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J C Reubi

Publications and source records attributed to J C Reubi.

At least 163 records · Page 9Linked to original sources
PubMed1990

Prognostic value of pS2 protein and receptors for epidermal growth factor (EGF-R), insulin-like growth factor-1 (IGF-1-R) and somatostatin (SS-R) in patients with breast and ovarian cancer.

The prognostic value of EGF-R, IGF-1-R and SS-R, and of cytosolic estrogen-regulated pS2 protein, was studied in patients (pts) with primary breast and advanced ovarian cancer. Ovarian cancer tissues were negative for pS2 (by immunoradiometric assay) IGF-1-R and EGF-R contents (by ligand binding assay, LBA) were of no or moderate prognostic value for breast cancer pts (n = 214). For advanced ovarian cancer pts, EGF-R content determined by LBA (n = 55) showed no prognostic value, whereas EGF-R status (n = 35) determined by immunohistochemistry (MoAb 2E9) significantly correlated with progression of disease (P less than 0.05). In breast cancer pts, both SS-R and pS2 showed no association with tumor size, nodal status and grade. For pS2 the best cut-off level with respect to relapse-free (RFS) and overall survival (OS) was found to be 11 ng/mg protein. Both SS-R (1 g% SS-R+, n = 135; P less than 0.04) and pS2 (27% pS2+, n = 197; P less than 0.001), which were mainly positive in ER+ tumors, were of prognostic value, especially within the subgroups with ER+/PgR+ tumors. Also within N+ and No pts the 5-yr RFS and OS showed a difference between pS2+ and pS2- (33 and 54% for N+, and 31 and 13% difference for No pts). In summary, SS-R and pS2 are valuable prognosticators in breast cancer pts, and prognostic significance of EGF-R in ovarian cancer pts needs further study.

Biomarkers, Tumor↗
PubMed1990

Genetic changes in somatostatin receptor positive breast tumors.

Forty-nine primary breast tumors were analyzed for the expression of the somatostatin receptor (SSR) and genetic changes in the RB tumor suppressor gene. Twenty-four tumor samples were shown to contain receptors for somatostatin and in eight of these SSR-positive tumors we observed a mutation in the RB gene. However, since also in the group of SSR-negative tumors in eight of the 25 cases an alteration of the RB gene was observed, loss of this tumor suppressor gene is not specific for the SSR-positive subgroup of breast tumors. A similar, equal distribution between SSR-positive and SSR-negative breast tumors was observed for the six tumor samples which showed amplification of the neu proto-oncogene.

Breast Neoplasms↗
PubMed1990

Somatostatin receptors in malignant tissues.

High affinity somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred human tumors. SS-R were found in most tumors originating from SS target tissues, i.e. GH- and TSH-producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors (including metastases) and brain tumors, including gliomas and neuroblastomas. SS-R were also expressed in several tumors originating from various other tissues, i.e. breast and small cell lung carcinomas, some colorectal cancers, and medullary thyroid carcinomas. In general, most of the SS-R+ tumors are well-differentiated and/or have neuroendocrine features. They often have low or absent epidermal growth factor receptor (EGF-R) expression. In some tumors (i.e. breast tumors) SS-R are not homogeneously distributed, making SS-R autoradiography a particularly useful tool for assessing SS-R status. SS-R are functional in pituitary and GEP tumors where they mediate hormone secretion inhibition. In these and in the other SS-R+ tumors, SS-R may also mediate antiproliferative effects of SS, as evidenced in animals where growth of SS-R+ tumor xenografts is inhibited by SS analogs. For diagnosis, SS-R+ tumors and metastases can be localized in vivo by scanning techniques after 123I-labelled SS analog injection.

Autoradiography↗
PubMed1990

Somatostatin receptor imaging in vivo localization of tumors with a radiolabeled somatostatin analog.

This paper presents the results of the visualization of somatostatin (SS) receptor positive tumors in man after the i.v. administration of the SS analog Tyr3-octreotide coupled to 123I. It is an easy, quick and harmless procedure which allows imaging of primary and (often unexpected) secondary deposits and/or multiple localizations of the majority of endocrine pancreatic tumors, metastatic carcinoids and pituitary tumors, as well as of a multitude of tumors with neuroendocrine characteristics and well-differentiated brain tumors and meningiomas. In the case of hormone-secreting tumors a positive scan in most instances also predicts the subsequent successful therapy with octreotide.

Humans↗
PubMed1990

Identification of somatostatin receptors in human small cell lung carcinoma.

Biopsy specimens obtained from eight patients with lung cancer were tested for content of somatostatin receptors by autoradiography. Somatostatin receptors were detected in two of three patients with small cell lung cancer (SCLC) but in none of five patients with non-small cell lung cancer (NSCLC) including adenocarcinoma (two), squamous cell carcinoma (two), and bronchoalveolar carcinoma (one). In those with SCLC, specific somatostatin receptor binding was evidenced only in tumor foci and not in surrounding stroma or normal lung parenchyma. Further tissue characterization by immunoperoxidase staining with the pancytokeratin monoclonal antibody, mAB-lu-5, revealed labeling to all of the NSCLC but to none of the SCLC specimen. Selective immunoreactivity was detected in both the SCLC and the NSCLC specimen to chromogranin and neuron-specific enolase (NSE) whereas none of the specimen had detectable immunostaining to somatostatin, bombesin, serotonin, adrenocorticotropic hormone, neurofilament, calcitonin, and synaptophysin. The identification of somatostatin receptors in primary human lung cancer may have a bearing on the biology of this disease and perhaps on the clinical application of somatostatin analogues in patients with SCLC.

Aged↗
PubMed1990

Somatostatin-receptor imaging in the localization of endocrine tumors.

BACKGROUND AND METHODS: A number of different tumors have receptors for somatostatin. We evaluated the efficacy of scanning with 123I-labeled Tyr3-octreotide, a somatostatin analogue, for tumor localization in 42 patients with carcinoid tumors, pancreatic endocrine tumors, or paragangliomas. We then evaluated the response to octreotide therapy in some of these patients. RESULTS: Primary tumors or metastases, often previously unrecognized, were visualized in 12 of 13 patients with carcinoid tumors and in 7 of 9 patients with pancreatic endocrine tumors. The endocrine symptoms of these patients responded well to therapy with octreotide. Among 20 patients with paragangliomas, 8 of whom had more than one tumor, 10 temporal (tympanic or jugular), 9 carotid, and 10 vagal tumors could be visualized. One small tympanic tumor and one small carotid tumor were not seen on the scan. CONCLUSIONS: The 123I-labeled Tyr3-octreotide scanning technique is a rapid and safe procedure for the visualization of some tumors with somatostatin receptors. A positive scan may predict the ability of octreotide therapy to control symptoms of hormonal hypersecretion.

Adenoma, Islet Cell↗
PubMed1990

Somatostatin receptor incidence and distribution in breast cancer using receptor autoradiography: relationship to EGF receptors.

Somatostatin receptors (SS-R) were measured with in vitro receptor autoradiography using the SS analog 125I-[Tyr3]-SMS 201-995 as radioligand in 342 breast-tumor samples. In a group of 158 "small" tumor samples (mean section surface: 14 mm2 +/- 0.4; mean +/- SEM), 34 tumors (21%) were SS-R positive. In a group of 72 "large" tumor samples (mean size: 180 mm2 +/- 8; mean +/- SEM), 33 tumors (46%) were SS-R positive. In this second group, more than half of the tumors had a non-homogeneous distribution of SS-R, i.e., tumor regions within SS-R positive tumors were SS-R negative. In a group of 48 additional patients, we could show that primaries and their metastases, or double primaries from right and left breasts, or 2 primaries resected consecutively, could both occasionally be SS-R positive. Finally, in 71 SS-R-positive primary tumors, 18 tumor samples were found to have simultaneously Epidermal Growth Factor receptors (EGF-R); in 12 of these 18 cases, the 2 receptor types were not topographically overlapping. Whereas SS-R were located on tumor tissue, EGF-R were often seen on adjacent normal lobules and ducts. These results show that a subgroup of breast tumors contain SS-R, in several cases non-homogeneously distributed. Their location does not coincide with that of EGF-R. Metastasis of SS-R-positive primaries may be SS-R-positive, as are sometimes second primaries. For evaluation of SS-R incidence and distribution, autoradiography is of advantage, specially if it is performed on large tumor samples, since it allows precise identification of the tissue elements containing these receptors.

Amino Acid Sequence↗
PubMed1990

Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas.

Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinated somatostatin analogues as radioligands, a [Leu8, DTrp22, Tyr25]somatostatin-28 and a somatostatin octapeptide, Tyr3-octreotide. The carcinoid tumors were either primaries (n = 32) or metastases (n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 metastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, 1 gastrinoma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS analogues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver metastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver metastases obtained by percutaneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary, SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell carcinomas, (b) their presence in metastases as well, (c) their continuous expression even during long term octreotide therapy, (d) the possibility of measuring SS receptors in percutaneous needle liver biopsies, and (e) the evidence of their functionality. This study therefore suggests that tumoral SS receptors may be the likely molecular basis for octreotide action and may be an important parameter for predicting the therapeutic efficacy of SS analogues in carcinoids and islet cell carcinomas.

Adenoma, Islet Cell↗
PubMed1990

Somatostatin receptors are present in small-cell but not in non-small-cell primary lung carcinomas: relationship to EGF-receptors.

Sixteen primary human lung tumours were analysed for their content of somatostatin receptors using receptor autoradiography with somatostatin-28 and somatostatin octapeptide analogues as radio-ligands. Two out of 4 small-cell lung carcinomas were somatostatin receptor-positive, with a high density of homogeneously distributed receptors on tumour tissue only. Somatostatin receptors were characterized in one of the tumours in homogenate binding assay as saturable, high-affinity binding sites (KD = 0.53 nM) with a number of sites (Bmax) equivalent to 189 fmoles/mg protein. These sites were specific for somatostatin, since only biologically active somatostatin analogues but not unrelated peptides showed high-affinity binding. Both receptor-positive patients had limited disease; furthermore, the small-cell lung carcinoma patient with the longest survival was receptor-positive, while the one with the shortest survival was receptor-negative. None of the 12 non-small-cell lung carcinomas (5 squamous carcinomas, 7 adenocarcinomas) contained somatostatin receptors. For comparison, epidermal growth factor receptors were found in all non-small-cell lung carcinomas. Neuroendocrine features (synaptophysin, chromogranin, neuron-specific enolase, protein gene product 9.5) were present in all small-cell lung carcinomas but absent in non-small-cell lung carcinomas. Given the receptor-mediated action of somatostatin in other neuroendocrine tumours, these data may have a bearing on the clinical application of somatostatin analogues in patients with small-cell lung carcinomas.

Adult↗
PubMed1990

The somatostatin analog Sandostatin (SMS201-995) in treatment of DMBA-induced rat mammary tumors.

The effects of treatment with a somatostatin analog (Sandostatin, SMS201-995) were investigated in female rats with dimethylbenzanthracene (DMBA)-induced rat mammary tumors. A 3-week treatment was performed using sandostatin, the LHRH-agonist buserelin alone, or buserelin in combination with sandostatin. Twice daily sandostatin treatment was performed with dosages of 0.05 microgram, 0.2 microgram, 1 microgram, 5 micrograms, and 20 micrograms. Buserelin was used in a 2 x 5 micrograms/day dosage. The combined results from six different experiments show that the various dosages of sandostatin caused no tumor growth inhibition. Somatostatin receptors could not be demonstrated in these mammary tumors. Sandostatin treatment by daily injections did not suppress levels of growth hormone, prolactin, or epidermal growth factor-like activities. Estrogen (ER) and progesterone (PgR) receptor contents of the mammary tumors were not changed. In contrast, buserelin treatment caused highly significant tumor remission. The combined treatment with sandostatin and buserelin did not alter the treatment results obtained after treatment with buserelin alone. In conclusion, sandostatin treatment in this tumor model had no direct growth inhibitory effect and did not cause an endocrine inhibition of mammary tumor growth. However, these results do not exclude antitumor effects in human breast cancer in view of the presence of somatostatin receptors in approximately 20-45% of human tumors, besides possible different endocrine effects.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Distribution of somatostatin receptors in normal and tumor tissue.

Specific receptors for somatostatin (SS), mediating the various actions of this peptide, have been described in SS target tissues in animal and man. Using homogenate binding assays, as well as receptor autoradiography, the presence of SS receptors has been demonstrated in various regions of the brain (cortex, limbic system, basal ganglia), the anterior pituitary, the endocrine and exocrine pancreas, the gastrointestinal tract, and the adrenals. There are species-, as well as age-, related variations. Furthermore, there is evidence for different SS receptor subtypes. Interestingly, a large variety of human tumors also contain SS receptors with similar characteristics as those found in normal tissue; in numerous tumors, the SS receptor density is even higher than in healthy tissue counterparts. Most GH- and TSH-producing pituitary adenomas, but also a subgroup of endocrine inactive pituitary adenomas, have SS receptors; most carcinoids and islet cell carcinomas, as well as their metastases, also contain SS receptors. Several differentiated (usually EGF receptor negative) glia tumors possess SS receptors, whereas undifferentiated (EGF receptor positive) glia tumors lack such receptors. Furthermore, a subgroup of breast tumors, usually steroid receptor positive and neuroendocrine-differentiated, contain SS receptors. Finally, small cell lung carcinomas, but not non-small cell carcinomas, often possess SS receptors. These receptors are likely to be functional since in 11 acromegalics and 18 gastroenteropancreatic tumor patients, a positive correlation was observed between their SS receptor status and their hormone secretion sensitivity to Sandostatin.

Animals↗
PubMed1990

Treatment with Sandostatin and in vivo localization of tumors with radiolabeled somatostatin analogs.

The presence of high numbers of somatostatin receptors seems to be the basis for the successful control by Sandostatin of hormonal hypersecretion by most growth hormone-secreting pituitary adenomas, endocrine pancreatic tumors, and carcinoids. In this report, we present preliminary data on in vivo somatostatin receptor imaging with a 123I-coupled somatostatin analog (204-090) in patients with these types of tumors.

Carcinoid Tumor↗
PubMed1990

The clinical use of somatostatin analogues in the treatment of cancer.

Somatostatin is a regulatory hormone or tissue factor which plays an inhibitory role in the normal regulation of several organ systems, including the central nervous system, hypothalamus and pituitary gland, the gastrointestinal tract and the exocrine and endocrine pancreas. Sandostatin is an analogue of somatostatin which has characteristics which makes it a better compound for clinical use than native somatostatin: it inhibits GH preferentially over insulin. It has a long half-life in the circulation, causing a prolonged inhibitory effect in somatostatin-responsive target organs. It is active after subcutaneous administration and rebound hypersecretion does not occur. Sandostatin is very well tolerated by most patients. Somatostatin receptors remain present on a variety of tumours which arise in tissues that contain these receptors normally. High numbers of somatostatin receptors have been found on GH-secreting pituitary tumours and on most metastatic endocrine pancreatic tumours and carcinoids. Sandostatin treatment ameliorates clinical symptoms in most acromegalic patients while GH hypersecretion and elevated concentrations of circulating IGF-I are well controlled. In most patients hormonal hypersecretion from endocrine pancreatic tumours and carcinoids is also suppressed during Sandostatin therapy. This results in an instant improvement in the quality of life. There is preliminary evidence of control of tumour growth. The presence of high numbers of somatostatin receptors on tumours enables in vivo receptor-imaging, with 123iodine coupled to a somatostatin analogue. This newly developed technique provides for the first time the possibility of localization of the primary tumours and their metastases and a prediction of which patients may respond to treatment with Sandostatin. Theoretically this somatostatin-receptor imaging technique represents a new approach which may be extended to other receptor-containing tumours. Therefore it may provide a new, powerful alternative to tumour localization performed with monoclonal antibody technology. Another potential development is the use of beta-emitting isotopes coupled to somatostatin analogues for therapeutic irradiation. Somatostatin analogues exert potent inhibitory effects on the growth of a variety of experimental tumour models in animals. Several mechanisms of action have been proposed including the direct antiproliferative effects of somatostatin and its analogues in a variety of tumour cell cultures. Most well-differentiated human brain tumours like meningiomas and low-grade astrocytomas contain somatostatin receptors, while undifferentiated brain tumours mainly contain EGF receptors. Fifteen percent of human breast carcinomas contain somatostatin receptors; those which do have a better prognosis. It can be concluded that somatostatin is an endogenous, naturally occurring inhibitory growth factor.(ABSTRACT TRUNCATED AT 400 WORDS)

Acromegaly↗
PubMed1990

Parallel in vivo and in vitro detection of functional somatostatin receptors in human endocrine pancreatic tumors: consequences with regard to diagnosis, localization, and therapy.

The effects of octreotide in vivo and in vitro on hormone release, in vivo [123I]Tyr3-octreotide scanning, and in vitro [125I]Tyr3-octreotide autoradiography were compared in five patients with endocrine pancreatic tumors. [123I]Tyr3-octreotide scanning localized the primary tumor and/or previously unknown metastases in four of the five patients. The patient with a negative scan had an insulinoma that did not respond to octreotide in vivo. No Tyr3-octreotide-binding sites were subsequently found at autoradiography of the tumor, whereas somatostatin-14 receptors were present at a high density. In parallel, culture studies with the cells prepared from this adenoma showed that insulin release was not affected by octreotide, while both somatostatin-14 and -28 significantly suppressed hormone release. Culture studies of the tumor cells from two gastrinomas showed a dose-dependent inhibition of gastrin release by octreotide. Octreotide exerted direct antiproliferative effects in one of these gastrinomas, which had been shown to be rapidly growing in vivo. Both gastrinomas had specific somatostatin receptors, as measured by in vitro receptor autoradiography. Somatostatin release by the cultured somatostatinoma cells from one of these patients was suppressed by octreotide. In conclusion, 1) the [123I]Tyr3-octreotide scanning procedure is valuable in the localization of primary endocrine pancreatic tumors as well their often clinically not yet recognized metastases; 2) the in vitro detection of somatostatin receptors in those tumors that were also visualized in vivo after injection of [123I] Tyr3-octreotide indicates that the ligand binding to the tumor in vivo indeed represents binding to specific somatostatin receptors; and 3) the parallel between the presence of somatostatin receptors on tumors and in in vivo and in vitro effects of octreotide on hormonal release from these tumors indicate that a positive scan predicts a good suppressive effect of octreotide on hormonal hypersecretion by these tumors.

Adult↗
PubMed1990

Receptor scintigraphy with a radioiodinated somatostatin analogue: radiolabeling, purification, biologic activity, and in vivo application in animals.

Radioiodinated Tyr-3-octreotide, a somatostatin analogue, is a useful ligand for the in vitro detection of somatostatin receptors. In this study, we have investigated the possible in vivo application of this radioligand in the detection of somatostatin receptor-bearing tumors by scintigraphy. The specific somatostatin-like biologic activity of radioiodinated Tyr-3-octreotide was confirmed in vitro: (a) radioiodinated Tyr-3-octreotide competes in the nanomolar range with specific receptor binding of somatostatin to suspended human meningioma membranes and (b) the secretion of growth hormone by cultured rat pituitary cells was similarly inhibited by iodinated Tyr-3-octreotide and somatostatin. In rats, intravenously injected 123I-Tyr-3-octreotide is rapidly cleared from the circulation mainly by the liver. Although this rapid clearance limits the amount of tracer available for somatostatin receptor-bearing tumors, the advantage of this rapid clearance is that the background level is rapidly reduced in favor of scintigraphic imaging of these tumors. Pancreatic tumors in rats were localized by scintigraphy after intravenous injection of 123I-Tyr-3-octreotide.

Animals↗
PubMed1990

Lack of evidence for autocrine feedback regulation by somatostatin in somatostatin receptor-containing meningiomas.

The somatostatin (SS), the SS mRNA, and the SS receptor contents were measured and compared in 25 human meningiomas. The SS tissue content, measured with radioimmunoassay, amounted to 2.89 +/- 0.82 pg/mg tissue (mean +/- SEM). The SS mRNA levels visualized by in situ hybridization using a 32P-labeled synthetic oligonucleotide probe were undetectable in all cases. SS receptors were measured with autoradiography using the octapeptide SS analogue 125I-204-090 as radioligand and were found to be present in high density in all meningiomas. For comparison, three SS-producing tumors, i.e., two human medullary thyroid carcinomas and one neuroendocrine gut tumor, were shown to have a high level of immunoreactive tissue SS, reaching, respectively, 2807, 401, and 22 pg/mg tissue, as well as moderate to high levels of SS mRNA detected with in situ hybridization. It can be concluded that meningioma tissue is not synthesizing significant amounts of SS in situ and that the low amount of tissue SS found in these tumors is likely to be due to SS transported there from a distant source, via blood, cerebrospinal fluid, or axons from nerve fibers terminating in this tissue. The high number of SS receptors found in meningiomas is therefore unlikely to be regulated by an autocrine SS production from the meningioma tissue itself but rather from another, unknown distant SS source.

DNA Probes↗