Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eighty-four carcinoids of the colon and rectum were studied with emphasis on prognostic features, immunohistochemical characteristics, and pitfalls in diagnosis. Follow-up data were available on 35 patients. Tumors with adenocarcinomatous components, or those resembling small cell carcinomas of the lung, were excluded. Eighty-one tumors were in the rectum and three tumors were in the distal sigmoid colon. Neuron-specific enolase, chromogranin, and Leu-7 were positive in 87%, 58%, and 53% of the tumors, respectively. Hormones were positive in the following percentages: serotonin, 45%; pancreatic polypeptide, 46%; glucagon, 10%; gastrin, 3%; somatostatin, 3%; adrenocorticotrophic hormone, 1%; cholecystokinin, 0%; calcitonin, 0%; and insulin, 0%. Many tumors elaborated more than one hormone. Fifty-five percent of the tumors were argyrophil and 28% were argentaffin. Carcinoembryonic antigen was present in 24% of the tumors; 82% of the tumors contained prostatic acid phosphatase. Three patients had liver metastases; their tumors ulcerated, invaded muscularis propria, and had more than 2 mitoses per 10 high-power fields (HPF). One patient with a 2.5-cm tumor without mitoses had regional lymph node metastases. All non-metastasizing tumors had less than one mitosis in 10 HPF. We conclude that large bowel carcinoid tumors are essentially limited to the rectum and sigmoid, that they are indolent if mitotically inactive and smaller than 2 cm, and that most show production of a selected group of endocrine markers.
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PMID:Rectal and colonic carcinoids. A clinicopathologic study of 84 cases. 229 59

Concentrations of seven neuropeptides have been determined in 69 human neurological tumours. The majority of tumours were intrinsic to the central nervous system, being astrocytomas. In general, within the the better differentiated tumours (Grade I/II astrocytomas) higher concentrations of five neuropeptides (neuropeptide Y, somatostatin, substance P, vasoactive intestinal peptide and cholecystokinin) were measured in comparison to the poorly differentiated tumours. Of the metastatic tumours, five were derived from oat cell carcinoma of the bronchus. Very high concentrations of bombesin were identified in these metastases.
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PMID:Neuropeptides in neurological tumours. 241 12

Using immunohistochemistry, well-preserved neuronal cell bodies and fibres containing neuropeptide Y, somatostatin, and cholecystokinin immunoreactivity have been identified in all seven supratentorial anaplastic astrocytomas studied. These neurones have been shown not only on the edge but also in the depth of the neoplastic tissue. These neuropeptides were not present in 18 other intracranial tumours (3 astrocytomas, 1 subependymoma, 8 glioblastoma multiformes, 1 meningioma, and 5 metastases). In all 25 intracranial tumours studied, no immunoreactivity was found for vasoactive intestinal polypeptide, substance P, methionine-enkephalin, leucine-enkephalin, synenkephalin, neurophysin I-II, and corticotropin releasing factor.
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PMID:Neuropeptide Y, somatostatin, and cholecystokinin neurone preservation in anaplastic astrocytomas. 290 6

Gallbladders removed at cholecystectomy are a potentially useful source of human receptor for the gastrointestinal peptide hormone cholecystokinin (CCK). Seven healthy gallbladders (removed incidentally at time of resection of hepatic metastases) and 50 diseased gallbladders were studied. Cholecystokinin radioligand binding to an enriched plasma membrane preparation from these tissues was shown to be rapid, reversible, temperature-dependent, saturable, specific, and high-affinity. Computer analysis of equilibrium binding data using the Ligand program best fit a single class of binding sites with Kd = 1.0 +/- 0.1 nM (mean +/- SEM). This was similar in health and disease, with no apparent differences related to age, gender, or body habitus. The structural specificity for binding to this site correlated well with relative potencies for CCK-gastrin peptides to stimulate gallbladder contraction. To biochemically characterize this receptor, we used a battery of reagents, including "long" (125I-Bolton Hunter-CCK-33) and "short" 125I-D-Try-Gly-[(Nle28,31)CCK-26-33] probes that were cross-linkable through their amino terminus and a monofunctional probe with a photolabile group at its carboxyl terminus 125I-D-Tyr-Gly[(Nle28,31,pNO2-Phe33)CCK-26-33]. All probes specifically labeled a human gallbladder muscularis protein of Mr = 85,000-95,000, which was also independent of diagnosis. Labeling of this band was inhibited in a concentration-dependent manner by CCK-8 and by L-364,718. Thus, the CCK receptor present on the very common surgically removed human gallbladder is functionally and biochemically intact and is useful for further characterization.
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PMID:Functional and biochemical characterization of the human gallbladder muscularis cholecystokinin receptor. 292 56

Decapeptide ceruletide (CRL), chemically related to cholecystokinin and gastrin, proved to have remarkable analgesic properties when administered to a group of 22 burned patients, 15 patients with acute myocardial infarction, and 8 patients suffering from pain caused by malignant tumours with metastases. Its effect was such, that many of the patients required no other analgesics (opiates) even after a prolonged administration (up to 10 days) of CRL. In some of the patients a marked euphoria developed. There were no substantial changes in EEG records during CRL administration in 15 controls, among them 4 epileptics. It is probable that CRL helps to activate the internal analgesic system. In the burned patients cortisol, testosterone, renin, prolactin and tri-iodothyronine (T3) levels in serum (plasma) were measured (radio-immunoassays). CRL did not block the stress response (no drop of increased cortisol levels, no increase in low T3 levels), but it modified (influenced) it (drop of the high renin levels, and a tendency to increase the very low testosterone levels). CRL appears to act as an endorphin releaser, as evidenced by the plasma levels of beta-endorphins (quotations). CRL and similar drugs may represent a new, more physiological and probably safer approach to the management of pain.
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PMID:Endorphin releasers: a new possible approach to the treatment of pain after burns--a preliminary report. 631 91

We report the histological, immunohistochemical and ultrastructural changes in mice containing a chimeric glucagon-simian virus 40 T antigen (SV40Tag) gene. Transgene expression was detected in endocrine cells of pancreas, small and large intestine. Hyperplasia of glucagon-containing cells developed in pancreas and large bowel by gestational day 19. In large bowel, hyperplastic cells increased in number postnatally and invasive carcinomas were identified at 4 weeks; several animals had lymph node metastases. In contrast, no pathology was detected in the small bowel in any of the transgenic mice. Colonic tumours expressed SV40Tag, proglucagon-derived peptides and peptide YY (PYY); scattered cells contained cholecystokinin or glycoprotein hormone alpha-subunit. Somatostatin or serotonin was also detected in some tumours. By electron microscopy, the colonic tumours retained features of endocrine differentiation, but secretory granules were smaller than those of non-tumorous intestinal glucagon-producing L cells. In postnatal pancreas, atypical cells containing SV40Tag and glucagon were initially clustered at the periphery of islets; this atypical hyperplasia progressed to neoplasia by 11-12 weeks. Some neoplastic pancreatic cells contained glucagon, PYY or vasoactive intestinal peptide immunopositivity, but most were negative for all peptides; they contained immunoreactivity for tyrosine hydroxylase and by electron microscopy, pancreatic tumour cells had neuronal features. Pancreatic polypeptide was not detected in the non-tumorous islets of transgenic animals. This line of transgenic mice provides a model for the analysis of endocrine tumour progression in the gut and pancreas.
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PMID:Development of colonic and pancreatic endocrine tumours in mice expressing a glucagon-SV40 T antigen transgene. 860 71

The expression of cholecystokinin (CCK) and gastrin (G) receptors in human gastrointestinal cancers remains poorly documented and is still of a controversial nature. We have measured the levels of mRNA for CCK-A and CCK-B/gastrin receptors using quantitative reverse transcription-polymerase chain reaction (RT-PCR) in primary digestive cancers and hepatic metastases. CCK-A-receptor mRNA was detected in 5 out of 8 esophageal cancers (0.1-1 fg/microg), in 5 out of 8 gastric cancers (0.05-4.2 fg/microg) and in 5 out of 12 colon cancers (0.1-1 fg/microg RNA). CCK-B/gastrin mRNA was not detected in esophageal cancers but was detected in 7 out of 8 gastric cancers (0.05-5.2 fg/microg), and in only 2 out of 12 colon adenocarcinomas (0.05-1 fg/microg RNA). The expression of the CCK-A receptor in esophageal, gastric and colon cancers and of the CCK-B/gastrin receptor in the majority of gastric adenocarcinomas screened may be an important indicator of the influence of CCK and gastrin of local or systemic origin on the growth of these cancers.
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PMID:Differential expression of the CCK-A and CCK-B/gastrin receptor genes in human cancers of the esophagus, stomach and colon. 937 53

Receptors for gastrin and cholecystokinin have been shown to be expressed in several types of human cancers. CCK-B receptors for instance have been identified in several types of neuroendocrine tumors. One of the highest incidences of CCK-B receptors has been reported in medullary thyroid cancers at the protein and at the mRNA level using in vitro receptor autoradiography and RT-PCR. It is likely that these receptors mediate the stimulation of calcitonin secretion from neoplastic C-cells by pentagastrin, a well established clinical test to detect occult medullary thyroid cancers. In order to target these tumors in vivo in patients, several peptide radiopharmaceuticals such as DTPA-linked minigastrins or non-sulfated CCK-8 analogs radiolabeled with 111Indium or 90Yttrium have recently been developed. As a proof of concept, it could be demonstrated that a majority of medullary thyroid cancer primary tumors and metastases are visualized in vivo with CCK-B receptor scintigraphy using these radioligands. More recently, radiotherapy of CCK-B receptor expressing medullary thyroid cancers with radiolabeled minigastrin has been successfully reported in a small number of patients, giving support to the proposal that CCK-B receptors overexpressed in tumors represent a useful target for clinical application.
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PMID:CCK receptors in human neuroendocrine tumors: clinical implications. 1171 69

The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic medullary thyroid cancer (MTC) suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs, but also in a high percentage of small-cell lung cancers, stromal ovarian tumors, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK-receptor binding tetrapeptide sequence-Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor to nontumor ratios were obtained with members of the gastrin family, because of their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivates of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 45 MTC patients with metastatic MTC were investigated; 23 had known and 22 had occult disease. CCK-B receptor scintigraphy was performed with (111)In-diethylenetriamine pentaacetic acid-d-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and, to a lesser extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding and to the kidneys, as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 hour postinjection, with increasing tumor to background ratios over time; at least 1 lesion was detected in 20 of 22 patients with occult disease (patient-based sensitivity, 91%). Among them were local recurrences and lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4 to 6-week intervals (30-50 mCi/m(2) per injection for a maximum of 4 injections). Hematologic and renal toxicities were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, and 4 experienced stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor-binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.
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PMID:Cholecystokinin-B/Gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies. 1196 5

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides. Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene-triamine-pentaacetate (DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin- or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivatives of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.
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PMID:Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. 1265 27


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