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J C Reubi

Publications and source records attributed to J C Reubi.

At least 55 records · Page 3Linked to original sources
PubMed1999

High gastrin and cholecystokinin (CCK) gene expression in human neuronal, renal, and myogenic stem cell tumors: comparison with CCK-A and CCK-B receptor contents.

Gastrin and cholecystokinin (CCK) are two major regulatory peptides synthesized by human gut and brain tissues as well as by selected tumors, in particular gastrin-producing neuroendocrine tumors. In the present study we have evaluated gastrin and CCK gene expression in a group of primary human tumors, including neuronal, renal, and myogenic stem cell tumors, using in situ hybridization techniques. In addition, CCK-A and CCK-B receptors were evaluated in the same group of tumors with receptor autoradiography. Most tumors had gastrin messenger ribonucleic acid (mRNA): 10 of 11 medulloblastomas, 5 of 5 central primitive neuroectodermal tumors, 11 of 11 Ewing sarcomas, 8 of 10 neuroblastomas, 4 of 4 Wilms' tumors, 5 of 5 rhabdomyosarcomas, and 10 of 10 leiomyosarcomas. CCK mRNA was restricted predominantly to Ewing sarcomas (9 of 11) and leiomyosarcomas (5 of 10). CCK-A and CCK-B receptors were not frequently found in these tumors, except for leiomyosarcomas. These data suggest that gastrin and CCK may play a previously unrecognized role in this group of human stem cell tumors. If the increased gastrin mRNA indeed translates into increased gastrin production, measurement of gastrinemia may have a diagnostic significance in the early detection of these tumors. As these two hormones have been reported to act as potent growth factors, they may be of pathophysiological relevance for patients with such stem cell tumors.

Blotting, Northern↗
PubMed1999

Immunohistochemical detection of somatostatin sst2a receptors in the lymphatic, smooth muscular, and peripheral nervous systems of the human gastrointestinal tract: facts and artifacts.

The cellular distribution of the somatostatin sst2A receptor protein was investigated in the lymphatic, smooth muscular, and nervous components of the human gastrointestinal tract using subtype-specific antibody R2-88 for immunohistochemical staining of cryostat and formalin-fixed, paraffin-embedded tissue sections. Germinal centers of intestinal lymphatic follicles were immunostained, exhibiting a predominantly plasma membrane localization of the receptor. Similarly, nerve fibers and cells in the submucosal and myenteric plexus were stained for sst2A. Antibody preabsorption with 100 nmol/L antigen peptide abolished staining in all of these tissues, and immunohistochemical staining correlated with the labeling observed after receptor autoradiography using the sst2-preferring radioligand 125I-[Tyr3]octreotide. Cytoplasmic immunostaining was detected in gastrointestinal smooth muscle cells and was inhibited by antibody pre-absorption with antigen peptide. However, 125I-[Tyr3]octreotide autoradiography was negative, and Western blots showed no band at the usual 70-90 kDa location for sst2A. Instead, a band was observed at 205 kDa. This band comigrated with the rabbit myosin standard, which was also stained with R2-88, although antibody sensitivity for myosin was less than 0.002% of that for the sst2A receptor. Rigorous computer-based sequence analysis demonstrated the peptide sequence chosen for antibody production was unique. Moreover, standard sequence alignment protocols were unable to identify the sequences in myosin responsible for the observed reactivity with the R2-88 antiserum. The observed cross-reactivity emphasizes the need for extensive controls to prove the specificity of immunostaining for such low abundance proteins as receptors even when the peptide sequence chosen for antibody production is unique. This study demonstrates for the first time the presence of specific sst2A receptor protein by immunohistochemistry in the human gastrointestinal lymphatic and nervous components, but not in gastrointestinal circular and longitudinal smooth muscle.

Animals↗
PubMed1999

Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas.

Human gliomas, especially of low-grade type, have been shown to express high-affinity somatostatin receptor type 2 (J-C. Reubi et al., Am. J. Pathol, 134: 337-344, 1989). We enrolled seven low-grade and four anaplastic glioma patients in a pilot study using the diffusible peptidic vector 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC) for receptor targeting. The radiopharmakon was locoregionally injected into a stereotactically inserted Port-a-cath. DOTATOC competes specifically with somatostatin binding to somatostatin receptor type 2 in the low nanomolar range as shown by a displacement curve of 125I-[Tyr3]-octreotide in tumor tissue sections. Diagnostic (111)In-labeled DOTATOC-scintigraphy following local injection displayed homogeneous to nodular intratumoral vector distribution. The cumulative activity of regionally injected peptide-bound 90Y amounted to 370-3300 MBq, which is equivalent to an effective dose range between 60 +/- 15 and 550 +/- 110 Gy. Activity was injected in one to four fractions according to tumor volumes; 1110 MBq of 90Y-labeled DOTATOC was the maximum activity per single injection. We obtained six disease stabilizations and shrinking of a cystic low-grade astrocytoma component. The only toxicity observed was secondary perifocal edema. The activity:dose ratio (MBq:Gy) represents a measure for the stability of peptide retention in receptor-positive tissue and might predict the clinical course. We conclude that SR-positive human gliomas, especially of low-grade type, can be successfully targeted by intratumoral injection of the metabolically stable small regulatory peptide DOTATOC.

Adult↗
PubMed1999

Preclinical and initial clinical evaluation of 111In-labeled nonsulfated CCK8 analog: a peptide for CCK-B receptor-targeted scintigraphy and radionuclide therapy.

UNLABELLED: The presence of cholecystokinin (CCK)-B (gastrin) receptors has been shown in more than 90% of medullary thyroid cancers (MTCs) and in a high percentage of small cell lung cancers, stromal ovarium cancers and several other tumor types. METHODS: The aim of this study was to evaluate in vitro and in vivo whether 111In-labeled CCK-B receptor-specific CCK8 analog [D-Asp26,Nle28,31]CCK26-33 (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2) is suitable for CCK-B receptor scintigraphy based on the finding that unlabeled nonsulfated diethylenetriamine pentaacidic acid [DTPA0]CCK8 and tetraazacyclododecanetetraacetic acid [DOTA0]CCK8 analogs show high and specific binding for CCK-B receptors in human tumors. Fifty percent inhibitory concentrations were in the low nanomolar range. RESULTS: In vitro, [111In-DOTA0]CCK8 showed specific internalization in CCK-B receptor-positive rat pancreatic tumor cells AR42J. Internalization of the analog appeared to be time and temperature dependent and receptor specific. From the data obtained with [111In-DOTA0]CCK8 and (125I)I-gastrin, the latter being a specific ligand for the CCK-B receptor, the rat pancreatic cell line CA20948 also appeared to be CCK-B receptor positive. This provides an in vitro and in vivo rat tumor model because this cell line can be grown to solid tumors in Lewis rats. In vivo biodistribution experiments in CA20948 tumor-bearing Lewis rats showed rapid clearance of [111In-DOTA0]CCK8, and specific uptake was found in the CCK-B receptor-expressing stomach and tumor. Furthermore, comparing [111In-DOTA0]CCK8 with the radioiodinated nonsulfated CCK10 analog (D-Tyr-Gly-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2), both ligands having high affinity for the CCK-B receptor, tumor-to-blood ratios were significantly higher for [111In-DOTA0]CCK8 than for 125I-CCK10, analogous to the findings with radioiodinated and 111In-labeled octreotide. The study in humans with [111In-DTPA0]CCK8 showed receptor-specific uptake in the CCK-B receptor-positive stomach and in metastases in the neck region up to 48 h after injection. CONCLUSION: [111In-DOTA0]CCK8 is most promising for scintigraphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of human CCK-B receptor-positive tumors such as MTC and small cell lung cancer.

Animals↗
PubMed1998

Localization of receptors for vasoactive intestinal peptide, somatostatin, and substance P in distinct compartments of human lymphoid organs.

Regulatory peptides, such as vasoactive intestinal peptide (VIP), somatostatin (SS), or substance P (SP), are considered to play a role in immune regulation. To localize the targets of these peptides in the human immune system, their receptors have been evaluated with in vitro receptor autoradiography in lymph nodes, tonsils, appendix, Peyer's patches, spleen, and thymus. The three peptide receptors were detected in all lymphoid tissues tested, but, unexpectedly, usually in distinct compartments. In lymph nodes, palatine tonsils, vermiform appendix, and Peyer's patches, VIP receptors were found in the CD3 positive zone around lymphoid follicles; SS receptors in the germinal centers of secondary follicles; and SP receptors mainly in interfollicular blood vessels. In the spleen, VIP receptors were detected in periarterial lymphatic sheaths, SS receptors in the red pulp, and SP receptors in the central arteries. In the thymus, VIP receptors were present in cortex and medulla, SS receptors in the medulla, and SP receptors in blood vessels. For comparison, cholecystokinin (CCK)-A and -B receptors were not demonstrated in any of these tissues. These results suggest a strong compartmentalization of the three peptide receptors in human lymphoid tissues and represent the molecular basis for the understanding of a very complex and interactive mode of action of these peptides.

Autoradiography↗
PubMed1998

A selective analog for the somatostatin sst1-receptor subtype expressed by human tumors.

Somatostatin mediates its actions through five different somatostatin receptor subtypes, sst1-sst5. Recently, the somatostatin analogs des-AA1,2,5-[D-Trp8, IAmp9]somatostatin and des-AA1,5-[Tyr2, D-Trp8, IAmp9]somatostatin were synthesized and shown to be sst1-selective when tested in COS-7 cells transfected with each of the sst subtypes. In the present study, we tested the binding affinity and specificity of the iodinatable analog in primary human tumors expressing various sst subtypes, selected on the basis of in situ hybridization experiments. Des-AA1,5-[Tyr2, D-Trp8, IAmp9]somatostatin was found to have a high affinity, comparable to that of the natural somatostatin-28, for sst1-expressing tumors such as prostate cancers. However, it had no affinity for tumors expressing the sst2, sst3, or sst5 subtypes. For comparison, the somatostatin analogs octreotide or Tyr3-octreotide have no affinity for sst1-expressing tumors, but high affinity for sst2- and sst5-expressing tumors and intermediate affinity for sst3-expressing tumors. These data represent the first characterization of a sst1-selective analog in human tumors; it may be of potential use in the therapy of sst1-expressing tumors as an antiproliferative agent, as well as providing a lead compound for the development of more potent sst1-selective radioligands for in vivo tumor scintigraphy.

Autoradiography↗
PubMed1998

Unsulfated DTPA- and DOTA-CCK analogs as specific high-affinity ligands for CCK-B receptor-expressing human and rat tissues in vitro and in vivo.

Receptors for regulatory peptides such as somatostatin or vasoactive intestinal polypeptide are expressed by a number of human neoplasms and can be visualized in vivo with peptide receptor scintigraphy. Recently, the CCK-B receptor, which binds both gastrin and cholecystokinin with high affinity, was shown using in vitro methods to be overexpressed in a number of human tumor tissues, including medullary thyroid carcinomas, small cell lung cancers, astrocytomas, gastrointestinal tumors, and stromal ovarian cancers. In the present study, we have designed novel, unsulfated CCK octapeptide analogs linked to the metal chelating DTPA and DOTA, and have tested them for their binding affinity to CCK-B receptor-positive tissue from human tumors: The most potent compounds assayed were DTPA-[Nle28, 31]-CCK(26-33) (MP2286) and DTPA-[d-Asp26,Nle28,31]-CCK(26-33) (MP2288) with an IC50 of 1.5 nM. For comparison, analogs with C-terminal DTPA, such as [Nle28,31,Aphe33(p-NH-DTPA)]-CCK(26-33) and CCK-(26-33)-NH(CH2)2 NH-DTPA, had an IC50 of >100 nM. DOTA-[D-Asp26, Nle28,31]-CCK(26-33) had an IC50 of 3.9 nM. The compounds were selective for CCK-B receptors as they did not bind with high affinity to CCK-A receptors expressed in human tumors (meningiomas or gastroenteropancreatic tumors). In vivo rat biodistribution studies with indium-111 labeled MP2286 and MP2288 showed that the primary mode of clearance was renal, and the primary sites of uptake (% ID/g 24 h p.i.) were kidneys (0.270 and 0.262, respectively) and the gastrointestinal tract. The CCK-B receptor-expressing gastric mucosa showed specific in vivo accumulation of 111In-labeled MP2288 which could be blocked in the presence of excess unlabeled MP2288. 111In-labeled MP2286 and MP2288 were also found to be stable in human plasma whereas both compounds were degraded in urine (>40% after 3 h at 37 degrees C). The affinity, specificity, biodistribution, and stability of these two DTPA-CCK analogs indicate that these compounds have substantial promise for use in the in vivo visualization of CCK-B receptor-expressing tumors.

Animals↗
PubMed1998

Use of indium-111 pentetreotide somatostatin receptor scintigraphy to detect recurrent thyroid carcinoma in patients without detectable iodine uptake.

We conducted a prospective evaluation of somatostatin receptor scintigraphy (SRS) for the diagnosis of recurrent vesicular or papillary thyroid carcinoma in 16 patients with no detectable iodine uptake. SRS was performed 1, 4 and 24 h after intravenous injection of 137-200 MBq of indium-111 pentetreotide. Results were interpreted in terms of assumed presence of tumoral tissue: there were three true-positives (19%), one false-positive (6%) and 12 false-negatives (75%). The three true-positive patients had multiple lesions visible on computerized tomography. SRS was negative in all patients with a high thyroglobulin level alone. In addition, we analyzed the consequences of interpretative criteria and somatostatin receptor expression variability for SRS positivity as well as the risk of false-positives. We conclude that when iodine uptake cannot be demonstrated in patients with suspected recurrence of differentiated thyroid carcinoma, SRS would not appear to contribute to diagnosis, and that interpretative criteria commonly used for tumours with a high receptor density may be too restrictive for tumours with a low receptor density.

Adult↗
PubMed1998

Immunohistochemical localization of somatostatin receptors sst2A in human tumors.

Human tumors frequently express somatostatin receptors. However, none of the receptor subtype proteins have been individually visualized in normal or neoplastic human tissues. Here, the distribution of the sst2A receptor was investigated using immunohistochemistry with the specific anti-peptide antibody R2-88 in 47 human tumors. All tumors selected for their abundance of sst2 mRNA and/or strong binding of the sst2-preferring ligand 125I-labeled Tyr3-octreotide were specifically immunostained with R2-88. Conversely, all tumors without somatostatin binding or expressing predominantly other somatostatin receptor subtype mRNAs (sst1 or sst3) were not specifically immunostained by R2-88. Specificity was shown in immunoblots, demonstrating receptor migration as a 70-kd broad band. In immunohistochemical and immunoblotting experiments, the abolition of staining after antibody blockade with antigen peptide was demonstrated. Immunostaining was identified in cryostat and in formalin-fixed, paraffin-embedded sections. Heat-induced epitope retrieval was necessary to visualize sst2A receptors in formalin-fixed sections. Moreover, because of occasional high nonspecific staining, the demonstration of complete abolition of immunostaining by treatment with antigen peptide was a prerequisite for the correct identification of sst2A-positive tumors. The sst2A receptors were clearly located at the membrane of the tumor cells. These results provide the first localization of a somatostatin receptor subtype in human tissues at the cellular level. The sst2A receptor identification and visualization in tumors with simple immunohistochemical methods in formalin-fixed, paraffin-embedded material will open new diagnostic opportunities for pathologists.

Animals↗
PubMed1998

Pituitary adenylate-cyclase-activating polypeptide (PACAP) binding sites and PACAP/vasoactive intestinal polypeptide receptor expression in human pituitary adenomas.

Pituitary adenylate-cyclase-activating polypeptide (PACAP) stimulates release of several anterior pituitary hormones by interacting with PACAP receptors on pituitary cells. To learn more about the distribution and possible regulatory roles of PACAP and its receptors in human pituitary adenomas, we investigated the expression of vasoactive intestinal polypeptide (VIP) and PACAP binding sites using receptor autoradiography, PACAP and PACAP/VIP receptor (PVR) mRNAs by reverse transcription polymerase chain reaction (RT-PCR), conventional in situ hybridization, and catalyzed reporter deposition in situ hybridization (CARD-ISH) analyses. PACAP mRNA was expressed in normal human hypothalamus, which was used as a positive control, but not in pituitary adenomas. Receptor autoradiography showed PACAP types I and II binding sites in all groups of pituitary adenomas, except prolactinomas. The highest levels were present in gonadotroph and null cell adenomas. PVR-2 mRNA was expressed in normal pituitaries and in all groups of pituitary adenomas by RT-PCR, whereas PVR-1 and -3 mRNAs were expressed in all groups of pituitary adenomas, except for most prolactinomas. Conventional in situ hybridization studies with digoxigenin-labeled probes demonstrated weak staining for PVR-1, -2, and -3 mRNAs in most tissues. The CARD-ISH technique, which increased the sensitivity of the in situ hybridization method, also revealed PVR-2 mRNA expression in all adenomas, whereas PVR-1 and -3 mRNAs were detected in nearly all adenomas except for prolactinomas. The presence of PACAP mRNA in the hypothalamus, but not in normal anterior pituitary or in pituitary adenomas, and the differential expression of PVRs in adenomas indicate a selective regulatory endocrine and paracrine role of PACAP in normal and neoplastic anterior pituitary cells.

Adenoma↗
PubMed1998

A possible role for somatostatin receptor scintigraphy in the diagnosis and follow-up of children with medulloblastoma.

The surgical resection of medulloblastoma (MB), the most frequent malignant brain tumor in children, often remains subtotal. To estimate the response to further treatment the residual tumor is monitored by CT or MRI. The interpretation of both imaging techniques is complicated by disturbances resulting from surgery and radiation. Our study searched for alternative imaging techniques and asked the following questions. 1) Do MB express somatostatin receptors (SSTR), 2) is SSTR scintigraphy a sensitive imaging technique for the follow-up and the detection of vital tumor tissue in children with MB, and 3) do the results of SSTR scintigraphy correlate with the in vitro analysis of MB tissue by SSTR autoradiography. We analyzed the SSTR status in 20 children with MB, aged 1 to 15 years. Sixteen SSTR scintigraphies using Indium-111-DTPA-D-Phel-pentetreotide were performed in 14 children. MB tissue of 14 children was analyzed by SSTR autoradiography using Iodine-125-Tyr3-octreotide. In 8 cases SSTR were measured by both methods in vivo and in vitro. In comparison with conventional imaging, results of SSTR scintigraphy were true positive in 7 of 7 patients, true negative in 9 of 9 patients, including one patient with false positive findings in MRI, false negative in only one patient with small spinal metastases (diameter < 3 mm) and false positive in none of the analyzed patients. In all cases with residual tumor (n = 3) and suspected relapse (n = 4) the diagnosis could be confirmed (n = 4) or excluded (n = 3), consistent with the results of MRI and tumor histology. All MB tissues analyzed by SSTR autoradiography (n = 14) showed an extremely high density of SSTR ranging from 4047 to 15526 dpm/mg MB tissue. MB (n = 8) which were analyzed by SSTR scintigraphy and autoradiography demonstrated consistent results in evaluation by both methods. In cases where the integrity of the blood-brain barrier was tested by Tc-99m-DTPA scintigraphy (n = 10), the SSTR-to-brain scintigraphy index confirmed the tumor specificity of radionuclide uptake. We conclude that 1) MB tissue expresses a particularly high density of SSTR, 2) the high density of SSTR in autoradiography correlates with a sensitive imaging of these tumors by SSTR scintigraphy, 3) SSTR scintigraphy might be a valuable imaging method for detection of vital MB tissue in patients with residual tumor or relapse.

Adolescent↗
PubMed1998

Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma.

BACKGROUND/AIMS: New imaging possibilities for early diagnosis of the devastating exocrine pancreatic adenocarcinomas would be highly welcome. Recently, pancreatic neuroendocrine tumours have been successfully visualised in vivo on the basis of their high density of receptors for the regulatory peptide somatostatin. Unfortunately, exocrine pancreatic tumours do not express sufficient amounts of somatostatin receptors. Therefore over-expression of other regulatory peptide receptors in these tumours needs to be found. METHODS: Receptors for the regulatory peptide neurotensin were evaluated in vitro by receptor autoradiography in 24 ductal pancreatic adenocarcinomas, 20 endocrine pancreatic cancers, 18 cases of chronic pancreatitis, and 10 normal pancreatic glands. RESULTS: Some 75% of all ductal pancreatic adenocarcinomas, most of them differentiated, were neurotensin receptor positive, whereas endocrine pancreatic cancers did not express neurotensin receptors. No neurotensin receptors were found in chronic pancreatitis or normal pancreatic tissues, including pancreatic acini, ducts, and islets. CONCLUSIONS: The selective and high expression of neurotensin receptors in ductal pancreatic adenocarcinomas could form the molecular basis for potential clinical applications, such as in vivo neurotensin receptor scintigraphy for early tumour diagnosis, radiotherapy with radiolabelled neurotensin analogues, and chemotherapy with neurotensin receptor antagonists.

Adenocarcinoma↗
PubMed1998

Immunohistochemical localization of somatostatin receptor sst2A in human pancreatic islets.

Somatostatin and octreotide inhibit endocrine pancreatic functions in man, via specific somatostatin receptors. However, the cellular distribution of the different somatostatin receptor subtype proteins has not been determined in the human pancreas. Here, the immunohistochemical distribution of the sst2A receptor was investigated using the sst2A receptor specific anti-peptide antibody R2-88 in cryostat as well as in formalin-fixed paraffin-embedded sections of human pancreatic tissue, and compared with insulin, glucagon and somatostatin immunostaining of adjacent sections. All pancreatic islets were immunostained with R2-88. Most islet cells were labeled: the sst2A receptors were present in insulin as well as glucagon producing cells, but were not detected in intra-islet vessels nor in adjacent acinar tissue. Absorption of the sst2A antibody with 100 nM of the antigen peptide abolished specific staining in tissue sections. Immunohistochemical staining with R2-88 correlated with the labeling observed after receptor autoradiography using the sst2-preferring radioligand, 125I-Tyr3-octreotide. Therefore, the clinical efficacy of octreotide on glucagon and insulin release can be explained by the presence of sst2A receptors in human A and B pancreatic islet cells. Moreover, absence of sst2A receptors in human acinar tissue suggests that the action of somatostatin on pancreatic exocrine secretion is mediated either indirectly or through a different somatostatin receptor subtype on acinar cells.

Glucagon↗
PubMed1997

Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors.

Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.

Autoradiography↗
PubMed1997

Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography.

Using in situ hybridization techniques with selective oligoprobes, the gene expression of sst1, sst2, sst3 and sst5 was studied in a series of 32 human pituitary adenomas, 28 breast tumors and 21 endocrine gastroentero-pancreatic tumors, shown to express somatostatin receptors to variable extents. In most of these tumors the sst2 receptor subtype was abundantly expressed, even though a significant number of pituitary adenomas, breast and gastroentero-pancreatic tumors expressed sst1 and/or sst3 as well. A very high incidence of the sst5 subtype was found in growth hormone-producing pituitary adenomas and, to a lesser extent, in inactive pituitary adenomas, whereas breast tumors seldom expressed sst5; gastroentero-pancreatic tumors showed all possible combinations of sst expression, with, however, a predominance of sst2 and sst1. Overall, the presence of sst2 mRNA and/or sst5 mRNA generally correlated with the presence of octreotide binding sites. A lack of octreotide binding sites corresponded with a lack of sst2 mRNA. Several tumors exhibiting a low number of octreotide binding sites had no measurable sst2 mRNA, despite abundance of beta-actin mRNA, suggesting in these cases a very low abundance of sst mRNAs or a too low sensitivity of the in situ hybridization methodology. In all other cases, the method allowed precise localization of the respective mRNAs on the tumor tissue, notably in breast tumors with non-homogeneous receptor distribution. Tumors without measurable amounts of somatostatin receptors had no detectable sst mRNA. Our results indicate a highly variable abundance of the various sst mRNAs in individual somatostatin receptor-containing tumors.

Autoradiography↗
PubMed1997

Localization of cholecystokinin A and cholecystokinin B-gastrin receptors in the human stomach.

BACKGROUND & AIMS: Gastrin and cholecystokinin (CCK) are gut-brain peptides, with multiple functions in the gastrointestinal tract mediated through CCK-B-gastrin and CCK-A receptors. The receptor localization is, however, not well established in humans. The aim of this study was to investigate the distribution and pharmacological characteristics of CCK-A and CCK-B receptors in the human upper gastrointestinal tract and compare them with those in the rat and dog. METHODS: CCK receptors were localized by in vitro receptor autoradiography with 125I-[Leu15]gastrin-I and 125I-[D-Tyr-Gly, Nle(28,31)]-CCK 26-33 in stomach and gallbladder. RESULTS: High concentrations of CCK-B-gastrin receptors were detected in the midglandular region of the human fundic mucosa. CCK-A receptors were found in the basal region of the antral and fundic mucosa. CCK-A receptors were also located in the muscularis propria of antrum, fundus, and gallbladder, whereas CCK-B-gastrin receptors were only detected in gastric fundic circular muscle. Two nonpeptide CCK receptor antagonists distinguish both receptor subtypes. Comparisons among humans, dogs, and rats suggest that localization and density of CCK receptor subtypes in the upper gastrointestinal tract are species-dependent. CONCLUSIONS: Localization of CCK receptor subtypes in human upper gastrointestinal tract provides a biochemical and morphological basis for the separate regulatory roles of gastrin and CCK.

Animals↗
PubMed1997

Evaluation of somatostatin analogues for the detection and treatment of gastrinoma in a dog.

Gastrinomas in dogs are difficult to diagnose, localise and treat. In humans, somatostatin analogues have improved localisation and treatment of gastrinomas. The somatostatin analogues pentetreotide and octreotide were evaluated for the detection and treatment of gastrinoma in a dog. 111indium-pentetreotide scintigraphy revealed multiple areas of activity in the patient's mid-ventral abdomen which were consistent with masses in the pancreas and liver at laparotomy. Immunohistochemistry, electron microscopy and binding of 125I-[Tyr3]-octreotide in vitro confirmed the lesion as a gastrinoma which expressed somatostatin receptors. Octreotide at doses of 2, 4 and 8 micrograms/kg caused transient decreases in circulating gastrin. Plasma somatostatin peaked at one hour after octreotide and was still detectable at four and six hours after administration of octreotide. Combination therapy with famotidine, omeprazole, sucralfate and increasing doses of octreotide allowed patient survival for 14 months.

Animals↗