Danila, J. N. S. Haidar, X. Zhang, L. Katznelson, M. D. Culler, and A. Klibanski Somatostatin Receptor-Specific Analogs: Effects on Cell Proliferation and Growth Hormone Secretion in Human Somatotroph Tumors J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2976 - 2981. [Abstract] [Full Text] [PDF]
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