Endocrine aspects of the diagnosis and treatment of primary brain tumours.
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Adult↗
Biomedical subjects
J C Reubi
Publications and source records attributed to J C Reubi.
Identification of somatostatin and gastrin receptors on enterochromaffin-like cells from Mastomys gastric tumors.
Histamine-secreting enterochromaffin-like (ECL) cells of the gastric fundus of the Mastomys can develop into solid ECL cell tumors, either spontaneously or after induction by acid inhibition. We used this tumor tissue to perform in vitro receptor autoradiography for somatostatin (SS), gastrin, and substance-P, using, respectively, [125I]Tyr3-octreotide, [125I]gastrin-17, and [125I]Bolton-Hunter-labeled substance-P as radioligands. A high density of SS receptors was found in the nontumor fundic mucosa, where gastrin receptors were only barely detectable. However, in the group of spontaneously developing ECL cell tumors, a high density of SS and gastrin receptors was observed, homogeneously distributed in the tumor tissue. In addition, the loxtidine-induced ECL cell tumors expressed a high density of SS and gastrin receptors. The receptors were specific for the respective peptide and of high affinity, with a dissociation constant (Kd) of 0.90 nM for SS receptor and 0.87 nM for gastrin receptors. No substance-P receptors were detected on the ECL cell tumors, although they were present in the muscle layers of the Mastomys gastric fundus. These results demonstrate that ECL-derived tumors express receptors for both SS and gastrin. This observation is consistent with the proposal that there is substantial regulation of the histamine-producing ECL cell by SS and gastrin. The presence of gastrin receptors is compatible with a role for gastrin as a trophic factor in ECL cell hyperplasia and neoplasia. The expression of SS receptors may be of diagnostic and therapeutic relevance in the regulation of ECL function and neoplastic transformation.
Animals↗
Dissociation of antiproliferative and antihormonal effects of the somatostatin analog octreotide on 7315b pituitary tumor cells.
The somatostatin (SS) analog octreotide has been successfully used in the treatment of (neuro)endocrine tumors. The mechanism of action of the tumor (growth) inhibitory action by octreotide is not fully understood. We have investigated the effect of octreotide on 7315b rat pituitary tumor cell growth, PRL release, and intracellular PRL concentrations in vitro. When cultured in medium with 10% fetal calf serum, the number of high affinity SS receptors increased with increasing culture time. On days 7, 14, and 21 of culture, the number of SS receptors amounted to 978 +/- 217, 3588 +/- 705, and 5865 +/- 3332 fmol/mg protein, respectively, whereas they were not measurable on day 0. From days 0-7, 7-14, and 14-21 of culture, octreotide (1 pM to 1 microM) inhibited PRL release and the intracellular PRL concentration, with IC50 values in the nanomolar range. However, no inhibition of cell growth was observed by these octreotide concentrations from day 0-7 of culture, while octreotide inhibited cell growth in a dose-dependent fashion from days 7-14 and 14-21 of culture (maximal inhibition by 25% and 26%, respectively). In a series of nine consecutive experiments we found a significant positive correlation between the percent inhibition of cell growth induced by 1 microM octreotide and the number of SS receptors on 7315b cells (r = 0.7865; P = 0.012). Inhibition of PRL release did not correlate with SS receptor numbers. Octreotide (1 microM) inhibited forskolin (0.5 microM)-stimulated cell growth and intracellular PRL concentrations, while in the presence of a high concentration of forskolin (10 microM), octreotide had no effect on forskolin-stimulated cell growth and intracellular PRL concentrations. In addition, its PRL release inhibitory effect was significantly lower in forskolin-stimulated cultures. Pretreatment of the cells with pertussis toxin (10 micrograms/liter) completely prevented the inhibition of cell growth by octreotide and diminished the inhibitory effect of octreotide on PRL release. Finally, 1 microM octreotide significantly inhibited forskolin-stimulated cAMP production (by 29% and 53% on days 7 and 14 of culture, respectively). We conclude that 1) octreotide inhibits 7315b rat pituitary tumor cell proliferation via a pertussis toxin-sensitive GTP-binding protein- and adenylate cyclase-dependent mechanism; and 2) the number of SS receptors on 7315b pituitary tumor cells may determine whether octreotide exerts a direct antiproliferative effect, whereas its antihormonal effect occurs in the presence of relatively low numbers of SS receptors. This suggests a dissociation of the antiproliferative and antihormonal effects induced by octreotide.
Adenylate Cyclase Toxin↗
Somatostatin inhibits the activity of adenylate cyclase in cultured human meningioma cells and stimulates their growth.
It has been reported previously that most human meningiomas have receptors for somatostatin. Here we report the results of investigations of the effect of somatostatin and the somatostatin analog octreotide on the growth in vitro of human meningioma cells. Neither somatostatin nor its analog showed a direct growth inhibitory action on cultured human meningioma cells. Rather, there was a slight but significant stimulation of growth in the presence of somatostatin. The somatostatin receptors in meningioma tissue were shown to be functional since somatostatin inhibited forskolin-stimulated formation of cAMP by meningioma membranes. In addition, cAMP inhibited the growth of cultured meningioma cells. We conclude that the stimulation by somatostatin of the growth of human meningioma cells in vitro is caused by its inhibitory effect on cAMP formation. These results suggest that therapeutic trials of patients with (recurrent) inoperable meningiomas with somatostatin analogs have to be carried out with great caution.
Adenylyl Cyclase Inhibitors↗
In vitro and in vivo detection of somatostatin receptors in pheochromocytomas and paragangliomas.
Fifty-one adrenal pheochromocytomas and 14 paragangliomas were evaluated for somatostatin (SRIH) receptor content with in vitro autoradiography on tissue sections from surgically removed tumors, using iodinated 125I[Tyr]3 octreotide as radioligand. Thirty-seven of 51 pheochromocytomas were SRIH receptor positive (73%), as well as 13 of 14 paragangliomas (93%). These SRIH receptors were of high affinity, pharmacologically specific for SRIH and localized on the tumor tissue. Using in vivo imaging techniques with radiolabeled SRIH analogs, paragangliomas could be visualized in five patients, as well as pheochromocytomas in two of three patients. All tumors tested subsequently in vitro (n = 7) were shown to contain SRIH receptors. A majority of pheochromocytomas were also shown to have a high tumoral SRIH content as measured by immunohistochemical techniques. Detection of SRIH messenger RNA in pheochromocytomas by in situ hybridization indicated that the SRIH was produced in the tumors. A weak inverse correlation was observed between SRIH receptor status and tumoral SRIH content, suggesting that SRIH receptors may be down-regulated by high levels of endogenous SRIH in some tumors. There was no correlation between the SRIH receptor status and sex, age, tumor size, benign vs. malignant tumor, or urinary metanephrine excretion. These tumors were also analyzed for allelic losses on various chromosomes and showed significant loss of heterozygosity (LOH) on chromosomes 1p, 3p, 17p, and 22q. All eight tumors with LOH on chromosome 1p were SRIH receptor positive (100%), whereas only 6 of 11 tumors without LOH on 1p (55%) were SRIH receptor positive, suggesting a correlation between LOH on 1p and SRIH receptor positive status. SRIH receptors thus represent a consistent pathobiochemical marker for most of these adrenal and extra-adrenal tumors. In addition, these receptors may be of potential interest for the in vivo localization of these tumors.
Adrenal Gland Neoplasms↗
Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro.
We have studied seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary macroadenoma, four of whom received long term, high dose octreotide treatment. We have attempted to correlate the presence of somatostatin receptors (SS-R) in the adenomas and the outcome of octreotide treatment, as measured by tumor size, improvements in visual field defects, and hormonal response. The presence of SS-R in the pituitary adenomas was demonstrated in vivo using [111indium]octreotide scintigraphy and in vitro by autoradiography of tissue fragments obtained after transsphenoidal surgery. Adenomas from six of the seven subjects were SS-R positive. High dose (1200 micrograms, sc, daily) octreotide treatment was given to four subjects, three of whom were SS-R positive. Improvement of the visual field defects was observed in three of four patients (including the SS-R-negative subject), although no computed tomographic scan-assessed tumor size reduction was found. Two of four patients showed small but significant reductions in serum FSH concentrations (to 83% and 93% of initial values) with treatment. These in vivo responses to high dose octreotide treatment could not be predicted by pretreatment responses to 200 micrograms TRH or 100 micrograms octreotide. Tissue fragments for cell culture were obtained from six patients, and in vitro release of gonadotropins and/or alpha-subunit could be demonstrated in five cultures. In vitro, octreotide (10 nmol/L) significantly decreased gonadotropiin or subunit release in three of five cultures, whereas bromocriptine (10 nmol/L) significantly reduced the release in four of five cultures and to a significantly greater extent than octreotide. In conclusion, in six of seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary adenoma, SS-R were demonstrated in the tumor. In vitro incubation of adenoma cells with octreotide resulted in mild inhibition of gonadotropin or alpha-subunit release. Although in vivo long term treatment with high doses of octreotide did not result in substantial tumor size reduction, improvement of visual field defects was observed in three of four subjects.
Adenoma↗
Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide.
Scintigraphy with 123I-Tyr-3-octreotide has several major drawbacks as regards its metabolic behavior, its cumbersome preparation and the short physical half-life of the radionuclide. The use of another radiolabeled analog of somatostatin, 111In-DTPA-D-Phe-1-octreotide, has consequently been proposed. DTPA-D-Phe-1-octreotide can be radiolabeled with 111In in an easy single-step procedure. DTPA-D-Phe-1-octreotide is cleared predominantly via the kidneys. Fecal excretion of radioactivity amounts to only a few percent of the administered radioactivity. For the radiation dose to normal tissues, the most important organs are the kidneys, the spleen, the urinary bladder, the liver and the remainder of the body. The calculated effective dose equivalent is 0.08 mSv/MBq. Optimal 111In-DTPA-D-Phe-1-octreotide scintigraphic imaging of various somatostatin receptor-positive tumors was obtained 24 hr after injection. In the six patients studied, tumor localization with 123I-Tyr-3-octreotide and with 111In-DTPA-D-Phe-1-octreotide were found to be similar. However, the normal pituitary is more frequently visualized with the latter radiopharmaceutical. In conclusion, 111In-DTPA-D-Phe-1-octreotide appears to be a sensitive somatostatin receptor-positive tissue-seeking radiopharmaceutical with some remarkable advantages: easy preparation, general availability, appropriate half-life and absence of major interference in the upper abdominal region, because of its renal clearance. Therefore, 111In-DTPA-D-Phe-1-octreotide may be suitable for use in SPECT of the abdomen, which is important in the localization of small endocrine gastroenteropancreatic tumors.
Adult↗
Somatostatin analogs in the treatment of acromegaly.
Medical therapy of acromegaly with the somatostatin analog octreotide is very successful. Both clinical symptomatology and hormonal hypersecretion by the growth hormone-secreting pituitary adenomas are controlled, and peripheral IGF-I levels also return to near normal levels. Tumor shrinkage is observed in most patients. Somatostatin analogs can be used after noncurative surgery and for a limited period after radiotherapy, and octreotide pretreatment might improve the outcome of surgery.
Acromegaly↗
Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth.
The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.
Animals↗
In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats.
Radioiodinated somatostatin analogues are useful ligands for the in vitro and in vivo detection of somatostatin receptors. [111In-DTPA-D-Phe1]-octreotide, a somatostatin analogue labeled with a different radionuclide, also binds specifically to somatostatin receptors in vitro. In this study we investigated its in vivo application in the visualization of somatostatin receptor-positive tumors in rats. The distribution of the radiopharmaceutical was investigated after intravenous injection in normal rats and in rats bearing the somatostatin receptor-positive rat pancreatic carcinoma CA 20948. After injection the radiopharmaceutical was rapidly cleared (50% decrease in maximal blood radioactivity in 4 min), predominantly by the kidneys. Excreted radioactivity was mainly in the form of the intact radiopharmaceutical. Ex vivo autoradiographic studies showed that specific accumulation of radioactivity occurred in somatostatin receptor-containing tissue (anterior pituitary gland). However, in contrast to the adrenals and pituitary, the tracer accumulation in the kidneys was not mediated by somatostatin receptors. Increasing radioactivity over the somatostatin receptor-positive tumors was measured rapidly after injection and the tumors were clearly visualized by gamma camera scintigraphy. In rats pretreated with 1 mg octreotide accumulation of [111In-DTPA-D-Phe1]-octreotide in the tumors was prevented. Because of its relatively long effective half-life, [111In-DTPA-D-Phe1]-octreotide is a radionuclide-coupled somatostatin analogue which can be used to visualize somatostatin receptor-bearing tumors efficiently after 24 hr, when interfering background radioactivity is minimized by renal clearance. This is an advantage over the previously used [123I-Tyr3]-octreotide which has a shorter effective half-life and shows high abdominal interference due to its hepato-biliary clearance. Therefore, [111In-DTPA-D-Phe1]-octreotide seems a better alternative for scintigraphic imaging of somatostatin receptor-bearing tumors.
Animals↗
Progesterone, oestradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics.
The presence of progesterone, oestrogen, somatostatin and epidermal growth factor receptors of 24 meningiomas was related with their radiological CT appearance. Progesterone receptors were present in 16 of 21 (76%), oestrogen receptors in 4 of 21 (19%), somatostatin receptors on 23 of 24 (96%) and epidermal growth factor receptors on 17 of 19 (89%) meningiomas. There was no relationship between the presence of these receptors and the age or sex of the patients, tumour histology, tumour localisation, the presence of perifocal oedema, displacement of the midline cerebri or obstructive hydrocephalus on CT scan. There was a negative correlation (P less than 0.05) between the number of progesterone receptors and "malignant" behaviour of the meningiomas on CT (e.g. the presence of necrosis, cyst formation, intratumoral haemorrhage, irregular surface and/or inhomogeneous attenuation of contrast). The observation that aggressive tumour behaviour on CT is accompanied by low numbers or absence of progesterone receptors makes these meningiomas less attractive candidates for medical therapy with antiprogestins.
ErbB Receptors↗
Specific binding of cholecystokinin, estradiol and somatostatin to human pancreatic cancer xenografts.
We recently reported that human pancreatic cancers differentially respond to the growth inhibitory effects of an estradiol (E2) receptor antagonist, tamoxifen, and a long-acting analogue of somatostatin, Sandostatin. In the present study two human pancreatic cancers, established as xenografts in nude mice, were examined as representative of cancers that respond to either tamoxifen (PGER) or Sandostatin (SKI), for the presence of binding sites for various hormones. Male nude mice were inoculated with either SKI or PGER, by passage of tumor chunks (3 mm2) to the interscapular region. Tumors, obtained from mice after approximately 30 days of in vivo growth, were analyzed for binding to cholecystokinin-octapeptide (CCK), somatostatin and E2, by published procedures, using either crude tumor membranes (CCK), cytosol and nuclear fractions (E2), or cryostat sections of whole tumors (somatostatin). SKI was highly positive for high-affinity (Kd = approximately 1 nM) CCK binding sites at the time of resection with a binding capacity of approximately 1000 fmol/mg protein. With increasing passages, the total number of high-affinity binding sites for CCK, were reduced to non-detectable levels in SKI tumors, while non-saturable binding (Kd = greater than 10 nM) became increasingly evident. Early passages of PGER tumors were similarly positive for high-affinity binding sites for CCK, that steeply declined with increasing passages. Specific binding sites for E2, were observed only in the cytosolic fractions of PGER, with a high binding affinity (Kd = approximately 0.05 nM) and a low binding capacity (15 +/- 3 fmol/mg cytosolic proteins), at all passages examined; E2 binding sites were not detected in cytosolic and nuclear fractions of SKI and in the nuclei of PGER, at all passages. SKI and PGER at different passages were examined for somatostatin binding, and both the early and late passages of PGER were devoid of somatostatin binding sites, while SKI tumors were positive for them. Based on the above results, it appears likely that Sandostatin directly inhibited the growth of SKI tumors, since SKI was positive for somatostatin binding sites; it appears less likely that Sandostatin indirectly mediated its inhibition by attenuating possible stimulatory effects of CCK. Growth inhibitory effects of tamoxifen on PGER were apparently via E2 binding sites, since only the tumors positive for E2 binding sites (PGER) responded to tamoxifen; it remains to be determined if tamoxifen can exert additional effects independent of E2 binding sites on pancreatic cancers.(ABSTRACT TRUNCATED AT 400 WORDS)
Adenocarcinoma↗
Experimental and clinical studies with somatostatin analogue octreotide in small cell lung cancer.
We have detected somatostatin receptors (SSR) by autoradiography in 3/4 established small cell lung cancer (SCLC) cell lines but not in two non-SCLC cell lines. The growth of 1/3 SSR positive SCLC cell lines was significantly inhibited by the long-acting somatostatin analogue octreotide (SMS 201-995, Sandostatin) 10(-9) M. We treated 20 SCLC patients with octreotide 250 micrograms three times daily for 1 week prechemotherapy (six patients) or at relapse after chemotherapy (14). Octreotide was well tolerated, and serum insulin-like growth factor-I levels were suppressed to 62 +/- 7% of pre-treatment levels. However there was no evidence of anti-tumour activity measured by tumour bulk or serum levels of neuron-specific enolase. In one patient metastatic skin nodules were shown to be SSR positive before and at the end of 2 weeks octreotide. Despite this the patient had progressive disease, and tumour cells obtained by fine needle aspirate before and after treatment showed no growth inhibition when cultured with octreotide immediately or following establishment as a cell line. In summary we saw little correlation between SSR expression and growth inhibition by octreotide, either in vitro or clinically.
Animals↗
The role of somatostatin and its analogs in the diagnosis and treatment of tumors.
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Animals↗
In vitro and in vivo detection of somatostatin receptors in human 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 and brain tumors. 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 positive tumors are well differentiated and/or have neuroendocrine features. Among endocrine GEP tumors, more than 80% of carcinoids and 70-100% of islet cell carcinomas have a high density of SS-R. All their metastases are SS-R positive. Undifferentiated, atypical carcinoids are usually SS-R negative. SS-R are functional and mediate hormone secretion inhibition. SS-R positive tumors and metastases can easily be localised non-invasively in vivo by scanning techniques after 123I-SS analog injection.
Adenoma↗
In vivo use of a radioiodinated somatostatin analogue: dynamics, metabolism, and binding to somatostatin receptor-positive tumors in man.
Somatostatin analogues, labeled with gamma-emitting radionuclides, are of potential value in the localization of somatostatin receptor-positive tumors with gamma camera imaging. We investigated the application in man of a radioiodinated analogue of somatostatin, 123I-Tyr-3-octreotide, which has similar biologic characteristics as the native peptide. The radiopharmaceutical is cleared rapidly from the circulation (up to 85% of the dose after 10 min) mainly by the liver. Liver radioactivity is rapidly excreted into the biliary system. Until 3 hr after injection, radioactivity in the circulation is mainly in the form of 123I-Tyr-3-octreotide. Thereafter, plasma samples contain increasing proportions of free iodide. Similarly, during the first hours after injection, radioactivity in the urine exists mainly in the form of the unchanged peptide. Thereafter, a progressive increase in radioiodide excretion is observed, indicating degradation of the radiopharmaceutical in vivo. Fecal excretion of radioactivity amounts to only a few percent of the dose. The calculated median effective dose equivalent is comparable with values for applications of other 123I-radiopharmaceuticals (0.019 mSv/MBq).
Adult↗
Somatostatin receptors and somatostatin content in medullary thyroid carcinomas.
Human medullary thyroid carcinomas from 19 patients were analyzed for their content in somatostatin (SRIF) receptors using receptor autoradiography with a SRIF-28 analogue and the SRIF octapeptide [Tyr3]-SMS 201-995 as iodinated radioligands. Four out of 19 cases were SRIF receptor positive with the SRIF octapeptide radioligand. These cases as well as four additional tumors were also positive with the SRIF-28 radioligand 125I-[Leu8, D-Trp22, Tyr25]-SRIF-28. High affinity binding sites pharmacologically specific for bioactive SRIF analogues, specifically located on tumor tissue, were identified. In some cases the SRIF receptors were distributed in a non-homogeneous pattern, with labelling occurring preferentially in highly differentiated tumor regions. Numerous cases were shown to have a high tumoral SRIF content measured by radioimmunoassay or immunohistochemical technique. However, there was no correlation between SRIF receptor status and tumor levels of endogenous SRIF. No correlation was seen between the clinical outcome or the survival of the patients and their tumoral SRIF receptor content. Whereas some medullary thyroid carcinomas seem to be a target for SRIF, the SRIF function in these tumors remains unclear. SRIF receptors in a group of medullary thyroid carcinomas may be useful morphological marker of these tumors and of potential interest for their in vivo localization.
Autoradiography↗
Somatostatin receptors in differentiated ovarian tumors.
The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands, 125I-[Tyr11]-somatostatin-14, 125I-[Leu8, D-Trp22, Tyr25]-somatostatin-28, or 125I-[Tyr3]-SMS 201-995. Three cases, all belonging to epithelial tumors, were receptor positive; specifically 1 of 42 adenocarcinomas, 1 of 3 borderline malignancies, and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas, 1 Brenner tumor), 4 sex cord-stromal tumors (2 fibrothecomas, 2 granulosa cell tumors), and 2 germ cell tumors (1 dysgerminoma, 1 teratoma) were receptor negative. In the positive cases, the somatostatin receptors were localized on epithelial cells exclusively, were of high affinity (KD = 4.6 nmol/l [nanomolar]), and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide [Tyr3]-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors, therefore, was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands.
Adenocarcinoma↗