gastrins and Lung-Neoplasms

Helicobacter pylori (Hp) is one of the most common bacteria infecting humans. Recently, certain extragastric manifestations, linked to Hp infection, have been widely investigated, suggesting that Hp infection might be a 'systemic' disease. Accumulating, yet limited, evidence points to a potential association between Hp infection and lung cancer risk. Epidemiologic studies have shown that odds ratios (estimated relative risks) of lung cancer with Hp infection range from 1.24 to 17.78 compared with the controls, suggesting an increased lung cancer risk in the population exposed to Hp infection although far from supporting a causal relationship between Hp and lung cancer. Many studies have demonstrated the existence of Hp in the mucosa of the upper respiratory tract with no direct evidence of Hp-localization in lung tissue in the published literatures, rendering the possible functional mechanism underlying the association an open question. We followed the classic hypothesis-generating path, where we have thoroughly reviewed the publications on lung cancer and Hp infection from serological association to possible mechanisms as: (i) p130cas activated by Src kinase following Hp-host communication and p130cas-related carcinogenesis as in various malignancies; and (ii) gastroesophageal reflux and inhalation of urease or gastrin, which are Hp-related carcinogenic factors and present in lung tissues. We propose rigorous investigations regarding the Hp-lung cancer association and, if confirmed, the mechanisms of Hp infection leading to lung cancer development and progression. Clarification on Hp-lung cancer association is important for the understanding of lung cancer beyond tobacco-smoking-related carcinogenesis.

Topics: Antigens, Bacterial; Bacterial Proteins; Crk-Associated Substrate Protein; Gastric Mucosa; Gastrins; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Lung Neoplasms; Odds Ratio; Stomach; Urease

Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lu

Topics: Animals; Bombesin; Carcinoma, Small Cell; Cholecystokinin; Colonic Neoplasms; ErbB Receptors; Gastrins; Humans; Lung Neoplasms; Mice; Neuropeptides; Neurotensin; Pancreatic Neoplasms; Phosphorylation; Protein Kinase C; Receptors, Leukotriene B4; Receptors, Purinergic P2; rho GTP-Binding Proteins; Signal Transduction; Swiss 3T3 Cells

Topics: Amino Acid Sequence; Animals; Base Sequence; Calcium; Carcinoma, Small Cell; Cell Division; Cholecystokinin; Clone Cells; Cloning, Molecular; Dogs; Gastrins; Gene Expression; Humans; Lung Neoplasms; Mice; Molecular Sequence Data; Rats; Receptors, Cholecystokinin; Sequence Homology, Amino Acid; Transfection; Tumor Cells, Cultured

As we expand our knowledge of the initiators and promoters of lung cancer, early detection and intervention strategies show great potential in individuals at high risk, especially smokers and exsmokers. Documented mutations of dominant oncogenes and tumor suppressor genes in human lung cancer cells may represent important steps in the pathogenesis of invasive cancer. The precise molecular events and their sequence that lead to tumor promotion in lung cancer, however, are less well understood. Chemointervention with agents like the retinoids may halt proliferation of cancer cells prior to the development of metastatic competence. Use of anti-growth-factor therapy and peptide hormone antagonists may also have a role in intervention approaches. This paper reviews present understanding of the initiation and promotion of lung cancer, as well as preventive strategies currently proposed for patients at risk.

Topics: Carcinogens; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Genes, ras; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Oncogenes; Peptides; Protein Processing, Post-Translational; Retinoids; Smoking; Tumor Cells, Cultured

Several families of very potent bombesin (Bn) receptor antagonist analogues have recently been developed and their biological potencies evaluated in a number of in vitro systems including guinea pig and rat pancreatic acini and Swiss 3T3 cells. These studies showed that analogues can exhibit diverse properties ranging from full antagonists, partial agonists, or full agonists depending on the assay system and animal species employed. We have developed two classes of more potent, shorter chain antagonists based on [psi CH2NH(13-14)]Bn(6-14) and desMet14Bn(6-13)NH2 structures. [D-Phe6 psi Leu13-Leu14] Bn(6-14)NH2 was a potent antagonist (Ki 6nM) in Swiss 3T3 cells and guinea pig acini but exhibited 10% partial agonist activity and lower binding affinity (Ki 60 nM) in rat acini. The partial agonism could be eliminated by using p-Cl-Phe or D-Phe at the C-terminus and partially eliminated using D-4-Cl-Phe in position 6. With the antagonist [D-Phe6]Bn(6-13)NH2 (Ki 96 nM), alkyl substituents on the amide group increased affinity 25-fold with the propylamide being the most potent peptide (Ki 4 nM) in 3T3 cells or guinea pig acini. It did, however, have high 40% partial agonist activity in rat acini. Alkyl esters or hydrazide derivatives were, in contrast, pure antagonists in all systems tested with [D-Phe6]Bn(6-13)OMe having the highest affinity in all systems and also excellent in vivo properties. All of the potent antagonists examined had little affinity for neuromedin B--preferring bombesin receptors, which had entirely new ligand structure-activity relationships.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3T3 Cells; Amino Acid Sequence; Animals; Bombesin; Drug Design; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Mice; Molecular Sequence Data; Peptides

Topics: Adrenocorticotropic Hormone; Brain Neoplasms; Calcitonin; Carcinoma, Small Cell; Gastrins; Glucagon; Hormones; Humans; Insulin; Insulin Secretion; Lung Neoplasms; Prognosis; Prolactin; Vasopressins

Topics: Adrenocorticotropic Hormone; Calcitonin; Chorionic Gonadotropin; Endocrine System Diseases; Erythropoietin; Gastrins; Hormones, Ectopic; Humans; Insulin; Lung Neoplasms; Neoplasms; Serotonin; Thyrotropin; Vasopressins

Lung cancer is one of the most common cancer, there is a significant difference between the treatment and prognosis of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC tumor cells usually express neuroendocrine tumor (NET) markers, among which there are many studies on chromogranin A (CgA), synaptophysin (Syn), neuronspecific enolase (NSE) and pro-gastrin-releasing peptide (Pro-GRP) with SCLC. The levels of CgA, NSE and pro-GRP were related to the stage of SCLC, which were significantly higher in patients with extensive stage than in patients with limited stage, and their expression was significantly correlated with lower survival rate. Syn as an auxiliary diagnostic index of SCLC is more sensitive than CgA, and has high practical value in the differential diagnosis of SCLC and poorly differentiated squamous cell carcinoma; NSE is the most commonly used tumor marker in SCLC; Pro-GRP has stronger diagnostic advantages than CEA and NSE in distinguishing SCLC from NSCLC. Although these net markers are not specific markers of SCLC, their combined use with each others or combined with CT as an auxiliary diagnostic index may improve the level of differential diagnosis of SCLC, and they have a certain value in the staging of the disease, which is very important for the formulation of SCLC treatment strategy, their detection is conducive to the prevention and control of the disease.. 肺癌是常见的癌症之一，小细胞肺癌（SCLC）与非小细胞肺癌（NSCLC）在治疗和预后上有显著差异。SCLC的肿瘤细胞可表达一些神经内分泌肿瘤（NET）标志物，其中关于嗜铬粒蛋白A（CgA）与突触素（Syn）和神经元特异性烯醇化酶（NSE）及胃泌素释放肽前体（Pro-GRP）与SCLC的相关研究较多。CgA、NSE及Pro-GRP水平均与SCLC的分期有关，广泛期患者其水平显著高于局限期患者，且其表达与较低的生存率显著相关。Syn作为SCLC的辅助诊断指标时敏感度高于CgA，且在SCLC与低分化鳞癌的鉴别诊断中有较高的实用价值；NSE是目前临床上SCLC中使用最多的肿瘤标志物；Pro-GRP在SCLC与NSCLC的区分上具有强于CEA和NSE的诊断优势。尽管这些NET标志物均不是SCLC的特异性标志物，但它们联合运用或作为辅助诊断指标与CT联合使用或许能提高对SCLC的鉴别诊断水平，且它们在疾病的分期上有一定的价值，而疾病分期对SCLC治疗策略的制定十分重要，它们的检测有利于疾病的预防和控制。.

Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Chromogranin A; Gastrins; Humans; Lung Neoplasms; Peptide Fragments; Phosphopyruvate Hydratase; Protein Precursors; Small Cell Lung Carcinoma; Synaptophysin

The diagnostic value of six tumor markers was investigated and the appropriate combinations of those tumor markers to discriminate small cell lung cancer was explored.. Patients suspected with lung cancer (1938) were retrospectively analyzed. Candidate tumor markers from carcinoembryonic antigen (CEA), squamous cell carcinoma-related antigen (SCC), cytokeratin 19 fragment 21-1 (CYFRA 21-1), neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), and progastrin releasing peptide (ProGRP) were selected to construct a logistic regression model. The receiver operating characteristic curve was used for evaluating the diagnostic value of the tumor markers and the predictive model.. ProGRP had the highest positive rate (72.3%) in diagnosed small cell lung cancer, followed by neuron-specific enolase (68.3%), CYFRA21-1 (50.5%), carcinoembryonic antigen (45.5%), tissue polypeptide antigen (30.7%), and squamous cell carcinoma-related antigen (5.9%). The predictive model for small cell lung cancer discrimination was established, which yielded the highest area under the curve (0.888; 95% confidence interval: 0.846-0.929), with a sensitivity of 71.3%, a specificity of 95.0%, a positive predictive value of 49.0%, and a negative predictive value of 98.0%.. Combining tumor markers can improve the efficacy for small cell lung cancer discrimination. A predictive model has been established in small cell lung cancer differential diagnosis with preferable efficacy.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Gastrins; Humans; Keratin-19; Lung Neoplasms; Phosphopyruvate Hydratase; Protein Precursors; Retrospective Studies; Sensitivity and Specificity; Serpins; Small Cell Lung Carcinoma; Tissue Polypeptide Antigen

背景 在欧洲和中国进行Elecsys®胃泌素释放肽前体（ProGRP）免疫检测的多中心评估研究。方法 在欧洲的3个中心和中国的2个中心，在肺癌中，通过不精密度、稳定性、方法学比较和鉴别诊断能力来评价该检测法。结果 5个分析物浓度的中间不精密度范围为变异系数：2.2%-6.0%。在不同储存条件下，血浆和血清样本均显示出良好的稳定性。在血浆中Elecsys®和ARCHITECT检测（斜率1.02，截距-2.72 pg/mL）之间表现出良好的相关性。同时，Elecsys®检测在血清和血浆样本之间表现出良好的相关性（斜率0.93，截距2.35 pg/mL；相关系数0.97）。ProGRP作为不受种族、年龄、性别或吸烟史相关影响的检测手段，可鉴别小细胞和非小细胞肺癌（NSCLC）；截断值为84 pg/mL时，曲线下面积为0.90，95%CI: 0.87-0.93；敏感性为78.3%，特异性为95%。ProGRP浓度中位数在良性病变（38 pg/mL）、其他恶性肿瘤（40 pg/mL）或NSCLC（39 pg/mL）中较低，而在3期以上慢性肾脏疾病中浓度较高（>100 pg/mL）。结论 Elecsys® ProGRP检测在血清和血浆中稳定性增加，较现有检测法明显更具优势。ProGRP检测在中国的首次评价在不同种族中显示出相当的鉴别能力。.

Topics: Adult; Aged; China; Europe; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Immunoassay; Lung Neoplasms; Male; Middle Aged; Protein Precursors

Cholecystokinin (CCK) receptors are G-protein coupled receptors (GPCR) which are present on lung cancer cells. CCK-8 stimulates the proliferation of lung cancer cells, whereas the CCK2R receptor antagonist CI-988 inhibits proliferation. GPCR for some gastrointestinal hormones/neurotransmitters mediate lung cancer growth by causing epidermal growth factor receptor (EGFR) transactivation. Here, the role of CCK/gastrin and CI-988 on EGFR transactivation and lung cancer proliferation was investigated. Addition of CCK-8 or gastrin-17 (100 nM) to NCI-H727 human lung cancer cells increased EGFR Tyr(1068) phosphorylation after 2 min. The ability of CCK-8 to cause EGFR tyrosine phosphorylation was blocked by CI-988, gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), and tiron (superoxide scavenger). CCK-8 nonsulfated and gastrin-17 caused EGFR transactivation and bound with high affinity to NCI-H727 cells, suggesting that the CCK2R is present. CI-988 inhibited the ability of CCK-8 to cause ERK phosphorylation and elevate cytosolic Ca(2+). CI-988 or gefitinib inhibited the basal growth of NCI-H727 cells or that stimulated by CCK-8. The results indicate that CCK/gastrin may increase lung cancer proliferation in an EGFR-dependent manner.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dipeptides; ErbB Receptors; Gastrins; Gefitinib; Hormone Antagonists; Humans; Indoles; Lung Neoplasms; Meglumine; Pyrimidines; Quinazolines

Peptide imprinted polymers were developed for detection of progastrin releasing peptide (ProGRP); a low abundant blood based biomarker for small cell lung cancer. The polymers targeted the proteotypic nona-peptide sequence NLLGLIEAK and were used for selective enrichment of the proteotypic peptide prior to LCMS based quantification. Peptide imprinted polymers with the best affinity characteristics were first identified from a 96-polymer combinatorial library. The effects of functional monomers, crosslinker, porogen, and template on adsorption capacity and selectivity for NLLGLIEAK were investigated and optimized. Ultimately, a solid phase extraction method was developed for highly selective enrichment of the target peptide from tryptic digests.

Topics: Adsorption; Amino Acid Sequence; Biomarkers, Tumor; Gastrins; Humans; Lung Neoplasms; Molecular Imprinting; Peptides; Protein Precursors; Small Cell Lung Carcinoma; Solid Phase Extraction

Topics: Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Carcinoma; Cytokines; Gastrins; Gastrointestinal Neoplasms; Helicobacter Infections; Humans; Lung Neoplasms; Mast Cells; Neoplasm Metastasis; Stress, Physiological

To distinguish lung cancer by detecting 6 tumor markers in serum and establishing three classifying models of artificial neural networks (ANN), decision tree (CART), Fisher discrimination analysis, and to compare the differences among three models.. The levels of serum CEA, gastrin, NSE, sialic acid (SA), Cu/ Zn, Ca in 50 healthy individuals, 40 patients with lung benign disease and 50 patients with lung cancers were detected by means of radioimmunology, spectrophotometry, atomic absorption spectrophotometry, respectively, and then developed ANN, CART and Fisher discrimination analysis models.. The sensitivity of ANN, CART and Fisher discrimination analysis models were 100%, 93.33%, 84.00%, the specificity were 100%, 100%, 98.89%, the accuracy were 91.67%, 86.11%, 85.00%. The areas under receiver operating curve (AUROC) of ANN, CART and Fisher discrimination analysis models were 0.964, 0.953, 0.812, respectively. There was no significantly statistical difference between ANN and CART (P > 0.05), while there were significantly statistical differences not only between Fisher discrimination analysis and ANN, but also Fisher discrimination analysis and CART (P < 0.05).. The effects of ANN, CART models established by 6 tumor markers were better than that of Fisher discrimination analysis in discrimination of lung cancer.

Topics: Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Decision Trees; Diagnosis, Differential; Discriminant Analysis; Gastrins; Humans; Lung Neoplasms; N-Acetylneuraminic Acid; Neural Networks, Computer; ROC Curve; Sensitivity and Specificity; Small Cell Lung Carcinoma

In a substantial proportion of cases with endocrine malignant disease the primary lesion cannot be localised and the pathologist hesitates upon the origin of the tumour. Well differentiated neuroendocrine carcinomas of the small bowel can usually be identified by the strong serotonin immunoreactivity, but foregut carcinoids may also stain positive for serotonin and the differential diagnosis between the various foregut tumours may be difficult. We examined if immunostaining for gastrin-releasing-peptide (GRP) may aid in establishing the origin of an unknown neuroendocrine tumour. Tumour tissue from 79 patients (27 lung carcinoids, 4 thymic carcinoids, 4 gastric neuroendocrine tumours, 17 pancreatic well differentiated neuroendocrine carcinomas, 1 duodenal well differentiated neuroendocrine tumour and 26 well differentiated neuroendocrine carcinomas of the small bowel) were immunostained with antibodies against GRP and serotonin. Positive staining for GRP was found in 12/27 lung carcinoids. All other tumour types were consistently GRP-negative (p?

Topics: Diagnosis, Differential; Female; Gastrins; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; In Vitro Techniques; Lung Neoplasms; Middle Aged; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Peptides; Prospective Studies; Thymus Neoplasms

p73, a new p53 family member, is a transcription factor that is increasingly recognized in cancer research as an important player in tumorigenesis as well as in chemotherapeutic drug sensitivity. Despite the substantial structural and functional similarities to p53, accumulating evidence suggests that p53 and p73 may differently regulate their transcriptional targets. In this study, we have investigated the role of p73 in regulation of the gastrin gene promoter. Gastrin is a peptide hormone and an important factor in determining the progression of a number of human malignancies. Our results show that p73 can bind to the gastrin promoter. This leads to transcriptional upregulation of gastrin mRNA. We also found that the levels of gastrin and p73 transcripts correlate in primary gastric tumors. Taken together, our results demonstrate a novel mechanism for regulation of gastrin gene transcription and support a concept that p53 and p73 may have different biological roles in tumors.

Topics: Animals; Cell Line, Tumor; DNA-Binding Proteins; Gastrins; Humans; Lung Neoplasms; Mice; Nuclear Proteins; Promoter Regions, Genetic; Protein Isoforms; RNA, Messenger; Stomach Neoplasms; Tumor Protein p73; Tumor Suppressor Proteins

The regional distributions and relative frequencies of some gastric endocrine cells of C57BL/6 mice were studied by immunohistochemical method using seven types of specific antisera against chromogranin A (CGA), serotonin, somatostatin, gastrin, cholecystokinin (CCK)-8, glucagon and human pancreatic polypeptide (HPP) after subcutaneous implantation of murine lung carcinoma (3LL) cells.. The experimental animals were divided into two groups, one is non-implanted sham and the other is 3LL-implanted group. Samples were collected from the two regions of stomach (fundus and pylorus) at 28 d after implantation of 3LL cells (1 x 10(5) cell/mouse).. In this study, all the seven types of immunoreactive (IR) cells were identified except for HPP. Most of these IR cells in the gastric portion were generally spherical or spindle in shape (open-type cell) while cells showing round in shape (closed-type cell) were found occasionally. The regional distributions of gastric endocrine cells in the 3LL-implanted group were similar to those of non-implanted sham. However, significant decreases of some types of IR cells were detected in 3LL-implanted group compared to those of non-implanted sham. In addition, the IR cells showing degranulation were numerously detected in 3LL-implanted group. CGA-, serotonin- and somatostatin-IR cells in the fundus and pylorus regions, and gastrin-IR cells in the pylorus regions of 3LL-implanted groups significantly decreased compared to those of non-implanted sham. However, no changes on frequencies of CCK-8- and glucagon-IR cells were demonstrated between 3LL-implanted and non-implanted groups.. Endocrine cells are the anatomical units responsible for the production of gut hormones, and the change in their density would reflect a change in the capacity of producing these hormones. Implantation of tumor cell mass (3LL) induced severe quantitative changes of gastric endocrine cell density, and the abnormality in density of gastric endocrine cells may contribute to the development of gastrointestinal symptoms such as anorexia and indigestion, frequently encountered in patients with cancer.

Topics: Animals; Antibodies; Carcinoma, Lewis Lung; Chromogranin A; Chromogranins; Enteroendocrine Cells; Female; Gastric Fundus; Gastrins; Glucagon; Immunohistochemistry; Injections, Subcutaneous; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Pancreatic Polypeptide; Protein Precursors; Pylorus; Serotonin; Sincalide; Somatostatin

The less processed forms of gastrin have recently been shown to act as trophic factors for both normal and malignant colonic cells. Although incompletely processed forms of gastrin such as glycine-extended gastrin and progastrin are also expressed in human lung cancers, the clinical significance of this expression has not been addressed. Consequently, we investigated the effects of overexpression of glycine-extended gastrin in a mouse strain that is prone to developing lung cancer and also examined the expression of incompletely processed gastrins in primary human lung cancers. We found that transgenic overexpression of glycine-extended gastrin in FVB/N mice resulted in a significant increase in the prevalence and growth of bronchoalveolar carcinoma. In addition, a substantial subset of human lung cancers was found to express progastrin and/or glycine-extended gastrin. Overexpression of glycine-extended gastrin by human lung cancers was associated with a significantly decreased survival. Taken together, these results suggest that glycine-extended gastrin may play a role in the growth and progression of some human lung cancers.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Division; Gastrins; Glycine; Humans; Lung Neoplasms; Mice; Mice, Transgenic; Middle Aged; Prognosis; Survival Analysis; Time Factors

Many neuroendocrine gastrointestinal and lung tumors express sst2A somatostatin receptors. Because the cellular location of sst2A in the corresponding non-neoplastic tissue is unknown, we searched for sst2A immuno-reactive cells and characterized their type in these tissues using a highly specific sst2A antibody (R2-88). Epithelial sst2A cells, identified as neuroendocrine, gastrin-producing cells, were found in large numbers in the antrum and the duodenum, but not in the gastric corpus. They were also present in the proximal jejunum, rarely noted in the distal jejunum and ileum, and absent in the large intestine and the appendix vermiformis. Moreover, sst2A cells were found abundantly in the neural plexus. sst2A receptors on antral gastrin cells could mediate somatostatin inhibition on gastrin secretion, whereas those in the neural plexus could mediate somatostatin effects on motility and ion transport in the lower gastrointestinal tract. Rare sst2A cells in bronchi and bronchioles located basally and parabasally in the gastrointestinal epithelium were detected that could represent stem/progenitor cells. It is currently not clear whether and which of the identified sst2A cells are at the origin of sst2A-positive neuroendocrine gut or lung tumors.

Topics: Gastrins; Humans; Immunohistochemistry; Intestinal Mucosa; Intestinal Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Receptors, Somatostatin; Respiratory Mucosa

Numerous epidemiologic studies suggest a relationship between lung cancer and peptic ulcer disease. Furthermore, various lung cancers synthesize and release a number of peptides such as gastrin and gastrin-releasing peptide that could cause acid hypersecretion; however, Zollinger-Ellison syndrome (ZES), because of a lung tumor, has never been described. We report such a patient for the first time. A 60-year-old man with a non-small cell lung carcinoma (large cell type) presented with diarrhea, heartburn, abdominal pain, and duodenal ulcers. Evaluation showed ZES was present (fasting hypergastrinemia, hyperchlorhydria) and control of all symptoms by omeprazole. No abdominal or cardiac tumor, the other known locations of gastrinomas causing ZES, was found on detailed tumor imaging studies. Resection of the lung tumor resulted in a decrease in gastrin levels to normal values. Plasma radioimmunoassays showed elevated gastrin, chromogranin A and normal levels of gastrin-releasing peptide, and 9 other hormones. The tumor showed similar immunocytochemical results. The characteristics of this case are compared with 100 cases of sporadic abdominal gastrinomas, and the evidence reviewed suggests why ZES should be considered in patients with lung cancer with peptic symptoms.

Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Chromogranin A; Chromogranins; Gastric Acid; Gastrins; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Synaptophysin; Zollinger-Ellison Syndrome

To evaluate the value of detection of 4 tumor markers(CEA, CA125, gastrin, and NSE) for histological types in patients with lung cancer and to improve the predicted efficiency of tumor markers for distinguishing between small cell lung cancer(SCLC) and non-small cell lung cancer (NSCLC), these 4 tumor markers in serum were determined in 51 patients (21 cases with SCLC, 30 cases with NSCLC) with confirmed primary diagnosis of lung cancer of different histology by radioimmunoassay. Linear learning machine method, PRIMA method and KNN method were used to classify SCLC and NSCLC. The levels of gastrin and NSE in SCLC were apparently higher than those of gastrin and NSE in NSCLC, but the levels of CEA and CA125 in SCLC were significantly lower than those in NSCLC. Smoking had an effect on the levels of CEA and CA125, but had little effect on those of gastrin and NSE. The total accuracy of the three methods was over 85% in distinguishing SCLC from NSCLC. So combined detection of the four tumor markers in serum might be useful in the prediction of histological types in patients with lung cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; CA-125 Antigen; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies have 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, some ovarian cancers, astrocytomas and potentially a variety of adenocarcinomas. The aim of this study was to systematically screen and optimize, in a preclinical model and a pilot clinical study, suitable radioligands for targeting CCK-B receptors in vivo.. A variety of CCK/gastrin-related peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing subcutaneous human MTC xenografts. Diethylenetriamine pentaacetic acid (DTPA) derivatives of suitable peptides were synthesized successfully, and their preclinical and initial clinical evaluations were performed, labeled with 111In.. All members of the CCK or gastrin families were stable in serum (with half-lives of several hours at 37 degrees C); nevertheless, the stability of those peptides bearing N-terminal pGlu residues or D-amino acids was significantly higher. In accordance with their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues. Sulfated CCK derivatives performed significantly better but also displayed a comparably high uptake in normal CCK-A receptor-expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC-bearing animals showed significant antitumor efficacy compared with untreated controls. DTPA derivatives of minigastrin were successfully developed. In a pilot clinical study, radioiodinated and 111In-labeled derivatives showed excellent targeting of physiological CCK-B receptor-expressing organs, as well as all known tumor sites.. CCK/gastrin analogs may be a useful new class of receptor-binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, hence lower accretion in normal CCK-A receptor-expressing organs.

Topics: Adult; Aged; Amino Acid Sequence; Animals; Carcinoma, Medullary; Carcinoma, Small Cell; Cholecystokinin; Data Interpretation, Statistical; Female; Gastrins; Humans; Indium Radioisotopes; Iodine Radioisotopes; Isotope Labeling; Lung Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, Nude; Middle Aged; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms, Experimental; Peptides; Radioisotopes; Radionuclide Imaging; Receptors, Cholecystokinin; Thyroid Neoplasms

Both precursor forms of gastrin and mature amidated gastrin peptides can enhance proliferation of colorectal tumours and may regulate growth in an autocrine manner. The purpose of this study was to evaluate the effect of neutralization of precursor and amidated gastrin on primary and secondary in vivo growth of a human colorectal tumour. The human colorectal cell line, AP5LV, when injected into the muscle layer of the abdominal wall of severe combined immunodeficient (SCID) mice, grows as a well-vascularized primary tumour and metastasis to the lung. AP5LV expressed the precursor gastrin forms; progastrin and glycine-extended gastrin and gastrin/CCKB receptors, as assessed by immunocytochemistry. Gastrimmune is a gastrin immunogen in which the amino terminus of the gastrin-17 molecule is linked to diphtheria toxoid and induces antibodies which neutralise the amidated and glycine-extended forms of gastrin-17. Rabbit antiserum, raised against Gastrimmune, was administered intravenously into SCID mice bearing AP5LV tumours. Control animals were treated with antiserum raised against diphtheria toxoid only. Antibodies raised against Gastrimmune significantly limited the growth of primary AP5LV tumours, as assessed by median cross-sectional area (controls = 244 mm2; antibody-treated = 179 mm2; P = 0.033). In addition Gastrimmune-induced antiserum limited the growth of lung metastasis as assessed by nodule number (controls = 3.5; antibody-treated = 1.0; P = 0.0001) and nodule cross-sectional as assessed by image analysis (controls = 11.9 mm2; antibody-treated = 3.75 mm2; P = 0.0064). In conclusion in vivo neutralization of gastrin forms, which may potentially be fueling growth by an autocrine pathway, inhibited both primary growth and, to a greater degree, lung metastasis of a human colorectal tumour cell line. Immunization against tumour-associated gastrin forms may provide an effective therapy for advanced colorectal cancer.

Topics: Animals; Antibodies, Neoplasm; Cancer Vaccines; Colorectal Neoplasms; Diphtheria Toxoid; Gastrins; Humans; Immunohistochemistry; Lung Neoplasms; Mice; Mice, SCID; Rabbits; Rats; Tumor Cells, Cultured

Progastrin-releasing peptide (proGRP) is a specific tumor marker in patients with small cell lung carcinoma (SCLC). It has been reported that serum proGRP levels rarely are elevated in patients with nonsmall cell lung carcinoma (NSCLC); the reported frequency is <3%. The purpose of this study was to examine the clinicopathologic features of NSCLC patients with high serum proGRP levels.. The authors measured serum proGRP levels with a TND-4 kit, a newly developed enzyme-linked immunoadsorbent assay, in 544 NSCLC and 206 SCLC patients. Pathologic features were examined using conventional hematoxylin and eosin staining and histochemical and immunohistochemical staining using polyclonal antibodies to proGRP, chromogranin A, calcitonin, and monoclonal antibody to the neural cell adhesion molecule (NCC-Lu-243).. The serum proGRP levels were elevated in 140 SCLC patients (68.0%) and in 23 NSCLC patients (4.2%). Seven of these 23 NSCLC patients had serum proGRP levels > or = 100 pg/mL. They included two patients with renal dysfunction, one patient diagnosed cytologically with adenocarcinoma without undergoing precise pathologic examination, two patients diagnosed histologically with squamous cell carcinoma with foci of small cell elements, and two patients diagnosed with large cell neuroendocrine carcinoma and poorly differentiated adenocarcinoma, respectively, which showed neuroendocrine differentiation on immunohistologic analysis. The remaining 16 NSCLC patients had serum proGRP levels < 70 pg/mL.. Nearly all NSCLC patients had serum proGRP levels < 100 pg/mL. However, if an NSCLC patient presents with a proGRP level > or = 100 pg/mL, the clinicopathologic features must be examined with regard to the small cell component, neuroendocrine differentiation, and renal dysfunction.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Protein Precursors; Renal Insufficiency

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

Thirty-two cases of so-called sclerosing hemangioma of the lung observed by light microscopy were further studied by electron microscopy and/or immunohistochemistry. Three histologic patterns were seen: hemangioma-like, papillary, and solid. The only significant component representing the nature of the lesion is characteristic round cells within the stroma in all these patterns, whereas the surface cells lining the papillary projections or cystic spaces are normal or are hyperplastic bronchioloalveolar cells with a few neuroendocrine cells. Immunohistochemical findings showed that the "stromal cells" (tumor cells) were positive for neuroendocrine markers, namely, chromogranin A (19 of 22 cases), neuron-specific enolase (24 of 24), synaptophysin (six of 10), adrenocorticotropic hormone (14 of 15), growth hormone (14 of 15), calcitonin (11 of 15), and gastrin (11 of 14). Besides, some tumor cells were positive for epithelial membrane antigen (four of four), carcinoembryonic antigen (one of four), and vimentin (one of one). All tumor cells were negative for polyclonal antikeratin antibody (25 cases), AE1 (one case), and AE3 (one case). However, in contrast to the "stromal cells," the surface cells of the cystic spaces stained positively for keratin (25 of 25 cases), AE1 (one of one), AE3 (one of one), epithelial membrance antigen (four of four), and carcinoembryonic antigen (four of four); only a few of them expressed neruoendocrine markers. Both surface and tumor cells were negative for factor VIII-related antigen (25 cases), CD31 (one case), and alpha1-antitrypsin (25 cases). Ten cases further studied by electron microscopy and six examined by ultrastructural morphometry showed that the surface cells were mainly type 2 pneumocytes containing many lamellar bodies in the cytoplasm. Lying among them, neuroendocrine cells were occasionally seen. The stromal tumor cells had no lamellar body, but dense core granules (neurosecretory granules) and microtubules. In six cases, 92.3% (345 of 374) of tumor cells contained neurosecretory granules, which were pleomorphic and 73 to 1056 nm in diameter (mean, 302 nm). Two to 193 (mean, 12) neurosecretory granules were found in each tumor cell. Both immunohistochemical findings and ultrastructural evidence indicate that so-called sclerosing hemangioma of the lung is a benign lesion composed of neoplastic neuroendocrine cells with areas of sclerosis. A suggested name for this tumor is benign neuroendocrine tumor of the lung

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adenoma; Adrenocorticotropic Hormone; Adult; Aged; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoid Tumor; Cell Transformation, Neoplastic; Chromogranin A; Chromogranins; Diagnosis, Differential; Female; Gastrins; Histiocytoma, Benign Fibrous; Human Growth Hormone; Humans; Immunohistochemistry; Lung Neoplasms; Male; Microscopy, Electron; Middle Aged; Neuroendocrine Tumors; Phosphopyruvate Hydratase; Synaptophysin; von Willebrand Factor

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Peptides; Phosphopyruvate Hydratase; Protein Precursors

Constitutive, unregulated autocrine growth is thought to be an important mechanism whereby cancer cells gain a proliferative advantage over nonmalignant cells. The question addressed here was whether the autocrine growth system for gastrin-releasing peptide (GRP) in human small cell lung carcinoma cells is, in fact, always expressed in a constitutive, unregulated fashion. Lag, rapid, and plateau growth states were defined for small cell lung carcinoma NCI-H345 cells based on periods during which they expressed different growth rates after plating as single cell suspensions. Immunoreactive GRP in the conditioned medium and in NCI-H345 cells harvested during each of these growth states, as well as cell DNA content, GRP mRNA expression, specific 125I-GRP uptake, specific 125I-GRP binding to solubilized membranes, and GRP and neuromedin B receptor mRNA expression by reverse transcription-PCR were analyzed. Maximal levels of GRP expression were observed during the lag growth state, with the highest concentration of immunoreactive GRP in the conditioned medium during the rapid growth state. Specific 125I-GRP uptake and binding were also highest during the lag growth state; however, GRP receptor mRNA did not significantly change. In contrast to prevailing concepts, these studies support the conclusion that the expression of the GRP autocrine growth system in NCI-H345 cells is indeed regulated. Furthermore, the components are maximally expressed before rapid growth begins, suggesting that other mechanisms are activated to support the actual proliferation.

Topics: Antibody Specificity; Base Sequence; Carcinoma, Small Cell; Cell Division; Flow Cytometry; Gastrin-Releasing Peptide; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Iodine Radioisotopes; Lung Neoplasms; Peptides; Polymerase Chain Reaction; Protein Binding; Receptors, Bombesin; RNA, Messenger; Tumor Cells, Cultured

Stimulation of small cell lung cancer (SCLC) cells with neuropeptides bombesin, bradykinin, gastrin, and neurotensin resulted in increased tyrosine kinase activity and tyrosine phosphorylation of a number of polypeptides including a p120 kDa polypeptide identified by immunoblotting as focal adhesion kinase (p125FAK). The neuropeptides stimulated a rapid, concentration-dependent phosphorylation of p125FAK (EC50 of 1 nM, 5 nM, and 2 nM for bombesin, bradykinin, and gastrin, respectively), which was receptor mediated and inhibited by both specific and broad-spectrum neuropeptide receptor antagonists. Specific inhibition of protein tyrosine kinase activity by tyrphostin-25 inhibited both basal and neuropeptide-stimulated SCLC cell growth. These results identify a novel neuropeptide-stimulated growth signaling event in SCLC cells.

Topics: Bombesin; Bradykinin; Carcinoma, Small Cell; Cell Adhesion Molecules; Cell Line; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Gastrins; Humans; Kinetics; Lung Neoplasms; Neuropeptides; Neurotensin; Phosphoproteins; Phosphorylation; Phosphotyrosine; Protein-Tyrosine Kinases; Tumor Cells, Cultured; Tyrosine

The gastrin gene is known to be expressed in all classes of bronchogenic carcinomas. Furthermore, high levels of gastrin have been reported in both the bronchoalveolar lavage (BAL) fluid and serum of patients with lung cancer. Based on these preliminary data a study was conducted to evaluate the usefulness of gastrin measurements in the diagnosis and staging of lung cancer.. Thirty-five patients with lung cancer (26 non-small cell (NSCLC) and nine small cell (SCLC)) and 25 patients with chronic obstructive pulmonary disease underwent fibreoptic bronchoscopy and BAL. Gastrin levels were determined in both BAL fluid and the serum and compared with each other and with staging.. No difference was found between the gastrin levels in the BAL fluid or serum of the study groups. There was no correlation with the stage in NSCLC and no correlation was found between the gastrin levels in the serum and the BAL fluid. A significant difference was seen in gastrin levels in BAL fluid between extensive and limited SCLC (p < 0.05).. There is no evidence of clinical usefulness for gastrin measurements in lung cancer.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Gastrins; Humans; L-Lactate Dehydrogenase; Lung Diseases, Obstructive; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging

We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenografts of the SCLC NCl-H69 line or non-SCLC NCl-H157 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bombesin/GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 micrograms per animal per day, inhibited the growth of H69 SCLC xenografts as shown by more than 70% reduction in tumour volumes and weights, as compared with the control group. Bombesin/GRP antagonists, RC-3440, RC-3095 and RC-3950-II, given s.c. peritumorally at a dose of 20 micrograms per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-II had the greatest inhibitory effect and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xenografts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearing either tumour model, administration of RC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 tumours, but not on non-SCLC H157 tumours. Receptor analyses demonstrated high-affinity binding sites for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and H157 tumours. EGF receptors were down-regulated on H69 tumours after treatment with RC-160 and bombesin/GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 tumours was decreased after treatment with RC-160, but bombesin/GRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/GRP antagonists inhibit the growth of H-69 SCLC, but not of H-157 non-SCLC xenografts in nude mice, whereas somatostatin analogue RC-160 is effective in both tumour models. This raises the possibility that these peptide analogues could be used selectively in the treatment of various subclasses of lung cancer.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Binding Sites; Body Weight; Bombesin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Division; Gastrin-Releasing Peptide; Gastrins; Gonadotropin-Releasing Hormone; Growth Hormone; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Peptide Fragments; Peptides; Receptors, Somatotropin; Somatostatin; Substrate Specificity; Transplantation, Heterologous

Topics: Adrenocorticotropic Hormone; Aged; Calcitonin; Carcinoma, Small Cell; Gastrins; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Somatostatin

Levels of circulating peptide (FSH, LH, prolactin, ACTH, calcitonin, gastrin and insulin-like growth factor-1 [IGF-1]) and steroid (estradiol, progesterone, DHEA-S and testosterone) hormones were estimated by radioimmunoassay (RIA) and immunoradiometric assay (IRMA) in male patients with lung cancer (n = 37) pre-therapeutically and compared with 25 age matched healthy controls. In this retrospective study, FSH, LH, prolactin, ACTH, calcitonin, gastrin and IGF-1 were significantly higher with concomitant lower levels of DHEA-S and testosterone, while the difference was statistically non-significant for estradiol and progesterone in patients with lung cancer when compared with controls. Early stage patients (Stage II) exhibited higher levels of gastrin as compared to advanced stage patients (Stages III and IV). It is suggested that hormonal imbalance might play an important role in the development and progression in male patients with lung cancer.

Topics: Adrenocorticotropic Hormone; Calcitonin; Gastrins; Gonadal Steroid Hormones; Gonadotropins, Pituitary; Hormones; Humans; Insulin-Like Growth Factor I; Lung Neoplasms; Male; Neuropeptides

Gastrin, cholecystokinin (CCK), and CCK-related peptides comprise a hormonal family characterized by an identical carboxy-terminal amino acid sequence, a domain critical for receptor binding. The addition of gastrin to small cell lung cancer (SCLC) cells causes a rapid and transient increase in the intracellular concentration of calcium ([Ca2+]i). Furthermore, gastrin acts as a direct growth factor through CCKB/gastrin receptors. We report here that the expression of the mRNA coding for CCKB/gastrin receptors correlates with the responsiveness of SCLC cells to gastrin in terms of Ca2+ mobilization and stimulation of clonal growth in semisolid medium. The GLC19 SCLC cell line had no detectable expression of CCKB/gastrin receptor mRNA. Accordingly, gastrin (1-100 nM) did not cause any measurable increase in [Ca2+]i. In contrast, the addition of cholecystokinin residues 26-33 (CCK-8) caused a rapid and transient increase in [Ca2+]i in this cell line. CCK-8 mobilized Ca2+ in a dose-dependent manner in the nanomolar range (half-maximal stimulatory concentration = 12 nM). Furthermore, the selective CCKA antagonist CAM-1481 inhibited the increase in [Ca2+]i induced by CCK-8 (half-maximal inhibitory concentration = 3 nM) in GLC19 but not in H510 cells. The selective CCKB/gastrin antagonist blocked the increase in [Ca2+]i induced by CCK-8 (half-maximal inhibitory concentration = 80 pM) in H510 but not in GLC19 cells. Thus, the effects of CCK-8 are mediated through CCKA receptors in GLC19 cells and via CCKB/gastrin receptors in H510 cells. CCK-8 markedly stimulated colony formation in GLC19 cells in a dose-dependent manner in the nanomolar range, whereas over the same concentration range, gastrin had no effect on clonal growth. CAM-1481 inhibited the CCK-stimulated colony formation in GLC19 but not in H510 cells. Our results show, for the first time, that CCKA receptors can mediate Ca2+ mobilization and growth in SCLC cells and that SCLC cells express two distinct functional CCK receptor subtypes.

Topics: Amino Acid Sequence; Animals; Base Sequence; Blotting, Northern; Bradykinin; Calcium; Carcinoma, Small Cell; Clone Cells; DNA Primers; Dogs; Gastrins; Gene Expression; Humans; Kinetics; Lung Neoplasms; Molecular Sequence Data; Muridae; Polymerase Chain Reaction; Rats; Receptors, Cholecystokinin; RNA, Messenger; RNA, Neoplasm; Sequence Homology, Amino Acid; Sincalide; Tumor Cells, Cultured

In this study, determination of gastrin concentration in bronchoalveolar lavage fluid and serum has been detected by radioimmunoassay in 30 cases of lung cancer and 24 cases of non-cancer pulmonary diseases. The results show that the gastrin concentration and its positive rate of lavage fluids from cancer lung are much higher than those from healthy lung and serum in lung cancer patients, and those from serum and both disease and healthy lung in non-cancer pulmonary disease patients (P less than 0.01). The gastrin ratio of lavage fluids from cancer lung to serum is also significantly higher than the ratio of lavage fluid from healthy lung to serum and all the ratios in the non-cancer pulmonary disease group. These results suggest that there is a high gastrin concentration in local tissue of lung cancer, which is signified by the high concentration of gastrin and its high positive rate in lavage fluids from the lung with cancer. Therefore, the gastrin determination in lavage fluids and gastrin ratio of lavage fluids to serum are more reliable in the differential diagnosis of benign from malignant pulmonary diseases than gastrin determination of serum alone.

Topics: Adenocarcinoma; Adult; Aged; Bronchoalveolar Lavage Fluid; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrins; Humans; Lung Diseases; Lung Neoplasms; Male; Middle Aged

Topics: Aged; Carcinoma, Small Cell; Gastrins; Humans; Lung Neoplasms; Male; Paraneoplastic Endocrine Syndromes; Stomach Ulcer; Zollinger-Ellison Syndrome

Serial changes in serum gastrin level were detected by radioimmunoassay in 58 lung cancer patients before and after operation. In comparing these tests with those of 40 cases of noncancerous thoracic lesions and 151 normal adults, the serum gastrin from lung cancer patients is significantly higher than that of noncancerous thoracic lesions and normal individuals (P less than 0.01). The gastrin level is closely related to stage of cancer, size of primary tumor, presence of lymph node metastasis, and type of histological classification. The serum gastrin was found to decrease gradually after the removal of the tumor and to return to normal on the 14th postoperative day. Those patients whose serum gastrin level can return to normal on the 14th postoperative day will have a good prognosis; if not, their prognosis will be very poor. These results suggest that serum from patients with lung cancer contains a high concentration of gastrin that can help differentiate benign from malignant thoracic lesions and evaluate prognosis of patients with lung cancer. Therefore, the cause of high serum gastrin in patients with lung cancer is likely due to the gastrin-producing property of the lung cancer cells.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Peptides; Postoperative Period; Prognosis; Thoracic Diseases

Gastrin has been postulated to be a physiological growth factor, but compelling in vitro evidence of this has been difficult to obtain. In the present study we investigated whether small cell lung carcinoma cell lines could provide a useful model system to study the effects of gastrin on signal transduction and cell proliferation in vitro. We found that the addition of gastrin to small cell lung cancer cells loaded with the fluorescent Ca2+ indicator fura 2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. The [Ca2+]i response was especially prominent in the small cell lung carcinoma cell line H510. In this cell line, gastrin I, gastrin II, cholecystokinin residues 26-33 (CCK-8), and unsulfated CCK-8 increased [Ca2+]i in a concentration-dependent fashion with half-maximum effects at 7, 2.5, 3, and 5 nM, respectively. The Ca(2+)-mobilizing effects of gastrin and CCK-8 were prevented by proglumide, benzotript, and the specific gastrin/CCKB receptor antagonist L365260. Gastrin stimulated the clonal growth of H510 cells in semisolid (agarose-containing) medium, increasing both the number and the size of the colonies. Gastrin and CCK agonists were equally effective in promoting clonal growth. The broad-spectrum neuropeptide antagonists [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P and [Arg6,D-Trp7,9,MePhe8] substance P (6-11) markedly inhibited gastrin-stimulated Ca2+ mobilization and clonal growth. These results show that gastrin acts as a direct growth factor through gastrin/CCKB receptors and demonstrate, for the first time, that these peptides can stimulate the proliferation of cells outside the gastrointestinal tract.

Topics: Benzamides; Calcium; Carcinoma, Small Cell; Cell Division; Gastrins; Humans; Lung Neoplasms; Proglumide; Sincalide; Tumor Cells, Cultured

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

We have evaluated an anti-autocrine growth factor monoclonal antibody for potential use in the treatment of patients with small-cell lung cancer. The monoclonal antibody, designated 2A11, binds to the C-terminal region of the autocrine growth factor gastrin-releasing peptide and neutralizes its growth-promoting effects in vitro and in vivo. Equilibrium-binding analysis demonstrated that the peptide binds to the antibody (dissociation constant = 1.5 x 10(-10) at least as avidly as it binds to the tumor peptide receptor. Pharmacokinetic studies in normal BALB/c mice demonstrated an initial clearance half-life (alpha t1/2) of 24.3 +/- 4 hours and a secondary clearance half-life (beta t1/2) of 1039.6 +/- 309 hours, and biodistribution studies revealed a distribution pattern which generally reflected blood flow. Single intravenous infusions of 2A11 (20 mg/20-25-kg dogs) into normal mongrel dogs with surgically created gastric fistulas antagonized the stimulatory effects of exogenously infused gastrin-releasing peptide or bombesin on plasma gastrin release and gastric acid secretion. Toxicology studies in normal dogs (with gastric fistulas) infused with 50 mg 2A11 intravenously three times a week for 4 weeks failed to reveal any adverse behavioral, clinical, or pathological effects. Four of six dogs developed an immune response to 2A11. Anti-idiotypic antibodies elicited in two cases did not mimic the functional effects of the peptide. We conclude that the concept of immunoblockade of an autocrine growth factor appears feasible in vivo.

Topics: Animals; Antibodies, Monoclonal; Bombesin; Carcinoma, Small Cell; Dogs; Gastric Acid; Gastrin-Releasing Peptide; Gastrins; Growth Substances; Lung Neoplasms; Mice; Mice, Inbred BALB C; Peptides; Tissue Distribution

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Biomarkers, Tumor; Bombesin; Gastrins; Glucagon; Hormones; Humans; Immunophenotyping; Lung Neoplasms; Male; Middle Aged; Somatostatin; Vasoactive Intestinal Peptide

Expression of the cholecystokinin (CCK), gastrin and enkephalin A genes were studied by Northern blot analysis and a library of sequence-specific radioimmunoassays in human cell lines. The human small-cell lung carcinoma line (SCLC) U-1690 expressed moderate levels of CCK mRNA as compared to the human neuroepithelioma cell line SK-N-MC. Neither gastrin nor (pro)enkephalin A mRNAs were detectable in the U-1690 cell line. In contrast, the SCLC-line H-69 expressed Enk A but no CCK mRNA. The radioimmunoassays showed that the CCK mRNA transcript in the SCLC line U-1690 also is translated, and that preproCCK is processed into bioactive, carboxyamidated CCK peptides. Thus, the human small cell carcinoma cell line U-1690 is a useful model for studies of cell-specific CCK gene expression.

Topics: Animals; Carcinoma, Small Cell; Cholecystokinin; Enkephalins; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Poly A; Protein Processing, Post-Translational; Rats; RNA, Messenger; Tumor Cells, Cultured

Gastrin releasing peptide (GRP) is a 27-residue peptide hormone which is analogous to the amphibian peptide bombesin. GRP serves a variety of physiological functions and has been implicated as an autocrine factor in the growth regulation of small cell lung cancer cells. We have developed a series of potent GRP antagonists by modification of the COOH terminus of N-acetyl-GRP-20-27. The most potent member of this series, N-acetyl-GRP-20-26-OCH2CH3, exhibits an IC50 of 4 nM in a competitive binding inhibition assay. This compound blocks GRP-stimulated mitogenesis in Swiss 3T3 mouse fibroblasts, inhibits GRP-dependent release of gastrin in vitro, and blocks GRP-induced elevation of [Ca2+]i in H345 small cell lung cancer cells. These results demonstrate that while residues 20-27 of GRP influence binding of the parent peptide to its receptor, the COOH-terminal amino acid is primarily responsible for triggering the subsequent biological response.

Topics: Amino Acid Sequence; Animals; Binding, Competitive; Bombesin; Calcium; Carcinoma, Small Cell; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Mice; Molecular Sequence Data; Oligopeptides; Peptides; Rats; Rats, Inbred Strains; Structure-Activity Relationship; Tumor Cells, Cultured

Using a library of radioimmunoassays against essential sequences of human progastrin and procholecystokinin, we have examined the occurrence of gastrin, cholecystokinin, and their precursors in bronchogenic adenocarcinomas, large-cell, small-cell, and squamous-cell carcinomas (n = 17). Progastrin and some of its bioactive (i.e., alpha-carboxyamidated) products were present in all tumors, irrespective of histological classification. The concentration of progastrin varied from 0.2 to 21.9 pmol/g tissue; glycine-extended intermediates constituted less than 0.1 to 0.5 pmol/g; and bioactive, carboxyamidated gastrin ranged from less than 0.1 to 6.1 pmol/g. Chromatography showed that the bioactive gastrins were exclusively gastrin-17 peptides, half of which were tyrosine O-sulfated. Neither procholecystokinin nor its processing products were found in the tumor extracts. Six samples of nonneoplastic human lung tissue contained traces of progastrin (range, less than 0.1-0.8 pmol/g), but neither bioactive gastrins nor any cholecystokinin. The results show that the gastrin gene is expressed in all classes of bronchogenic carcinomas. Due to incomplete posttranslational processing measurement of progastrin may be necessary to detect such expression.

Topics: Base Sequence; Carcinoma, Bronchogenic; Cholecystokinin; Chromatography, Gel; Gastrins; Humans; Lung Neoplasms; Neoplasm Proteins; Protein Precursors

The gastrin-releasing peptide (GRP) is a neuropeptide hormone and growth factor produced normally by neural and neuroendocrine cells, as well as by human small-cell lung cancer (SCLC) tumors and derived cell lines. This study compares the structure of the human prepro-GRP gene in four SCLC cell lines that express variable levels of steady-state GRP mRNA. The regulation of GRP gene expression appears to be at the level of primary transcription based on nuclear run on studies. In the two SCLC cell lines expressing GRP we find a single transcription start site for GRP mRNA, and near this site we find four DNase I hypersensitive sites. These hypersensitive sites are absent in the two cell lines that do not express GRP. The presence of DNase hypersensitive sites in the promoter region of the GRP gene is the structural feature that best correlates with transcriptional activation. These four DNase hypersensitive sites are candidates for cis acting regulatory regions, which may be important in determining the level of transcription of the human prepro GRP gene.

Topics: Base Sequence; Carcinoma, Small Cell; Cell Line; Deoxyribonuclease I; DNA (Cytosine-5-)-Methyltransferases; Gastrin-Releasing Peptide; Gastrins; Gene Amplification; Gene Expression Regulation; Humans; Lung Neoplasms; Molecular Sequence Data; Nucleotide Mapping; Peptides; Promoter Regions, Genetic; Protein Precursors; RNA, Messenger; Transcription, Genetic

Most peptide hormone assays measure only fully processed bioactive peptides. Such assays are unsuited to detect hormone gene expression by alternative or attenuated prohormone processing (tissue- or cell-specific processing). The gastrin system is expressed in several different tissues and is therefore useful for studies of tissue-specific processing. Consequently we have developed a simple processing-independent radioimmunoanalysis for progastrin. Using antisera against the NH2-terminus of a sequence, devoid of processing sites (preprogastrin76-86) after trypsination of neighboring cleavage sites, the assay quantitates the mRNA product irrespective of degree of processing. Used together with a conventional assay for the mature carboxyamidated gastrins, the processing-independent analysis shows that in different tissues only 1 to 55% of the total translation product is processed to bioactive gastrins. Thus processing-independent analysis greatly improves the detection of gastrin gene expression at the peptide level. The principle of the assay should be applicable to all protein and peptide systems.

Topics: Amino Acid Sequence; Chromatography, Gel; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Lung Neoplasms; Molecular Sequence Data; Peptide Fragments; Protein Precursors; Protein Processing, Post-Translational; Radioimmunoassay; Trypsin

Topics: Carcinoma, Small Cell; Cell Count; Cell Line; DNA; Gastrin-Releasing Peptide; Gastrins; Gastrointestinal Hormones; Growth Substances; Humans; Lung Neoplasms; Mitosis; Molecular Weight; Peptides; Protein Biosynthesis; RNA; Time Factors

We have described a case of MEN-I in association with a benign pulmonary carcinoid tumor. Two other members of our patient's family also had MEN-I and benign carcinoid or adenomatous lung tumors. Hormonal assays of our patient's carcinoid lesion showed the production of gastrin, gastrin-releasing peptide, neurotensin, and somatostatin, but not serotonin, a hormonal profile distinct from those previously reported in carcinoid lung tumors unassociated with MEN-I.

Topics: Carcinoid Tumor; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Middle Aged; Multiple Endocrine Neoplasia; Neurotensin; Pedigree; Peptides; Somatostatin

Human gastrin-releasing peptide (GRP) mRNA was detected in the tumor tissues of medullary thyroid carcinomas and small cell lung carcinomas using synthetic oligodeoxyribonucleotides as hybridization probes. The amount of GRP mRNA was estimated by radiodensitometric hybridization assay. A good correlation was found between the amount of GRP mRNA and the concentration of immunoreactive GRP in the tumor tissues.

Topics: Carcinoma; Carcinoma, Small Cell; Densitometry; Gastrin-Releasing Peptide; Gastrins; Humans; Immunologic Techniques; Lung Neoplasms; Nucleic Acid Hybridization; Oligodeoxyribonucleotides; Peptides; Radioimmunoassay; RNA, Messenger; Thyroid Neoplasms

Topics: Bombesin; Bronchial Neoplasms; Carcinoid Tumor; Carcinoma, Small Cell; Chorionic Gonadotropin; Diagnosis, Differential; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Immunoenzyme Techniques; Lung Neoplasms; Middle Aged; Peptides; Phosphopyruvate Hydratase

Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours.

Topics: Adenoma; Adrenal Gland Neoplasms; Amino Acid Sequence; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Humans; Intestinal Neoplasms; Lung Neoplasms; Neoplasms; Neurosecretory Systems; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Pituitary Neoplasms; Thyroid Neoplasms

A consecutive series of 38 lung carcinoid tumours (36 surgical and two necropsy specimens) was studied. Histopathological features and amine and peptide hormone immunoreactivity were correlated with gross characteristics (size, location) and clinical data. Peripheral carcinoids were detected a decade later than central carcinoids and tended to be bigger. In general, the histological characteristics of peripheral and central carcinoids were similar; atypical features, however, were more common in peripheral carcinoids. Most carcinoids contained many argyrophilic cells (58%). Although argentaffinic cells were not found, serotonin immunoreactive cells were present in 32% of the tumours. Peptide hormone immunoreactivity (adrenocorticotrophic hormone (ACTH), calcitonin, somatostatin, gastrin) was rare. In one case massive ACTH production had caused clinically manifest Cushing's syndrome. In two other cases few ACTH immunoreactive cells were found and in one case calcitonin immunoreactive cells were present. The relative rarity of hormone production in lung carcinoids and the predominantly benign course of the tumour preclude the use of peptide hormone production as a prognostic indicator.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Calcitonin; Carcinoid Tumor; Cushing Syndrome; Female; Gastrins; Hormones, Ectopic; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Middle Aged; Serotonin; Somatostatin

The case of a patient with small-cell carcinoma of the lung, bone marrow metastases, and hypertrophic pulmonary osteoarthropathy is reported. Normal growth hormone serum concentrations contrasted with significant increases in ACTH, beta-MSH, calcitonin, and gastrin. A hormonal etiology has previously been suggested for hypertrophic pulmonary osteoarthropathy. Our findings indicate that the hormone responsible for hypertrophic pulmonary osteoarthropathy may be an APUD polypeptidic substance, that differs from immunoreactive GH but is related to somatomammotropins.

Topics: Adrenocorticotropic Hormone; Aged; Calcitonin; Carcinoma; Gastrins; Humans; Lung Neoplasms; Male; Melanocyte-Stimulating Hormones; Osteoarthropathy, Secondary Hypertrophic

To elucidate the ectopic hormonal pattern in patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, serum gastrin, plasma glucagon, serum insulin, plasma secretin, plasma VIP, serum growth hormone, serum hCG/LH, the total of serum hCG and hCG-beta-subunit,serum alpha-subunit, serum human placental lactogen, urine ADH, urine 5-HIAA, urine VMA, urine HVA, and urine hCG-LH were measured prior to therapy in 75 patients. Twenty-two patients (29%) had elevated plasma ACTH, and 18 of these had concomitant increased values of corticosteroid in a 24-hour urine sample. Forty-eight patients (64%) were found to have elevated serum calcitonin, and one-third of the patients were diagnosed as having the ectopic ADH syndrome. Serum gastrin concentrations were increased in 20% of the patients, but the elevations were marginal in almost all cases. None of the remaining substances was found to be significantly elevated. Concentrations of plasma ACTH, serum calcitonin, and urine ADH were not found to be correlated with the stage of the disease, and no correlation of these substances with the histological subtypes of small cell carcinoma was disclosed.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Amines; Arginine Vasopressin; Calcitonin; Carcinoma, Small Cell; Chorionic Gonadotropin; Female; Gastrins; Gastrointestinal Hormones; Hormones; Humans; Lung Neoplasms; Male; Middle Aged; Placental Lactogen

Endocrine and immunohistochemical studies were performed in a patient with lung cancer associated with gynecomastia. Elevated level of human chorionic gonadotropin (hCG) in plasma and mild hyperadrenocorticism were demonstrated by hormone assays. Postmortem examination proved the existence of anaplastic small cell carcinoma of the lung mixed with a feature of chorioepithelioma. The presence of significant amounts of adrenocorticotropic hormone (ACTH), beta-melanocyte stimulating hormone (beta-MSH), calcitonin, gastrin, hCG, hCG-alpha, hCG-beta and human chorionic somatomammotropin (hCS) in tumor tissues was demonstrated by radioimmunoassays, bioassay and immunohistochemical techniques. We present here a unique case of multiple hormones producing tumor elaborating both hormones of amine precursor uptake and decarboxylation (APUD) series (ACTH, beta-MSH, calcitonin and gastrin) and of placental origin (hCG, hCG-alpha, hCG-beta and hCS).

Topics: Adrenocorticotropic Hormone; Apudoma; Calcitonin; Carcinoma, Small Cell; Choriocarcinoma; Chorionic Gonadotropin; Gastrins; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Melanocyte-Stimulating Hormones; Middle Aged; Placental Lactogen

The relations of calcitonin concentrations to the presence of bone marrow metastases and to the concentrations of calcium, parathormone and gastrin in serum were investigated in 74 untreated patients with small cell carcinoma of the lung. Calcitonin concentrations were enhanced in two thirds of the patients, while serum calcium concentrations were normal in all. In 19 of 57 patients parathormone concentrations were slightly above the normal range, but the concentrations of parathormone and calcitonin were not correlated. Bone marrow metastases had no influence on the concentration of serum calcitonin. Finally, a small inverse correlation between the concentrations of gastrin and calcitonin in serum was observed. The results resemble those of the calcitonin-producing medullary carcinoma of the thyroid, supporting the suggestion of an ectopic source of hypercalcitoninemia in small cell carcinoma of the lung.

Topics: Bone Neoplasms; Calcitonin; Carcinoma, Small Cell; Gastrins; Humans; Lung Neoplasms; Parathyroid Hormone

Plasma hCT levels were less than 50 pg/ml in 50 normal subjects. In 16 patients with medullary carcinoma of the thyroid (MCT), plasma hCT levels were distinctively elevated and they fell significantly after total thyroidectomy, but in 11 of them plasma levels were still high, indicating the presence of metastases. In 74 patients with the other types of malignancy, plasma hCT levels were found to be high in 9 cases (3 oat cell carcinoma of the lung, 4 malignant carcinoids, one malignant pheochromocytoma and one acute myelocytic leukemia). Except for the leukemic case, all these tumors were derived from neural crest. In 12 patients with primary hyperparathyroidism, plasma hCT levels were less than 20 pg/ml. In 13 hypoparathyroid patients, two with pseudohypoparathyroidism and one with pseudoidiopathic hypoparathyroidism, plasma hCT levels were slightly elevated. Some patients with uremia had elevated plasma hCT levels, but there was no relation between plasma levels of hCT and those of PTH, urea nitrogen or creatinine. In response to Ca (4.5 mg/kg/10 min) or tetragastrin (4 mug/kg/5 min) infusion, a marked increase in plasma hCT was observed in all patients with MCT, but not in normal subjects. In 5 hypoparathyroid patients, a significant increase to both stimuli was also observed in all cases. Two patients with pseudopseudohypoparathyroidism responded to the Ca load. These results indicate that the determination of plasma hCT levels especially after a short Ca or tetragastrin infusion is important to study various pathological conditions.

Topics: Calcitonin; Calcium; Carcinoma; Carcinoma, Small Cell; Cross Reactions; Dose-Response Relationship, Drug; Gastrins; Humans; Hyperparathyroidism; Infusions, Parenteral; Lung Neoplasms; Thyroid Neoplasms; Thyroidectomy

With better methods of diagnosis, patients will be identified earlier in the course of their disease and will often have atypical and borderline manifestations of the syndrome. Serum gastrin measurements with calcium and especially with secretin challenge will be the most important method of diagnosis. Any patient with acid hypersecretion who has a high serum gastrin level that does higher on secretin infusion should be considered to have the Zollinger-Ellison syndrome. A firm diagnosis of the Zollinger-Ellison syndrome should be made, if at all possible, prior to operation. At operation, a thorough search of the pancreas, duodenum, stomach, greater and lesser omentum and liver should be made for primary and secondary gastrinomas. If the preoperative data firmly establish the diagnosis of the Zollinger-Ellison syndrome, a total gastrectomy should be carried out even if no primary tumor is found. Similarly, a total gastrectomy should be done even if there are massive hepatic metastases. If total gastrectomy is not performed, the patient is apt to die of complications of acid hypersecretion. The only possible exceptions to the rule of always performing a total gastrectomy are in asymptomatic patients with easily excisable tumors or patients with tumors of the duodenum that are easily excisable, providing that in both instances after the excision of the tumor the output of gastric acid as measured at operation is immediately halted. All possible metastatic tumor tissue should be removed. The more tumor tissue removed, the longer the patient will survive. Metastases should be treated aggressively. They do not disappear after total gastrectomy in our experience, and they may kill patients. Patients should be followed after operation with serial measurements of serum gastrin concentrations and by hepatic scintillation scans and hepatic angiography. If hepatic metastases develop, intrahepatic artery infusions of 5-fluorouracil may slow tumor growth.

Topics: Adenocarcinoma; Adult; Aged; Angiography; Calcium; Endoscopy; Female; Gastrectomy; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptic Ulcer; Postoperative Complications; Preoperative Care; Radioimmunoassay; Secretin; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Female; Follow-Up Studies; Gastrectomy; Gastrins; Humans; Hypophysectomy; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Zollinger-Ellison Syndrome