| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Departments of Internal Medicine III and Pathology (MJMK), Erasmus University, Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: L. J. Hofland, Department of Internal Medicine III, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: hofland{at}inw3.fgg.eur.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Four NFA cultures did not secrete detectable amounts of 
-subunit,
FSH, and/or LH. In the other cultures, hormone and/or subunit release
was inhibited by DA-agonists (10 nM) in 9 of 11, by SS (10
nM) in 7 of 11, and by octapeptide SS-analogs (10
nM) in 3 of 10 cultures. In three NFA cultures, hormone
release was sensitive to SS but not to SS-analogs. In all cultures,
except for one, DA-agonists were the most effective in inhibiting
hormone release. In the prolactinoma cultures, PRL release was
inhibited by DA-agonists (10 nM) in 7 of 7, by SS in 4 of
4, and by octapeptide SS-analogs in 3 of 7 cultures. A dissociation
between the effects of SS and SS-analogs was found in 3 cases. In the
cultures sensitive to both bromocriptine and SS-28, bromocriptine was
the most potent compound in 2 out of 4 cultures. In the 2 other
cultures, both compounds were equally effective. In 2 insulinoma
cultures, insulin release was inhibited by SS, and by octapeptide
SS-analogs in only one. The presence or absence of an inhibitory effect
by octreotide was in all cases in parallel with the presence or absence
of the inhibitory effect by BIM-23014 and RC-160.
Autoradiographic studies using [125I-Tyr0]SS28 showed specific binding in 4 of 5 NFAs, 1 of 2 prolactinomas, and 1 of 1 insulinoma. Specific [125I-Tyr3]octreotide binding was found in 2 of 5 NFAs, in 1 of 2 prolactinomas, and in the insulinoma. Two NFAs showed binding of SS28, but not of the sst2,5 specific ligand octreotide. The tumors showed variable sst1 and/or sst3 mRNA expression, whereas no sst2 expression was found.
In conclusion, a dissociation between the inhibitory effects of SS on the one hand and of the octapeptide SS-analogs octreotide, BIM-23014 and RC-160 on the other hand, is observed in a small subgroup of NFAs, prolactinomas, and insulinomas, suggesting that novel sst subtype specific SS-analogs might be of benefit in the treatment of selected patients with somatostatin receptor positive secreting tumors not responding to octapeptide SS-analogs. However, in the majority of NFAs and prolactinomas, DA-agonists were equally or more effective than SS in the suppression of tumoral secretion products.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
From several studies using different techniques, it has become clear now that the majority of the human sst positive tumors express multiple sst subtypes. While the majority of the neuroendocrine tumors carry sst with a high affinity for native SS as well as for the octapeptide SS-analog octreotide, small subgroups of tumors have been described with high affinity binding sites for SS but not for octreotide (6). Among these tumors are certain insulinomas, carcinoids, medullary thyroid carcinomas, ovarian tumors, and pituitary adenomas. Absence of the sst2 subtype has been associated with an absent hormonal response to treatment with octreotide, suggesting that sst2 is involved in the antihormonal actions of SS-analogs like octreotide (7, 8), whereas sst2 seems to be involved in the inhibition of GH secretion in rats (9). So far, however, the functional role of the other sst subtypes, is unclear.
In a previous study, we have compared the effects of the three SS-analogs (octreotide, BIM-23014, and RC-160) on hormone release by pituitary GH-adenomas and a gastrinoma in vitro (10). In this study, we found that GH-adenomas with an absent hormonal response to octreotide were unresponsive to BIM-23014 and RC-160 as well. Still, two major questions remain. First, are there differences between the inhibitory effects of the above mentioned three clinically applicable SS-analogs in other types of secreting tumors? Second, is there evidence for a functional role of sst subtypes other than those with a high affinity for octapeptide SS-analogs?
In order to further investigate these questions, we have compared in the present study the effects octreotide, BIM-23014, and RC-160 with that of native SS on hormone release by the cultured cells prepared from 15 NFAs, 7 prolactinomas, and 2 insulinomas. In the pituitary adenoma cultures, a comparison with the effects of dopamine agonists was also made. Whereas several authors have described the effects of either SS or octreotide on NFAs (11, 12), a direct comparison between SS and SS-analogs on hormone release by NFAs has not been made yet.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Pituitary tumor samples were obtained by transsphenoidal operation from 18 patients with NFAs and from 7 patients with prolactinomas, as described previously (13). Tumor samples of 2 insulinomas were obtained within 30 min after surgical removal of the tumors. Diagnosis was made on the basis of clinical and biochemical characteristics of the patients, in combination with (immuno)histochemistry of the tumor samples. All patients gave their informed consent for the use of tumor material for research purposes. When sufficient adenoma tissue was obtained, pieces were frozen on dry ice and stored at -80 C.
Cell dispersion and cell culture.
Fifteen out of 18 NFAs and 7 prolactinomas were used for the cell culture studies. Single cell suspensions of the pituitary adenoma tissues were prepared by enzymatic dissociation with dispase as described in detail previously (13). Tumor tissue from the insulinoma patients was dissociated as described (14).
Short-term incubation of monolayer cultures. the dissociated cells were plated in 48-well plates (Costar, Cambridge, MA) at a density of 105 (prolactinomas and insulinomas) or 2 x 105 (NFAs) cells per well per 1 ml culture medium. After 3–4 days, the medium was changed, and 72-h incubations without or with SS, SS-analogs, or DA-agonists were started. 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.
Long-term incubation studies in Transwells (15). The isolated tumor cells were plated in Transwell-COL membranes (Costar, Badhoevedorp, The Netherlands) at a density of 105 (prolactinomas and insulinomas) or 2 x 105 (NFAs) cells per well. The transwells were then placed into multiwell plates (24-well, Costar) containing 1 ml culture medium. After 24 h, the transwells were transferred to wells containing fresh medium (without or with test substances). Every 3–4 days, the cells were placed into fresh medium and the incubation media were collected and stored at -20 C until determination of hormone concentrations.
In all experiments SS (SS-14 and/or SS-28), octapeptide SS-analogs (octreotide, BIM-23014, RC-160) and DA-agonists (bromocriptine and/or quinagolide) were used at a concentration of 10 nM. The cells were cultured at 37 C in a CO2-incubator. The culture medium consisted of MEM D-valine with Earle’s salts supplemented with nonessential amino acids, sodium pyruvate (1 mmol/L), 10% FCS, penicillin (1 x 105 U/L), fungizone (0.5 mg/L), L-glutamine (2 mmol/L), and sodium bicarbonate (2.2 g/L). Unfortunately, generally not enough tumor material was obtained to test each tumor on its responsiveness to all of the above indicated drugs.
Hormone determinations
Human PRL, LH, and FSH concentrations in the media were
determined by immunoradiometric assays (MedGenix Diagnostics, Fleurus,
Belgium) as described previously (13, 15). Glycoprotein -subunit
concentrations were determined by an immunoradiometric assay from
Immunotech S. A. (Marseille, France). Insulin concentrations were
determined by a double antibody RIA as described (14). Dilution of PRL,
LH, FSH, -subunit and insulin in the media was in parallel to the
respective standards supplied with the kits.
Test substances
Somatostatin-14 (SS-14) was obtained from Sigma (St. Louis, MO). BIM-23014 (lanreotide) and somatostatin-28 (SS-28) were obtained from Bachem (Hannover, Germany). RC-160 (vapreotide) was obtained from Peninsula (Belmont, CA). Octreotide, bromocriptine and quinagolide (CV205–502) were obtained from Sandoz Pharma (Basle, Switzerland).
Receptor autoradiography
Receptor autoradiography was carried out as described by Reubi et al., (16). Ten-micrometer sections were mounted onto precleaned gelatin coated microscope slides, and stored at -80 C. Adjacent sections were used for in situ hybridization and processed further as described below. To wash out endogenous somatostatin, the sections were preincubated at room temperature for 10 minutes in 170 mM Tris-HCl, pH 7.4. Thereafter, the sections were incubated for 60 minutes at room temperature in 170 mM Tris-HCl, pH 7.4, 5 mM MgCl2, 1% BSA, 40 µg/ml bacitracin in the presence of [125I-Tyr3]-octreotide (about 80–160 pmol/L) or [125I-Tyr0]SS28 (final concentration 80–160 pmol/L; ANAWA Laboratories, Wangen, Switzerland). Nonspecific binding was determined in a sequential section in the presence of excess unlabeled Tyr3-octreotide (1 µM) or SS-28 (1 µM). The incubated sections were washed twice for 5 min in incubation buffer containing 0.25% BSA and once in incubation buffer without BSA. After a short wash with distilled water to remove salt, the sections were air dried and exposed to Kodak X-OMAT AR or Hyperfilm-3H (Amersham) for 3–7 days in x-ray cassettes. Histology was performed on hematoxylin-azophloxine stained sequential cryosections.
In situ hybridization histochemistry of sst1, sst2, and sst3 mRNA
The protocol and oligonucleotides used for in situ
hybridization were the same as described by Reubi et al.
(17). Forty-eight base pair oligonucleotides complementary to the bases
coding for amino acids 2–17 of the hsst1 mRNA sequence,
237–252 of the hsst2 sequence, and 366–381 of the
hsst3 sequence (17) were synthesized and purified over a
Pharmacia NAP-10 column by Pharmacia Biotech (Roosendaal, The
Netherlands). 3'-end labeling by using [-32P]dATP
(3000 Ci/mmol; Du Pont NEN , Boston, MA) was performed as
described previously (18). Specificity of hybridization signal obtained
with the above oligonucleotide probes was established previously (17).
In our study, sequential cryostat sections of the tumors (see above)
were incubated in duplicate with 32P-labeled
oligonucleotide probes without or with a 20-fold excess of unlabeled
oligonucleotide to demonstrate specificity of the hybridization signal
obtained. A tumor was considered positive for the respective mRNA when
the hybridization signal obtained in a control section was displaced by
a 20-fold excess of unlabeled oligonucleotide by more than 50%. The
hybridization signals obtained were analyzed densitometrically.
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 comparison between treatment groups was made using the Newman-Keuls test.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Table 1
shows basal release of
-subunit, FSH, and LH by cultured cells of NFAs 1–6. Five out of 6
NFA cultures secreted detectable amounts of -subunit in
vitro, 5 out of 6 secreted FSH, whereas only 2 of 6 (no. 1 and 2)
secreted LH. Hormone release was not inhibited by SS-28 (10
nM), octreotide (10 nM), RC-160 (10
nM), or BIM-23014 (10 nM) in a 72-h exposure of
the cells in 3 out of 6 cultures (nos. 2, 4, and 5, data not shown). In
culture no. 5, however, the DA-agonist quinagolide (10 nM)
significantly inhibited -subunit and FSH release by 48 and 30%,
respectively (P < 0.01 vs. control cells,
data not shown). The effect of SS-28, SS-analogs, and quinagolide (all
used at a concentration of 10 nM) on -subunit or FSH
release by NFA cultures 1, 3, and 6 is shown in Fig. 1. Quinagolide
significantly inhibited -subunit or FSH release during a 72-h
exposure in all cultures (P < 0.01 vs.
control cells), whereas in cultures no. 1 and 3 both SS-28 and
octreotide significantly inhibited hormone release (P
< 0.01 vs. control cells). In culture no. 3, SS-28,
octreotide, RC-160, and BIM-23014 were equally effective. However, in
culture no. 6, which was sensitive to the inhibitory effect of SS-28,
none of the three octapeptide SS-analogs were effective in inhibiting
FSH release. In NFA culture no. 1, the response of FSH and LH release
was comparable with that of -subunit release, whereas in culture no.
3, -subunit release was not inhibited (data not shown).
|
|
-subunit
(data not shown). Figure 2 shows the
effects of the abovementioned drugs on -subunit release by cultured
cells from NFA no. 7 and no. 10. In the cells of patient 7, -subunit
release was progressively inhibited to the same extent by SS-28 and the
three SS-analogs. The degree of inhibition after 2 weeks of exposure
in vitro was comparable to that of bromocriptine. In NFA
culture, no. 10 bromocriptine and SS-28 also increasingly inhibited
-subunit release, although bromocriptine was most effective. After
drug withdrawal on day 14, these inhibitory effects recovered,
suggesting that the increasing inhibitory actions of bromocriptine,
SS-28 and SS-analogs, represented inhibition of hormone release and or
production and not inhibition of cell proliferation. Table 2 shows the effects of bromocriptine,
SS-28, and SS-analogs on -subunit-, FSH and/or LH release by NFAs
no. 7–11, at day 14 of incubation. In all NFA cultures (7, 8, 9, 10, 11)
bromocriptine (10 nM) significantly inhibited hormone
release. SS-28 significantly inhibited hormone release in cultures 7,
9, 10, and 11. Octreotide, BIM-23014, and RC-160 significantly
inhibited hormone release in culture no. 7.
|
|
Prolactinomas
Quinagolide (10 nM) significantly inhibited PRL release during a 72-h incubation in three prolactinoma cultures (nos. 1, 2, and 3) by 25, 33, and 50% respectively (data not shown). In these three cultures, octreotide (10 nM) did not significantly inhibit PRL release. At the same time, 10 nM RC-160 (in culture nos. 2 and 3) or 10 nM BIM-23014 (in culture no. 3) were also ineffective (data not shown).
In 4 prolactinoma cultures (nos. 4–7), the effects of SS-28,
octreotide, RC-160, BIM-23014, and bromocriptine (all at a
concentration of 10 nM) were studied during prolonged
incubation of the cells in Transwells. Figure 3 shows that PRL release by the cells of
adenoma no. 4 was slightly sensitive to octreotide (statistically
significant inhibition of PRL release at days 3, 10, and 14) but
responded very well to SS-28 and bromocriptine (90 and 84% inhibition,
respectively, day 14 of culture). In addition, we found that PRL
release by the cells of patient 5 was also increasingly inhibited by
bromocriptine and SS-28 (by 40 and 40%, respectively, day 14 of
culture; P < 0.01 vs. control cells), in
contrast to the slight (approximately 17%, day 14 of culture), but
significant inhibition by the three SS analogs. Comparable to the NFA
cultures, drug withdrawal on day 14 in culture no. 5, led to a recovery
of PRL release. It is also important to note that the maximal
inhibition of PRL release by both SS-28 and bromocriptine was
considerably less in the culture of adenoma no. 5 in comparison with
culture no. 4. Patient no. 5 had become insensitive to DA-agonist
therapy, whereas patient no. 4 was operated because of intolerance to
DA-agonist therapy. Table 3 shows the
effects of the above compounds on PRL release by culture nos. 6 and 7,
at day 14 of incubation. PRL release by adenoma cells from patients no.
6 and 7 (operated because of intolerance to DA-agonist therapy) was
significantly inhibited by bromocriptine, and slightly by SS-28.
Octreotide significantly inhibited PRL release in culture no. 6 only.
The cells of patient 7 were unresponsive to octreotide, BIM-23014, and
RC-160.
|
|
Insulinomas
Table 4 shows the effect of SS-14,
SS-28, and octreotide and RC-160 (72 h incubation) on insulin release
by cultured cells of insulinoma no. 1. Both SS-14 (10 nM)
and SS-28 (10 nM) significantly inhibited insulin release
by 29 and 32%, respectively (P < 0.01 vs.
control). Octreotide (10 nM) and RC-160 (10 nM)
were ineffective, however.
|
shows that SS-14, SS-28, and the
SS-analogs octreotide, BIM-23014, and RC-160 progressively inhibited
insulin release to the same extent.
|
Table 5 shows the results of the
autoradiographic and in situ hybridization experiments. It
should be mentioned that not sufficient material was obtained from each
adenoma to perform both the receptor and cell culture studies.
|
). One NFA (no. 11), which
showed binding of both radioligands, did not express sst1,
sst2, or sst3 mRNA. Two other adenomas (NFA no.
17 and prolactinoma no. 6) showed sst3 expression, whereas
no ligand binding was detected, possibly due to low levels of
expression of the receptor protein. Furthermore, the expression of
sst1 and sst3 was variable. Insulinoma no. 2,
which had a high density of receptors, expressed sst1 and
sst3 mRNA only (Fig. 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We found that, in a small subgroup of NFA cultures (3/10), prolactinomas (3/4), and insulinomas (1/2), hormone release in vitro was insensitive or showed a very low sensitivity to the inhibitory effects of the octapeptide SS-analogs octreotide, RC-160 and BIM-23014, while at the same time hormone release was inhibited by SS-14 and/or SS-28. In line with the observation that the three octapeptide SS-analogs show a comparable binding profile to the five sst subtypes, we found no differences between the maximal inhibitory effects of octreotide, BIM-23014, and RC-160. Comparable results were found in GH-secreting adenomas in a previous study (10). In this study, we also found that those adenoma cell cultures that did not respond to octreotide did not respond to BIM-23014 and RC-160 as well (10).
Octreotide, RC-160, and BIM-23014 bind with a high and relative high
affinity to sst2 and sst5, respectively, with
low affinity to sst3, and display no binding to
sst1 and sst4 (1, 2, 3, 4). This suggests that the
tumors mentioned above lack the expression of sst2,
sst5, and possibly also sst3. In a few selected
cases, sufficient tissue was obtained to perform both cell culture
studies and ligand binding and in situ hybridization
studies. In one NFA, which showed a high density of
[125I-Tyr0]SS28 binding sites, and
sst1 mRNA expression only, hormone release was only
slightly sensitive to SS-28 and not to octreotide, suggesting that
activation of sst1 is not important in mediating an
antihormonal effect. However, ßLH and ßFSH secretion was not
measured in our study. Previously, Klibansky et al. (12)
showed that SS significantly inhibited ßLH and ßFSH secretion
in vitro in 53% of patients with NFAs, whereas -subunit
secretion was inhibited in only 17% of these tumors. Further studies
are needed to elucidate this point. Two prolactinomas that showed a low
sensitivity to SS-28 in vitro expressed sst1 and
sst3 mRNA, respectively. Prolactinoma no. 6, which
responded to both octreotide and SS-28, did not express
sst2, suggesting that sst subtypes other than
sst2 are involved in the regulation of hormone secretion in
this particular case. On the other hand, the low density of SS binding
sites may also account for their low sensitivity to SS in
vitro. The insulinoma, which was highly sensitive to the
inhibitory effects of SS-28, SS-14, as well as to the three octapeptide
SS-analogs octreotide, BIM-23014 and RC-160, did not express
sst2 mRNA, suggesting that other sst subtypes
(i.e. sst5) are also important in mediating the
inhibition of insulin release in this case. The involvement of
sst3, which is also expressed in this case, cannot be fully
excluded, however. Moreover, disregulation of receptor/signaling
systems, like density of receptors, desensitization, signaling, or gene
regulation, can be involved in determining the response of hormone
secretion to SS and SS analogs as well.
In conclusion, sst subtypes other than sst2 and sst5 may mediate an antihormonal effect because, in particular tumors that were not responsive to the three octapeptide SS-analogs, native SS was effective. Therefore, it seems reasonable to develop sst1, sst3, and/or sst4- subtype selective SS-analogs for the treatment of this small subgroup of patients.
Our observations seem well in agreement with the results of studies by Greenman and Melmed (7, 19). These investigators demonstrated by RNAse protection and RT-PCR assays the absence of sst2 mRNA in prolactinomas, whereas the majority of the tumors expressed sst1 (4 out of 5), sst3 (3 out of 3), and sst5 (3 out of 3) mRNA. It is also known for some time that the vast majority of the patients with prolactinomas do not respond to treatment with octreotide (22, 23). However, data concerning sst subtype mRNA expression in pituitary adenomas are conflicting. Other groups demonstrated sst2 mRNA expression by RT-PCR analysis in prolactinomas in 100, 67, and 100% of the cases, respectively (20, 21, 24). The high sensitivity of the RT-PCR technique may be an explanation for this observation but also for the discrepancy between clinical studies using octreotide in prolactinoma patients on the one hand and the high incidence of sst2 mRNA positive prolactinomas when evaluated by RT-PCR.
In conclusion, our study demonstrates that, in a subgroup of NFAs, prolactinomas, and insulinomas, hormone release is inhibited by native SS, but not by the octapeptide SS-analogs octreotide, RC-160, or BIM-23014. This suggests that, in selected neuroendocrine tumors, sst-subtypes other than sst2 may be involved in the inhibition of hormone release and that novel sst-subtype specific SS-analogs might be of value in the treatment of selected patients harboring tumors with ssts with low affinity for octapeptide SS-analogs.
|
Acknowledgments |
|---|
Received February 28, 1997.
Revised June 3, 1997.
Accepted June 9, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-subunit and prolactin release
by cultured pituitary adenoma cells from acromegalic patients:
correlation with GH release. Clin Endocrinol. 30:601–611.[Medline]
-subunit release
from pituitary adenomas during long-term culture. J Clin
Endocrinol Metab. 71:718–724.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  T. Florio, F. Barbieri, R. Spaziante, G. Zona, L. J Hofland, P. M van Koetsveld, R. A Feelders, G. K Stalla, M. Theodoropoulou, M. D Culler, et al. Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study Endocr. Relat. Cancer, June 1, 2008; 15(2): 583 - 596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fusco, G. Gunz, P. Jaquet, H. Dufour, A. L. Germanetti, M. D Culler, A. Barlier, and A. Saveanu Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas Eur. J. Endocrinol., May 1, 2008; 158(5): 595 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Gillam, M. E. Molitch, G. Lombardi, and A. Colao Advances in the Treatment of Prolactinomas Endocr. Rev., August 1, 2006; 27(5): 485 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 S.-G. Ren, J. Taylor, J. Dong, R. Yu, M. D. Culler, and S. Melmed Functional Association of Somatostatin Receptor Subtypes 2 and 5 in Inhibiting Human Growth Hormone Secretion J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4239 - 4245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ferone, R. Pivonello, P. M. Van Hagen, M. Waaijers, J. Zuijderwijk, A. Colao, G. Lombardi, A. J. J. C. Bogers, S. W. J. Lamberts, and L. J. Hofland Age-related decrease of somatostatin receptor number in the normal human thymus Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E791 - E798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Van den Bruel, J. Fevery, J. Van Dorpe, L. Hofland, and R. Bouillon Hormonal and Volumetric Long Term Control of a Growth Hormone-Releasing Hormone-Producing Carcinoid Tumor J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3162 - 3169. [Full Text]
|
|
|
|
|
|
L.J. Hofland, Q. Liu, P.M. van Koetsveld, J. Zuijderwijk, F. van der Ham, R.R. de Krijger, A. Schonbrunn, and S.W.J. Lamberts Immunohistochemical Detection of Somatostatin Receptor Subtypes sst1 and sst2A in Human Somatostatin Receptor Positive Tumors J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 775 - 780. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) bromocriptine, (
) SS-28, (•) octreotide,
(
) BIM-23014, (
) RC-160. The arrow at day 14 of
culture indicates the time-point of drug withdrawal.
) SS-14,
(•) octreotide, (
) RC-160.