cholecystokinin and Neoplasms

Cholecystokinin (CCK) is a classic gut hormone. CCK is also a complex system of peptides expressed in several molecular forms in enteroendocrine I cells, in cerebral and peripheral neurons, in cardiac myocytes and spermatozoa. CCK gene expression has now been found at protein or peptide level in different neuroendocrine tumors; cerebral gliomas and astrocytomas and specific pediatric tumors. Tumor hypersecretion of CCK was recently reported in a patient with a metastatic islet cell tumor and hypercholecystokininemia resulting in a novel tumor syndrome, the cholecystokininoma syndrome. This review presents an overview of the cell-specific biogenesis of CCK peptides, and a description of the CCK expression in tumors and of the cholecystokininoma syndrome. Finally, assays for the diagnosis of CCK-producing tumors are reviewed.

Topics: Biomarkers, Tumor; Cell Proliferation; Cholecystokinin; Gene Expression Regulation, Neoplastic; Humans; Multigene Family; Neoplasms; Prognosis; Protein Binding; Protein Processing, Post-Translational; Protein Transport; Receptors, Cholecystokinin; RNA, Messenger

Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [(111)In-DOTA]MG11 ([((111)In-DOTA)DGlu(10)]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients.

Topics: Animals; Carcinoma, Neuroendocrine; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Glycopeptides; Humans; Kidney; Kidney Neoplasms; Ligands; Mice; Mice, SCID; Models, Chemical; Neoplasm Transplantation; Neoplasms; Neprilysin; Peptides; Radiopharmaceuticals; Receptor, Cholecystokinin B; Thyroid Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The (111)In-labelled somatostatin analogue octreotide (OctreoScan) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours.

Topics: Animals; Bombesin; Cholecystokinin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Ligands; Neoplasms; Octreotide; Pentetic Acid; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Receptor, Cholecystokinin B; Receptors, Bombesin; Receptors, Cholecystokinin; Receptors, CXCR4; Receptors, Glucagon

Nuclear medicine techniques are becoming more important in imaging oncological and infectious diseases. For metabolic imaging of these diseases, antibody and peptide imaging are currently used. In recent years peptide imaging has become important, therefore the rationale for the use of peptide imaging is described in this article. Criteria for a successful peptide tracer are a high target specificity, a high binding affinity, a long metabolic stability and a high target-to-background ratio. Tracer internalization is also beneficial. For oncological imaging, many tracers are available, most originating from regulatory peptides, but penetrating peptides are also being developed. Peptides for imaging inflammatory and infectious diseases include regulatory peptides, antimicrobial peptides and others. In conclusion, for the imaging of oncological, imflammatory and infectious diseases, many promising peptides are being developed. The ideal peptide probe is characterized by rapid and specific target localization and binding with a high tumour-to-background ratio.

Topics: Antimicrobial Cationic Peptides; Bombesin; Cholecystokinin; Gastrin-Releasing Peptide; Glucagon-Like Peptide 1; Humans; Infections; Inflammation; Isotope Labeling; Neoplasms; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Somatostatin; Vasoactive Intestinal Peptide

Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH(2) in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides.

Topics: Animals; Cholecystokinin; Gastrins; Humans; Isotope Labeling; Neoplasms; Radioisotopes; Radionuclide Imaging; Receptor, Cholecystokinin B

The singular gene for a peptide hormone is expressed not only in a specific endocrine cell type but also in other endocrine cells as well as in entirely different cells such as neurons, adipocytes, myocytes, immune cells, and cells of the sex-glands. The cellular expression pattern for each gene varies with development, time and species. Endocrine regulation is, however, based on the release of a given hormone from an endocrine cell to the general circulation from whose cappilaries the hormone reaches the specific target cell elsewhere in the body. The widespread expression of hormone genes in different cells and tissues therefore requires control of biogenesis and secretion in order to avoid interference with the function of a specific hormonal peptide from a particular endocrine cell. Several mechanisms are involved in such control, one of them being cell-specific processing of prohormones. The following pages present four examples of such cell-specific processing and the implications of the phenomenon for the use of peptide hormones as markers of diseases. Notably, sick cells - not least the neoplastic cells - often process prohormones in a manner different from that of the normal endocrine cells.

Topics: Animals; Cholecystokinin; Endocrine System; Gastrins; Gene Expression Regulation; Hormones; Humans; Models, Biological; Neoplasms; Neurotensin; Peptides; Proglucagon; Protein Precursors; Signal Transduction

The use of peptides as targeting tools has been validated in different applications. In particular radiolabelled peptides with adequate stability, receptor-binding properties and biokinetic behaviour have been investigated as an important class of radiopharmaceuticals for cancer pathology imaging and therapy. This review focuses on recent progress in design and synthetic modifications of small biologically active peptides used in diagnosis and therapy. In particular, we report the current development and optimization of suitable peptides for targeting three relevant biological receptors (CCK, somatostatin, and integrin receptors) involved in specific tumour diseases.

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Drug Delivery Systems; Humans; Integrins; Molecular Sequence Data; Neoplasms; Peptides; Radiopharmaceuticals; Receptors, Cholecystokinin; Receptors, Somatostatin; Somatostatin

The accurate assessment of pain is needed to control cancer pain and its treatment. Pain itself is subjective experience and is difficult to estimate quantitatively. Until now, there is no precise method to quantitate the cancer pain objectively. First, we show the tools to assess cancer pain by patient's description, including visual analogue scales, verval rating scales and numerical rating scales and so on. These scales have been used to evaluate the intensity of clinical pain, however they cannot assess the quality of cancer pain and only McGill Pain Questionnaire (MPQ) has specificity for the qualitative and quantitative properties of clinical pain. Molecular biological approach has been advanced in the neuroscience field to find the candidate of neuropathic pain. In this article, we would like to show the results of the proteomics research for neuropathic pain. We also tried to discuss about the biomarker and its possibility whether it can reflect cancer pain and effect of cancer treatment.

Topics: Animals; beta-Endorphin; Biomarkers; Cholecystokinin; Cytokines; Humans; Neoplasms; Oxidative Stress; Pain; Pain Measurement

Regulatory peptide receptors are overexpressed in numerous human cancers. These receptors have been used as molecular targets by which radiolabeled peptides can localize cancers in vivo and, more recently, to treat cancers with peptide receptor radiation therapy (PRRT). This review describes the candidate tumors eligible for such radiotherapy on the basis of their peptide receptor content and discusses factors in PRRT eligibility. At the present time, PRRT is performed primarily with somatostatin receptor- and cholecystokinin-2 (CCK2)-receptor-expressing neuroendocrine tumors with radiolabeled octreotide analogs or with radiolabeled CCK2-selective analogs. In the future, PRRT may be extended to many other tumor types, including breast, prostate, gut, pancreas, and brain tumors, that have recently been shown to overexpress several other peptide receptors, such as gastrin-releasing peptide-, neurotensin-, substance P-, glucagon-like peptide 1-, neuropeptide Y-, or corticotropin-releasing factor-receptors. A wide range of radiolabeled peptides is being developed for clinical use. Improved somatostatin or CCK(2) analogs as well as newly designed bombesin, neurotensin, substance P, neuropeptide Y, and glucagon-like peptide-1 analogs offer promise for future PRRT.

Topics: Animals; Biomarkers, Tumor; Bombesin; Cholecystokinin; Clinical Trials as Topic; Drug Delivery Systems; Drug Evaluation, Preclinical; Humans; Neoplasms; Peptides; Practice Guidelines as Topic; Practice Patterns, Physicians'; Radioisotopes; Radiopharmaceuticals; Receptors, Peptide; Somatostatin; Substance P; Treatment Outcome

Gastrin, produced by G cells in the gastric antrum, has been identified as the circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that has been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of enterochromaffin-like cells, and neoplastic transformation. Here, we review the models used to study the effects of gastrin on cell proliferation in vivo and in vitro with respect to mechanisms by which this hormone might influence normal and cancerous cell growth. Specifically, human and animal models of hypergastrinemia and hypogastrinemia have been described in vivo, and several cells that express cholecystokinin (CCK)B/gastrin receptors have been used for analysis of intracellular signaling pathways initiated by biologically active amidated gastrins. The binding of gastrin or CCK to their common cognate receptor triggers the activation of multiple signal transduction pathways that relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades, including mitogen-activated protein kinase, is an important early response to these signaling peptides. Gastrin and CCK also induce rapid Rho-dependent actin remodeling and coordinate tyrosine phosphorylation of cellular proteins including the non-receptor tyrosine kinases p125fak and Src and the adaptor proteins p130cas and paxillin. This article reviews recent advances in defining the role of gastrin and CCK in the control of cell proliferation in normal and cancer cells and in dissecting the signal transduction pathways that mediate the proliferative responses induced by these hormonal GI peptides in a variety of normal and cancer cell model systems.

Topics: Animals; Cholecystokinin; Gastrins; Humans; Neoplasms; Signal Transduction

Topics: Amino Acid Sequence; Cholecystokinin; Gastrins; Gastrointestinal Diseases; Mental Disorders; Molecular Sequence Data; Neoplasms; Receptors, Cholecystokinin; Structure-Activity Relationship

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Gastrins; Humans; Molecular Sequence Data; Neoplasms; Protein Processing, Post-Translational; Receptors, Cholecystokinin

Studies of the cell-specific processing of neuroendocrine peptides have shown that neuroendocrine cells occasionally fail to mature the biosynthetic precursors to bioactive peptides, or that they do so to a negligible extent only. Instead, inactive precursors and processing intermediates accumulate in the cells. Thus, the expression of genes encoding hormonal peptides is in certain cells and under certain conditions attenuated at the postranslational level. The exact molecular mechanisms of posttranslational attenuation are still largely unknown. The review emphasizes that posttranslational attenuation may play a significant role during normal cell differentiation and in the carcinogenic transformation of cells. The existence of postal attenuation may play a significant role during normal cell differentiation and in the carcinogenic transformation of cells. The existence of post-translational attenuation has significant biological and clinical implications.

Topics: Age Factors; Amino Acid Sequence; Animals; Cholecystokinin; Gastrins; Gene Expression Regulation; Molecular Sequence Data; Neoplasms; Neuropeptides; Protein Processing, Post-Translational

Information concerning GEP hormones has progressively advanced since the initial discovery of a GEP hormone, secretin, in 1902. Studies in this area flourished with the advent of radioimmunoassay, and have provided an understanding of the secretion, regulation, metabolic actions, and role in certain diseases of major GEP hormones. Measurement of GEP hormones has achieved importance in clinical medicine and allowed understanding of the pathophysiology of several clinical disorders. The decade to come should witness additional advances in this rapidly expanding field.

Topics: Chemical Phenomena; Chemistry; Cholecystokinin; Diabetes Mellitus; Diarrhea; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypoglycemia; Motilin; Neoplasms; Neurotensin; Pancreatic Polypeptide; Peptic Ulcer; Secretin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Cholecystokinin; Gastric Juice; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Precancerous Conditions; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Alkaline Phosphatase; Bone and Bones; Cholecystokinin; Dietary Fats; Electrophoresis, Polyacrylamide Gel; Female; Humans; Intestinal Absorption; Intestine, Small; Isoenzymes; Kinetics; Liver Diseases; Molecular Weight; Neoplasms; Phenotype; Placenta; Polyethylene Glycols; Pregnancy; Radioimmunoassay; Secretin; Subcellular Fractions; Urea

Gastrointestinal tract function and it's integrity are controlled by a number of peptides whose secretion is influenced by severe inflammation. In stomach the main regulatory peptide is ghrelin. For upper small intestine cholecystokinin and lower small intestine glucagon-like peptide- 1 are secreted, while fibroblast growth factor-21 is secreted by several organs, including the liver, pancreas, and adipose tissue [12]. Hematopoietic stem cell transplantation causes serious mucosal damage, which can reflect on this peptides.. The aim of the study was to determine fasting plasma concentrations of ghrelin, cholecystokinin, glucagon- like peptide-1, and fibroblast growth factor-21, and their gene expressions, before and 6 months after hematopoietic stem cell transplantation.27 children were studied, control group included 26 healthy children.. Acute graft versus host disease was diagnosed in 11 patients (41%, n = 27). Median pre-transplantation concentrations of gastrointestinal peptides, as well as their gene expressions, were significantly lower in studied group compared with the control group. Only median of fibroblast growth factor-21 concentration was near-significantly higher before stem cell transplantation than in the control group. The post-hematopoietic transplant results revealed significantly higher concentrations of the studied peptides (except fibroblast growth factor-21) and respective gene expressions as compare to pre transplant results. Median glucagone like peptide-1 concentrations were significantly decreased in patients with features of acute graft versus host disease. Moreover, negative correlation between glucagone like peptide-1 concentrations and acute graft versus host disease severity was found.. Increased concentrations and gene expressions of gastrointestinal tract regulation peptides can be caused by stimulation of regeneration in the severe injured organ. Measurement of these parameters may be a useful method of assessment of severity of gastrointestinal tract complications of hematopoietic stem cell transplantation.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Cholecystokinin; Female; Fibroblast Growth Factors; Gene Expression Regulation, Neoplastic; Ghrelin; Glucagon-Like Peptide 1; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Neoplasms; Severity of Illness Index

The cholecystokinin (CCK) receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose)-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK) and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2) (DOTA-[Nle]-cCCK), were synthesized and radiolabeled with (177)Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for (177)Lu-labeling, in which the peptides were radiolabeled with (177)Lu by a high radiolabeling yield. A competitive displacement of (125)I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50) was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that (177)Lu-DOTA-[Nle]-cCCK has higher binding affinity than (177)Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors.

Topics: Animals; Cell Line, Tumor; Cholecystokinin; Heterografts; Humans; Lutetium; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Pancreatic Neoplasms; Peptides, Cyclic; Protein Binding; Radioisotopes; Radioligand Assay; Receptors, Cholecystokinin

In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor-mediated uptake (p  =  .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.

Topics: Animals; Binding, Competitive; Cell Line, Tumor; Cholecystokinin; Chromatography, High Pressure Liquid; Coordination Complexes; Drug Screening Assays, Antitumor; Gastrins; Inhibitory Concentration 50; Male; Mice; Mice, Nude; Neoplasms; Peritoneal Neoplasms; Positron-Emission Tomography; Rats; Receptor, Cholecystokinin B; Subcutaneous Tissue; Tissue Distribution

Radiolabeled cholecystokinin-8 (CCK8) peptide analogues can be used for peptide receptor radionuclide imaging and therapy for tumors expressing CCK2/gastrin receptors. Earlier findings indicated that sulfated CCK8 (sCCK8, Asp-Tyr(OSO(3)H)-Met-Gly-Trp-Met-Asp-Phe-NH(2)) may have better characteristics for peptide receptor radionuclide therapy (PRRT) than gastrin analogues. However, sCCK8 contains an easily hydrolyzable sulfated tyrosine residue and two methionine residues which are prone to oxidation. Here, we describe the synthesis of stabilized sCCK8 analogues, resistant to hydrolysis and oxidation. Hydrolytic stability was achieved by replacement of the Tyr(OSO(3)H) moiety by a robust isosteric sulfonate, Phe(p-CH(2)SO(3)H). Replacement of methionine by norleucine (Nle) or homopropargylglycine (HPG) avoided undesired oxidation side-reactions. The phenylalanine analogue Phe(p-CH(2)SO(3)H) of l-tyrosine, synthesized by a modification of known synthetic routes, was incorporated in three peptides: sCCK8[Phe(2)(p-CH(2)SO(3)H),Met(3,6)], sCCK8[Phe(2)(p-CH(2)SO(3)H),Nle(3,6)], and sCCK8[Phe(2)(p-CH(2)SO(3)H),HPG(3,6)]. All peptides were N-terminally conjugated with the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) and radiolabeled with In-111. In vitro binding assays on CCK2R-expressing HEK293 cells revealed that all three peptides showed specific binding and receptor-mediated internalization, with binding affinity values (IC(50)) in the nanomolar range. In vitro oxidation studies demonstrated that peptides with Nle or HPG indeed were resistant to oxidation. In vivo targeting studies in mice with AR42J tumors showed that tumor uptake was highest for (111)In-DOTA-sCCK8 and (111)In-DOTA-sCCK8[Phe(2)(p-CH(2)SO(3)H),Nle(3,6)] (4.78 +/- 0.64 and 4.54 +/- 1.15%ID/g, respectively, 2 h p.i.). The peptide with the methionine residues replaced by norleucine ((111)In-DOTA-sCCK8[Phe(2)(p-CH(2)SO(3)H), Nle(3,6)]) showed promising in vivo characteristics and will be further investigated for radionuclide imaging and therapy of CCK2R-expressing tumors.

Topics: Animals; Cholecystokinin; Female; Humans; Indium Radioisotopes; Isotope Labeling; Mice; Mice, Inbred BALB C; Molecular Structure; Neoplasms; Organometallic Compounds; Oxidation-Reduction; Peptide Fragments; Rats; Receptor, Cholecystokinin B; Stereoisomerism; Tissue Distribution

Anorexia is a noxious symptom, and over half of patients with advanced cancer experience it. Neuropeptide Y (NPY), leptin, and cholecystokinin 8 (CCK8) have been implicated.. This exploratory study 1) compared circulating concentrations of NPY and leptin between anorectic cancer patients and historic controls and 2) explored whether NPY, leptin, or CCK8 may serve as correlates of anorexia severity. Cancer patients met predefined eligibility criteria: 1) weight loss > or = 2.3 kg over the preceding 2 months and/or a physician-estimated caloric intake of < 20 calories per kilogram of body weight per day and 2) patient acknowledgment that appetite or weight loss was an ongoing problem.. Seventy-three cancer patients were studied, and > 90% reported a > or = 50% decline in appetite from baseline in the preceding 2 months. NPY levels were lower than control values: mean +/- standard deviation, 466 pg/mL +/- 161 pg/mL versus 560 pg/mL +/- 151 pg/mL, respectively (P = 0.004). Because a few (but not all) earlier studies suggested an age-related decline in NPY levels, a subgroup analysis was performed and found no age-adjusted difference in NPY levels between groups. Similarly, leptin concentrations were not different between groups. Significant correlations were not observed between anorexia severity and NPY, leptin, or CCK8 levels.. There were no differences in leptin and CCK8 levels between anorectic cancer patients and historic controls. Circulating concentrations of NPY, leptin, and CCK8 did not correlate with anorexia severity. However, the current results suggest a need for further examination of NPY in cancer-associated anorexia.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Cholecystokinin; Female; Humans; Leptin; Male; Middle Aged; Neoplasms; Neuropeptide Y; Peptide Fragments

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.

Topics: Animals; Autoradiography; Cholecystokinin; Female; Humans; Indium Radioisotopes; Neoplasms; Pentetic Acid; Radioligand Assay; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Tissue Distribution

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.

Topics: Autoradiography; Breast Neoplasms; Carcinoma, Small Cell; Cholecystokinin; Female; Gastrins; Humans; Lung Neoplasms; Neoplasms; Neuroendocrine Tumors; Ovarian Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Thyroid Neoplasms

In order to develop a processing-independent analysis for procholecystokinin (proCCK) and its products, antibodies were raised against the synthetic fragment 62-71 of human proCCK. All rabbits (n = 8) responded to the immunization. One (No. 89,009) produced antibodies of particularly high titer (1:350,000), homogeneity (Sips' index approximately 1.0) and binding affinity (K0 eff approximately 0.88 x 10(12) l/mol). A radioimmunoassay using this antiserum and [125I]tyrosine-extended fragment 62-71 measured the total CCK mRNA product after tryptic cleavage at Lys61 in normal and neoplastic tissue independent of the degree of precursor processing. In addition to previously known CCK producing tumors, CCK was found also in a thoracic round-cell tumor (Askin tumor) and in brain tumors (gliomas and astrocytomas). These tumors processed proCCK poorly. Thus, they contained 11 and 23 (mean n = 5) pmol/g of proCCK and its products before, versus 71 and 99 (mean) pmol/g after tryptic cleavage, respectively. Accordingly, gel chromatography revealed significant amounts of unprocessed proCCK, large molecular forms of glycine-extended CCKs and the well-known carboxyamidated and tyrosine O-sulfated bioactive CCK-83, -58, -33, -22 and -8. We conclude that monospecific antibodies directed against the N-terminus of sequence 62-71 of human proCCK are suitable for processing-independent analysis (PIA) for proCCK and its products. Moreover, we suggest that such PIA should be used for quantitation of CCK gene expression at peptide level in normal tissue and tumors.

Topics: Amino Acid Sequence; Animals; Antibodies; Antibody Specificity; Cholecystokinin; Dogs; Gene Expression; Humans; Iodine Radioisotopes; Molecular Sequence Data; Neoplasms; Peptide Fragments; Protein Precursors; Radioimmunoassay; RNA, Messenger; Sequence Homology

The presence of 3 different neuropeptide mRNAs with a strict cell-specific expression in vivo was investigated in 13 tumor cell lines from neuroendocrine and in 23 tumor cell lines from non-neuroendocrine origin. Northern blots showed no expression of mRNA for vasopressin (VP) in the 36 tested cell lines. Very low oxytocin (OT) mRNA hybridization signals were detected in the rat pituitary tumor cell line GH4C2 and the rat pancreas tumor cell line RIN5. Both the rat pituitary tumor cell line AtT-20 and the human myeloid leukemia cell line K562, contained proopiomelanocortin (POMC) mRNA. The low incidence of VP, OT and POMC gene expression in the tested tumor cell lines was not influenced by treatments inducing differentiation. In contrast, the cholecystokinin (CCK) gene which is widely present in nervous and endocrine systems was abundantly expressed in the human primitive neuroepithelioma cell line SK-N-MC and its clonal derivative SK-N-MC-IX-C. The results indicate that the expression of neuropeptide genes is very rare in tumor cell lines. The lack of expression in undifferentiated cells agrees with the appearance of expression after day 13 of the embryogenesis when maturation of neurons begins.

Topics: Animals; Blotting, Northern; Cell Differentiation; Cholecystokinin; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasms; Neoplasms, Experimental; Neoplasms, Nerve Tissue; Neuropeptides; Oxytocin; Paraneoplastic Endocrine Syndromes; Pro-Opiomelanocortin; Rats; RNA, Messenger; RNA, Neoplasm; Swine; Tumor Cells, Cultured; Vasopressins

We have examined a wide range of cultured human tumor cell lines and found that a specific subset of tumors expresses the cholecystokinin (CCK) gene. All neuroepitheliomas (eight) and Ewing sarcoma (eight) cell lines that were tested express CCK RNA. In addition, two of six rhabdomyosarcoma cell lines also express the CCK gene, suggesting that rhabdomyosarcomas are probably heterogenous and that a subset may be similar to Ewing sarcoma and neuroepithelioma. Very few of the positive tumors express completely processed immunoreactive CCK. However, we have used a radioimmunoassay that detects the CCK precursor to demonstrate synthesis of CCK precursor-like peptides by all of the Ewing sarcoma and neuroepithelioma lines that were tested and by the rhabdomyosarcoma cell line that expresses CCK mRNA. These data demonstrate a consistent association of CCK gene expression with a specific group of human neoplasms. The data also add credence to the theory that Ewing sarcoma and neuroepithelioma are derived from the same transformed cell type. Finally, our results suggest that CCK gene expression may serve as a marker to distinguish these tumors, which are considered to be small-round-cell tumors of childhood, from other pediatric tumors.

Topics: Cholecystokinin; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Molecular Weight; Neoplasm Proteins; Neoplasms; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured

Populations eating low-fat or low-fat, high-fiber diets have lower mortality rates for many cancers and coronary heart disease. The importance of nutrient composition in the lumen on absorption and on function of the gastrointestinal tract as a factor in the development of these diseases has not been studied. We investigated the plasma levels of gut-CNS peptide hormones in lean and obese Dutch women fed a high-fat meal and administered cholecystokinin (CCK). After a high-fat meal the increase in plasma CCK was similar in lean and obese women. CCK administration significantly decreased insulin release in lean and obese women, decreased glucagon release in obese women, but caused a rapid increase in plasma glucagon in lean women. Although the CCK response was similar to a fat meal in lean and obese women, differences in the control of peptide hormone release occurred in response to fat meals and CCK administration.

Topics: beta-Endorphin; Cholecystokinin; Cholesterol; Coronary Disease; Diet; Diet, Vegetarian; Dietary Fiber; Female; Gastrins; Glucagon; Humans; Insulin; Lipids; Middle Aged; Neoplasms; Obesity; Risk Factors

The neurally programmed APUD-cells from ectodermal origin are of peculiar significance in two respects: 1. They represent the largest endocrine gland of the whole organism and the peptides, which are secreted by the different APUD-cells, exercise a great influence on most of the motoric and secretory processes within the whole gastrointestinal tract just as on many metabolic processes as demonstrated on the so-called "enteropancreatic axis". Neoplasias of these APUD-cells, the "Apudomes", give rise to peculiar clinical syndromes. Early diagnosis of an apudome can be reached today by radioimmunologic detection of high concentrations of the responsible peptide in the blood enabling us to initiate an effective therapy at least for some of the known apudomes. 2. Beyond that the APUD-cells and their corresponding peptides are representing the so-called "peptidergic" division of the nervous system which acts as third-line effector to modulate not only the actions of the autonomic division but also of each other. The given example of the modulating effect of substance P or of the endorphines on the perception of pain is only one single aspect of the broad functional spectrum of these neuropeptides. The discovery, that the very same peptide can be detected in endocrine cells as well as in neurones, has opened one of the most fascinating and provocative developments in biology of the present time and some surprising new details can be expected in the next future.

Topics: APUD Cells; Cholecystokinin; Hormones; Humans; Intestinal Diseases; Neoplasms; Nervous System Diseases; Neurotensin; Neurotransmitter Agents; Peptides; Substance P

Topics: Achlorhydria; APUD Cells; Apudoma; Carcinoid Tumor; Carcinoma; Cholecystokinin; Diarrhea; Endocrine System Diseases; Humans; Hypokalemia; Malignant Carcinoid Syndrome; Neoplasms; Pancreatic Diseases; Paraganglioma; Paraneoplastic Endocrine Syndromes; Peptides; Prostaglandins E; Somatostatin; Syndrome; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Topics: Animals; Anura; Bombesin; Cholecystokinin; Dogs; Gastrins; Gastrointestinal Hormones; Glucagon; Guinea Pigs; Humans; Neoplasms; Neurosecretory Systems; Secretin

Topics: Animals; Cholecystokinin; Digestive System; Gastrins; Gastrointestinal Hormones; Haplorhini; Humans; Neoplasms; Papio; Peptides; Radioimmunoassay; Secretin