pituitrin and Carcinoma--Small-Cell

Topics: Binding Sites; Carcinoma, Small Cell; Cyclic AMP; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Introns; Lung Neoplasms; Promoter Regions, Genetic; Transcription Factors; Transcription, Genetic; Vasopressins

It is proposed that neuropeptide production by tumours is an important part of a special process of oncogenic transformation rather than a pre-existing condition of progenitor cells; this concept is called Selective Tumour gene Expression of Peptides essential for Survival (STEPS). All small-cell lung cancers and breast cancers evidently express the vasopressin gene, and this gene seems to be structurally normal in all but exceptional cases. Vasopressin gene expression in cancer cells leads to the production of both normal and abnormal forms of tumour vasopressin mRNA and proteins. Although the necessary post-translational processing enzymes are expressed in these cells, most processing seems to be extragranular, and most of the protein products become components of the plasma membrane. Small-cell lung cancer and breast cancer cells also express normal genes for all vasopressin receptors and produce normal vasopressin receptor mRNAs and V1a and V1b receptor proteins, and the vasopressin-activated calcium mobilising (VACM) protein; plus both normal and abnormal forms of the V2 receptor. Through these receptors, vasopressin exercises multifaceted effects on tumour growth and metabolism. A normal protein vasopressin gene promoter seems to be present in small-cell lung cancer cells, and this promoter contains all of the transcriptional elements known to be involved in gene regulation within hypothalamic neurones. Since these elements largely account for regulation of tumour gene expression observed in vitro, it is likely that as yet unknown factors are selectively produced by tumours in vivo to account for the observed seemingly autonomous or unregulated production of hormone in tumour patients. Promoter elements thought to be responsible for selective vasopressin gene expression in small-cell lung cancer probably include an E-box and a neurone restrictive silencer element close to the transcription start site. It is possible that transcription factors acting at these same elements can explain selective vasopressin expression, not only in small-cell tumours, but also in all other tumours such as breast cancer. By extrapolation, similar mechanisms might also be responsible for the expression of additional features that characterize the 'neuroendocrine' profile of these cancers.

Topics: Animals; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Receptors, Vasopressin; Vasopressins

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Neoplasms; Neurophysins; Oxytocin; RNA, Messenger; Vasopressins

Topics: Acromegaly; Adrenocorticotropic Hormone; Animals; Blood Glucose; Calcitonin; Carcinoma, Small Cell; Cell Transformation, Neoplastic; Chorionic Gonadotropin; Corticotropin-Releasing Hormone; Cushing Syndrome; Dexamethasone; Female; Galactorrhea; Gene Expression Regulation; Growth Hormone; Humans; Hypercalcemia; Lymphokines; Nerve Tissue Proteins; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Peptide Biosynthesis; Pregnancy; Pro-Opiomelanocortin; Prolactin; Prostaglandins; Transforming Growth Factors; Vasopressins; Vitamin D

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Carcinoma, Small Cell; Estrogens; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Middle Aged; Vasopressins

Topics: Animals; Carcinoma, Small Cell; Glycopeptides; Gonads; Humans; Hypothalamo-Hypophyseal System; Lung Neoplasms; Oxytocin; Pituitary Gland, Posterior; Rats; Vasopressins

Topics: Adrenocorticotropic Hormone; Carcinoma, Small Cell; Chorionic Gonadotropin; Cushing Syndrome; Diagnosis, Differential; Gynecomastia; Hormones, Ectopic; Humans; Hypercalcemia; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Vasopressins

Topics: Adenocarcinoma; Amine Oxidase (Copper-Containing); Antigens, Neoplasm; Calcitonin; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Creatine Kinase; Humans; Lung Neoplasms; Microscopy, Electron; Neurophysins; Vasopressins

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

Topics: Adrenocorticotropic Hormone; APUD Cells; Calcitonin; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Syndrome; Vasopressins

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Adult; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chorionic Gonadotropin; Cushing Syndrome; Dexamethasone; Gynecomastia; Humans; Hypercalcemia; Lomustine; Lung Neoplasms; Male; Mechlorethamine; Neoplasm Metastasis; Neostigmine; Parathyroid Hormone; Smoking; Vasopressins; Water-Electrolyte Balance

Topics: Adrenocorticotropic Hormone; Bronchial Neoplasms; Calcitonin; Carcinoma, Small Cell; Erythropoietin; Fluorescent Antibody Technique; Gastrointestinal Hormones; Gonadotropins, Pituitary; Growth Hormone; Histocytochemistry; Hormones, Ectopic; Humans; Hypercalcemia; Insulin; Insulin Secretion; Neoplasm Metastasis; Neurophysins; Oxytocin; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Placental Lactogen; Prolactin; Thyrotropin; Vasopressins

Topics: Adolescent; Bronchial Neoplasms; Carcinoma, Small Cell; Child, Preschool; Cushing Syndrome; Diagnosis, Differential; Hormones, Ectopic; Humans; Hyperaldosteronism; Hypercalcemia; Hyperparathyroidism; Hyponatremia; Kidney Neoplasms; Paraneoplastic Endocrine Syndromes; Renin; Sodium Chloride; Syndrome; Vasopressins

Topics: Carcinoma, Small Cell; Central Nervous System Diseases; Endocrine System Diseases; Hormones, Ectopic; Humans; Hyponatremia; Kidney; Lung Diseases; Lung Neoplasms; Osmolar Concentration; Paraneoplastic Endocrine Syndromes; Syndrome; Vasopressins; Water Intoxication; Water-Electrolyte Balance

Vasopressin-neurophysin (hNpI), oxytocin-neurophysin (hNpII) and blood osmolality were assayed before any treatment in basal conditions in 35 patients suffering from lung carcinoma (20 oat cell, 6 undifferentiated and 9 well-differentiated epidermoid cell carcinomas). Plasma vasopressin (antidiuretic hormone, ADH) was also assayed in 7 of the 20 patients suffering from oat cell carcinoma. We found a close correlation (r = 0.98) between plasma ADH and hNpI levels in the 7 patients. Further, hNpI was elevated in 13 out of the 20 oat cell carcinoma patients and in none of the epidermoid-cell carcinoma group; however, searching for an abnormality of ADH secretion as reflected by a detectable plasma hNpI level together with subnormal plasma osmolality revealed 2 additional positive results in the oat cell carcinoma group, and 2 out of the 6 in the undifferentiated-cell carcinoma group. hNpII was increased together with an increase in hNpI in 6 oat cell carcinoma patients; it was specifically increased without hNpI increment in 2 additional oat cell carcinoma patients and in 2 patients of the undifferentiated-cell carcinoma group (different from the 2 positive for the hNpI-osmolality ratio). hNpI and hNpII were normal in the majority of undifferentiated and all of the differentiated epidermoid-cell carcinoma group. Hence, our results show that simultaneous measurements of hNpI, hNpII, and blood osmolality could detect abnormalities in 17 out of 20 oat cell carcinoma patients, in 4 of the 9 undifferentiated-cell carcinoma patients, but in none of the differentiated epidermoid-cell carcinoma patients, suggesting that the neurophysin assay can be used for the early detection of oat cell- and possibly other neuroendocrine-derived carcinomas.

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Neurophysins; Osmolar Concentration; Oxytocin; Vasopressins

Thymic neuroendocrine tumours are rare anterior mediastinal neoplasms often associated with paraneoplastic syndromes. A patient presented with intractable hyponatraemia and a DOTATATE-avid mediastinal mass. Following medical optimization, she underwent thoracoscopic thymectomy with en bloc thymic small-cell carcinoma resection. Her symptoms resolved and her sodium levels normalized. In localized disease, curative-intent, minimally invasive thymic neuroendocrine tumour resection is safe and effective following preoperative staging and paraneoplastic syndrome management.

Topics: Carcinoma, Small Cell; Female; Humans; Paraneoplastic Syndromes; Positron-Emission Tomography; Radionuclide Imaging; Thymoma; Thymus Neoplasms; Vasopressins

Small cell carcinoma of the cervix is a rare malignant tumor in the clinical setting. Clinical manifestations of this tumor are mostly similar to those of normal types of cervical cancer. Small cell carcinoma of the cervix only shows symptoms of neuroendocrine tumors, such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most of the hyponatremia caused by SIADH can be managed after removal of the cause. Hyponatremia is a predictor of poor prognosis and can be used as an indicator of partial recurrence. We report a case of small cell carcinoma of the cervix complicated by SIADH. Our patient presented with irregular vaginal bleeding after menopause. After one cycle of chemotherapy, there was trembling of the limbs, and a laboratory examination showed low Na

Topics: Carcinoma, Small Cell; Cervix Uteri; Female; Humans; Inappropriate ADH Syndrome; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms; Vasopressins

Small cell carcinoma (SCC) of the bladder is a rare malignancy, representing less than 1% of bladder cancers diagnosed annually in the USA. In contrast to SCC of the lung, paraneoplastic syndromes are rarely documented in cases of extrapulmonary SCCs, particularly those of genitourinary origin. We present a case of SCC of the bladder presenting with paraneoplastic syndrome of inappropriate antidiuretic hormone, which resolved after treatment with sequential chemoradiation.

Topics: Aged, 80 and over; Carcinoma, Small Cell; Chemoradiotherapy; Cystoscopy; Fluorine Radioisotopes; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Paraneoplastic Syndromes; Positron Emission Tomography Computed Tomography; Treatment Outcome; Urinary Bladder; Urography; Vasopressins

A 66-year-old man was referred to our hospital with esophageal tumor. He was diagnosed with esophageal small cell carcinoma by endoscopic biopsy. He had a low serum sodium level at admission and was diagnosed syndrome of inappropriate secretion of antidiuretic hormone (SIADH). His CT scan revealed esophageal wall thickness and swelling of thoracic and abdominal lymph nodes. He was classified as Stage IV a (cT3cN4cM0). He received systemic chemotherapy with CDDP and CPT-11. After three courses of chemotherapy, his tumor disappeared on CT scan and endoscopy. He was diagnosed as in complete remission and his SIADH recovered. The patient was then discharged and visited our outpatient clinic. Seven months after diagnosis, a tumor recurrence was indicated by CT scan and endoscopy. He received radiation therapy, and chemotherapy of paclitaxel, followed by CBDCA+VP-16. He is presently alive sixteen months after diagnosis.

Topics: Aged; Biopsy; Carcinoma, Small Cell; Combined Modality Therapy; Esophageal Neoplasms; Humans; Inappropriate ADH Syndrome; Male; Tomography, X-Ray Computed; Vasopressins

Syndrome of inappropriate antidiuretic hormone secretion is frequent in small-cell lung carcinomas. We report on a case of syndrome of inappropriate antidiuretic hormone secretion after each of the first 2 cycles of chemotherapy for small-cell lung cancer. The association with chemotherapy-induced tumor lysis is proposed, particularly based on the course of antidiuretic hormone levels, and a review of the literature is presented. Syndrome of inappropriate antidiuretic hormone secretion can occur during tumor lysis syndrome.

Topics: Carcinoma, Small Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Middle Aged; Paraneoplastic Syndromes; Tumor Lysis Syndrome; Vasopressins

The purpose of this study is to elucidate the influence of serum arginine-vasopressin (AVP) level on prognosis of extensive-disease small-cell lung cancer (ED-SCLC).. We retrospectively investigated the clinical records of 163 patients with ED-SCLC, who were admitted to Okayama University Hospital or National Shikoku Cancer Center Hospital. The influence of 14 pretreatment variables on survival was analyzed.. In a multivariate analysis of 163 patients, elevation of serum LDH level (P = 0.028) and poor performance status (PS > or = 2, P = 0.002) were independent poor prognostic factors. In 34 patients whose serum AVP levels were available, high serum AVP level was related to the poor prognosis (P < 0.001). The serum-sodium level did not affect the survival. Median serum level of osmotic pressure in 34 patients was normal (284.9 mOsm/kg), although, serum osmotic pressure was low in four of six patients with high serum AVP level. In all patients with high serum AVP level, serum LDH level was elevated.. The data from the current study suggested that serum LDH level and PS were the poor prognostic factors for ED-SCLC. But we additionally identified the prognostic significance of serum AVP level, which may be a more useful factor than serum-sodium level.

Topics: Adult; Aged; Aged, 80 and over; Arginine; Biomarkers, Tumor; Carcinoma, Small Cell; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Medical Records; Middle Aged; Multivariate Analysis; Osmotic Pressure; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Factors; Vasopressins

Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT- and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90RSK). Pre-incubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca2+ chelator significantly reduced OT- and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT- and VP-induced p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, PKC and ERK1/2 are absolutely required for the OT- and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT- and VP-induced mitogenic effects on SCLC are respectively mediated by OTR and V1aR signalling and that this mitogenic signalling passes through the phosphorylation of ERK1/2 and p90RSK in a PLC-, Ca2+-, PKC- and MEK1/2-dependent pathway.

Topics: Calcium; Carcinoma, Small Cell; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Oxytocin; Phosphorylation; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Vasopressins

[Arg(6),D-Trp(7,9),N(me)Phe(8)]-substance P (6-11) (SP-G) is a novel anticancer agent that has recently completed phase I clinical trials. SP-G inhibits mitogenic neuropeptide signal transduction and small cell lung cancer (SCLC) cell growth in vitro and in vivo. Using the SCLC cell line series GLC14, 16 and 19, derived from a single patient during the clinical course of their disease and the development of chemoresistance, it is shown that there was an increase in responsiveness to neuropeptides. This was paralleled by an increased sensitivity to SP-G. In a selected panel of tumour cell lines (SCLC, non-SCLC, ovarian, colorectal and pancreatic), the expression of the mitogenic neuropeptide receptors for vasopressin, gastrin-releasing peptide (GRP), bradykinin and gastrin was examined, and their sensitivity to SP-G tested in vitro and in vivo. The tumour cell lines displayed a range of sensitivity to SP-G (IC(50) values from 10.5 to 119 microM). The expression of the GRP receptor measured by reverse transcriptase-polymerase chain reaction, correlated significantly with growth inhibition by SP-G. Moreover, introduction of the GRP receptor into rat-1A fibroblasts markedly increased their sensitivity to SP-G. The measurement of receptor expression from biopsy samples by polymerase chain reaction could provide a suitable diagnostic test to predict efficacy to SP-G clinically. This strategy would be of potential benefit in neuropeptide receptor-expressing tumours in addition to SCLC, and in tumours that are relatively resistant to conventional chemotherapy.

Topics: Animals; Antineoplastic Agents; Bradykinin; Calcium; Carcinoma, Small Cell; Cell Division; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Fibroblasts; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Mice; Mice, Nude; Peptide Fragments; Rats; Receptors, Bombesin; Receptors, Neuropeptide; Substance P; Transplantation, Heterologous; Tumor Cells, Cultured; Vasopressins

An autopsy case of primary small cell carcinoma (SCC) of the prostate in a 68-year-old man is reported. The patient was admitted to hospital because of a bloody stool and suspected rectal cancer. However, a diagnosis of prostate cancer was made on the basis of a digital rectal examination, the serum level of prostate-specific antigen, and a needle biopsy of the prostate. The patient also experienced a syndrome of inappropriate secretion of antidiuretic hormone. He died 29 days after admission. At autopsy, the tumor had invaded the rectum, bladder and pelvic peritoneum. Metastases to the heart, vertebrae and lymph nodes were observed. Microscopically, the tumor was composed of small round cells that showed a solid growth pattern. Rosette formations were observed. Immunohistochemically, the tumor cells were positive for a prostatic epithelial marker and neuroendocrine markers. A high level of antidiuretic hormone was detected in the tumor tissue. To our knowledge, this is the first reported case of SCC of the prostate in which both a prostatic epithelial marker and neuroendocrine markers have been found in the same tumor. This finding supports the hypothesis that SCC of the prostate originates from a multipotential stem cell of the prostatic epithelium.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Small Cell; Fatal Outcome; Humans; Immunohistochemistry; Inappropriate ADH Syndrome; Male; Neuroendocrine Tumors; Prostate-Specific Antigen; Prostatic Neoplasms; Vasopressins

The objective of the present work was to investigate the existence of an oxytocin (OT)-mediated autocrine/paracrine signaling upon small cell carcinoma of the lung (SCCL) cell growth. In that view, OT receptor (OTR) expression, concomitant with OT synthesis and secretion, was evidenced on three different SCCL cell lines (DMS79, H146, and H345) and related to the vasopressin (VP) system. Specific OT, VP, OTR, V1a VP receptor (V1aR), and V1b/V3 VP receptor (V1bR/V3R) transcripts were identified by reverse transcription-PCR in all cell lines studied. Binding of 125I-(d(CH2)(5)(1), Tyr(Me)(2),Thr(4),Orn(8),Tyr(9)-NH2)-vasotocin (OVTA) was observed on all SCCL cell lines, with a K(d) (dissociation constant) ranging from 0.025-0.089 nM, depending on the cell line and the analytical method. Selectivity of 125I-OVTA binding was confirmed by displacement curves obtained with various OTR and VP receptor agonists and antagonists (OT, OVTA, L-371,257, VP, F180). Immunocytochemistry identified cellular OT and VP, and peptide secretion was measured in supernatants of SCCL cultures. [3H]Thymidine incorporations, applied on H345 cells, demonstrated a dose-dependent mitogenic effect of exogenous OT (1 and 100 nM) that was abolished by the OTR antagonist OVTA. A decrease of proliferation was also observed with OVTA alone, showing a functional mitogenic effect of tumor-derived OT. Taken together, these observations demonstrate the existence of a functional OT-mediated autocrine/paracrine signaling actively implicated in growth and development of SCCL tumors. Furthermore, these findings point to the potential of OT antagonists for development as therapeutic agents for the treatment of SCCL.

Topics: Animals; Carcinoma, Small Cell; Cell Division; CHO Cells; Cricetinae; Humans; Immunohistochemistry; Lung Neoplasms; Neurophysins; Oxytocin; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured; Vasopressins

The vasopressin (VP) gene is largely expressed in hypothalamic neurons, where the resultant pro-VP protein is enzymatically cleaved into its peptide hormone components, which include the neuropeptide VP, VP-associated neurophysin, and VP-associated glycopeptide (VAG). Small cell lung cancer (SCLC) tumors also express the VP gene, but the tumor pro-VP protein can remain intact and localize to the cell surface membrane. Previous studies have shown that polyclonal antibodies directed against different regions of the pro-VP protein bind specifically to the surface of cultured SCLC cells and recognize proteins of approximately 20 and approximately 40 kDa in cultured SCLC whole-cell lysate. Thus, these proteins have been designated neurophysin-related cell surface antigen (NRSA). A monoclonal antibody (mAb) designated MAG-1 was raised in this laboratory using a synthetic peptide representing the COOH-terminal sequence of VAG. The MAG-1 mAb recognizes NRSA in SCLC cell and tissue lysates by Western analysis, whereas immunofluorescent cytometric and microscopic analyses indicate that MAG-1 reacts specifically with NRSA on the surface of viable SCLC cells of both the classical and the variant subtype. Immunohistochemical analysis demonstrates that MAG-1 reacts with human SCLC tumor, but not with normal pulmonary epithelial cells in lung tissue. Additionally, a MAG-1 Fab fragment was generated that was also able to recognize NRSA. This is the first study to demonstrate that a mAb directed to the VAG region of the pro-VP protein has the potential for development into an in vivo diagnostic and therapeutic tool that targets plasma membrane-incorporated NRSA.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antigens, Surface; Arginine Vasopressin; Blotting, Western; Carcinoma, Small Cell; Glycoproteins; Immunoenzyme Techniques; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neurophysins; Oxytocin; Protein Precursors; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Vasopressins

[Arginine]vasopressin (AVP) is a neuropeptide physiologically synthesized in the hypothalamus but pathologically expressed by small-cell lung cancer (SCLC). A minimal 65 bp AVP promoter can restrict basal activity to SCLC in vitro, but a 199 bp fragment directs 5-fold higher expression in SCLC [Coulson, Stanley and Woll (1999) Br. J. Cancer 80, 1935-1944]. Several predicted E-box motifs occur within the 199 bp fragment, and we now describe an enhancer which contributes to AVP promoter tumour-specificity in some cell lines. The deletion of two adjacent E-boxes (-157 to -131) resulted in an approx. 70% loss of reporter gene expression in a SCLC line (Lu-165) with high endogenous AVP production. Using a series of AVP promoter deletion constructs and site-directed mutagenesis, we show that both these E-box sites were required for enhancer function, whereas mutation of an adjacent AP-1 site had no effect on the promoter activity. Electrophoretic-mobility-shift analysis indicated that, although both the predicted E-box motifs bound specific complexes, only one appeared to function as a strong E-box which binds basic helix-loop-helix (bHLH) factors. This motif formed a complex in lung tumour-cell extracts, which was particularly strongly bound in Lu-165, and was competed for by a characterized E-box motif from the preprotachykinin A promoter. Antibody supershifts indicate that this complex is a heterodimer of upstream stimulatory factor (USF)-1 and USF-2. Non-bHLH complexes weakly bound the second potential E-box motif in a SCLC-specific manner. These complexes were not recognized by the bHLH antibodies and remain unidentified; however, they were detected in seven of eight SCLC cell lines and not in four control lines. We postulate that there is a co-operative and complex interaction between an E-box and an adjacent site constituting a SCLC-specific enhancer within the AVP proximal promoter.

Topics: Base Sequence; Carcinoma, Small Cell; DNA-Binding Proteins; Enhancer Elements, Genetic; Gene Expression Regulation, Neoplastic; Genes, Reporter; Helix-Loop-Helix Motifs; Humans; Lung Neoplasms; Molecular Sequence Data; Mutagenesis, Site-Directed; Promoter Regions, Genetic; Regulatory Sequences, Nucleic Acid; Sequence Deletion; Transcription Factors; Transfection; Tumor Cells, Cultured; Vasopressins

Vasopressin is one of several small neuropeptides that are reported to be autocrine growth factors for small cell carcinoma of the lung (SCCL). It has been assumed that this peptide exercises its mitogenic influences through the vasopressin V1a receptor, and we have previously demonstrated that this receptor is expressed by classical and variant SCCL. Activation of the vasopressin V1a receptor produces changes in phospholipases C, D, and A2, in protein kinase C, and in Ca2+ mobilization. This study demonstrates that SCCL cells express not only vasopressin V1a receptors but also mRNAs and proteins representing normal V1b receptors and V2 receptors. They were also shown to express mRNA for a human form of the putative receptor rabbit vasopressin-activated calcium-mobilizing receptor (VACM-1). Additionally, SCCL tumor cells were found to express mRNA and protein representing a possible nonfunctional, shortened, "diabetic" form of the vasopressin V2 receptor that is the product of incomplete posttranscriptional splicing. At least four of these five vasopressin receptors were produced by cell lines exemplifying classical and variant forms of SCCL. No differences in the sequences for the V1 receptors between classical and variant SCCL were found. However, although the nature and expression of both vasopressin V1 receptors and human VACM are apparently unaffected by dedifferentiation in SCCL, only the abnormal (and probably nonfunctional) form of the V2 receptor could be demonstrated in variant cell line NCI H82. Functional engagement of vasopressin V2 receptors is reported to produce rises in cAMP and activation of protein kinase A, whereas stimulation of V1b receptors is believed to produce similar changes to those produced by V1a receptors, i.e., activation of phospholipases and of protein kinase C. Stimulation of VACM receptors raises intracellular free Ca2+ through currently unknown but phosphoinositide-independent mechanisms. The presence of all known vasopressin receptors that are, together, potentially capable of inducing several different transduction cascades in small cell tumor cells suggests that this peptide serves a multifaceted role in tumor physiology.

Topics: Animals; Base Sequence; Blotting, Northern; Blotting, Western; Carcinoma, Small Cell; DNA Primers; Humans; Lung Neoplasms; Molecular Sequence Data; Polymerase Chain Reaction; Rabbits; Receptors, Vasopressin; RNA, Messenger; Tumor Cells, Cultured; Vasopressins

A 72-year-old man was hospitalized with asymptomatic hyponatremia. Despite hyponatremia, urinary sodium excretion with urine osmolality exceeding plasma osmolality persisted. Plasma vasopressin levels were high and independent of plasma osmolality during hypertonic saline infusion. Computed tomography of the chest showed enlarged mediastinal and right hilar lymph nodes. Microscopically, a specimen of lymph nodes obtained by biopsy represented vasopressin-producing small cell lung carcinoma. Chemotherapy plus irradiation improved the hyponatremia. Thus, careful evaluation is necessary to determine the cause of hyponatremia disorders in elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Bronchoscopy; Carcinoma, Small Cell; Follow-Up Studies; Humans; Hyponatremia; Inappropriate ADH Syndrome; Lung Neoplasms; Magnetic Resonance Imaging; Male; Osmosis; Radiotherapy, Adjuvant; Sodium; Tomography, X-Ray Computed; Vasopressins

A polymorphism in the nucleic acid sequence encoding the signal peptide of the human prepro-vasopressin (AVP) has been reported in an AVP producing small cell lung carcinoma (SCLC) cell line. The difference predicts expression in tumor cells of a variant signal peptide with Pro for Leu 11. To clarify whether this difference is required for AVP secretion from SCLC cells and/or reflects increased mutagenesis in malignant tumors, the exon encoding the signal peptide of prepro-AVP in two AVP producing SCLC and 9 non-producing lung tumors was amplified using polymerase chain reaction. The variant sequence was neither found by direct sequencing nor by restriction enzyme analysis. These results suggest that similar to the hypothalamus the normal signal peptide is functional in tumor cells and that the variant signal peptide is not a prerequisite for AVP secretion from SCLC cells.

Topics: Animals; Base Sequence; Carcinoma, Small Cell; DNA Restriction Enzymes; Exons; Genotype; Humans; Lung Neoplasms; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Polymerase Chain Reaction; Protein Precursors; Protein Sorting Signals; Sequence Analysis, DNA; Tumor Cells, Cultured; Vasopressins

In a 59-year-old woman suffering from the syndrome of inappropriate antidiuretic hormone secretion, a small cell carcinoma of the uterine cervix was detected. The tumor was immunoreactive for antidiuretic hormone as well as for neuron specific enolase, chromogranin A, and Leu-7, but not vimentin. Electron microscopic examination of the tumor revealed neurosecretory granules. To our knowledge, this is only the second report of the syndrome of inappropriate antidiuretic hormone secretion with small cell carcinoma of the uterine cervix and the first one confirmed immunohistopathologically.

Topics: Carcinoma, Small Cell; CD57 Antigens; Chromogranin A; Chromogranins; Female; Humans; Immunohistochemistry; Inappropriate ADH Syndrome; Middle Aged; Phosphopyruvate Hydratase; Uterine Cervical Neoplasms; Vasopressins

Expression of the vasopressin gene appears to be a property common to all small-cell lung tumours. For some cultures of small-cell lung carcinoma (SCCL), Northern and Western Blot analyses have revealed that expression of this gene and its protein products are regulated by cAMP and glucocorticoids. In this study, these evaluations have been extended by examining the production of vasopressin-associated human neurophysin (VP-HNP) by computer-enhanced quantitative immunocytochemistry in a classical cell-line (H69) of SCCL, and defining the amount of protein in cells by area of positive staining above an arbitrarily set threshold. Intracellular cAMP was raised by incubating cells with either 8,Br-cAMP (0.5 mM) and IBMX (0.5 mM), or with forskolin (25 microM) and IBMX (0.5 mM). Both of these treatments caused a significant increase in the amount of positive VP-HNP immunoreactivity in the cells, an increase that was further enhanced by simultaneous administration of dexamethasone (0.1 microM). Addition of dexamethasone alone, however, caused a significant decrease in VP-HNP levels. Results confirm earlier findings from Western Blot analysis revealing the influence these agents have on production of vasopressin gene-related proteins by H69 cells, and indicate that computer-enhanced quantitative immunocytochemistry can be effectively used to provide a suitable index of this production.

Topics: 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Carcinoma, Small Cell; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Densitometry; Dexamethasone; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Image Processing, Computer-Assisted; Immunoenzyme Techniques; Lung Neoplasms; Neoplasm Proteins; Neurophysins; Tumor Cells, Cultured; Vasopressins

A 76-year-old man with small cell lung cancer associated with the syndrome of inappropriate secretion of ADH (SIADH) visited our hospital. The serum Na level was normal on the first visit, but 2 weeks later it decreased to 114 mEq/L with an extremely high plasma vasopressin (VP) level of 1520 pg/ml. Serum Na was normalized after the reduction of the tumor size by chemotherapy, but the plasma VP level remained between 150 to 600 pg/ml. On gel filtration of plasma VP two peaks of immunoreactive VP were eluted at the positions of a larger molecule than authentic VP and authentic VP, and VP in urine gave only one peak compared to that of authentic VP. The dilution curve of plasma VP was almost parallel and that of urine was completely parallel to the standard curve. These findings suggest that a larger VP with low physiological activity was predominantly secreted in the present patient and manifested relatively mild symptoms despite the extremely high plasma VP level.

Topics: Aged; Carcinoma, Small Cell; Chromatography, Gel; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Sodium; Vasopressins

Bromocriptine, a dopaminergic agonist, inhibited the growth of human small cell lung cancer (SCLC) implanted as tumor xenografts in athymic nude mice; the effect was dose dependent. In mice bearing a SCLC with ectopic vasopressin production, plasma levels of human vasopressin-associated neurophysin decreased concomitantly. Electron microscopy of tumor tissues revealed marked degenerative changes, including pyknosis, densely aggregated chromatin masses, and vacuolization of cytoplasm after bromocriptine treatment. When a SCLC cell line, NCI-H69, was grown in semisolid medium, bromocriptine inhibited its clonal growth in a dose-related manner. Coincubation with dopamine D2 receptor antagonist, metoclopramide, or domperidone, completely blocked the inhibitory effect of bromocriptine. Receptor studies with a dopamine D2 receptor ligand, [125I]iodosulpride, showed high affinity binding sites on the membranes of SCLC cells. These results indicate that SCLC cells are enriched with dopamine D2 receptors, which may mediate the growth-inhibitory effect of bromocriptine on SCLC. Dopaminergic agonists may be useful in the medical treatment of SCLC.

Topics: Animals; Bromocriptine; Carcinoma, Small Cell; Cell Division; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Receptors, Dopamine; Transplantation, Heterologous; Vasopressins

Four classical and three variant small-cell carcinoma of the lung (SCCL) cell lines were examined for vasopressin and vasopressin V1a-receptor immunoreactivity. One of these classical cell lines, NCI-H345, and one variant cell line, NCI-H82, were further investigated for binding of V1 and V2 vasopressin-receptor antagonists, vasopressin-induced calcium mobilization, and vasopressin-induced thymidine uptake. All classical and variant SCCL cell lines examined contained vasopressin and vasopressin-receptors as determined by immunocytochemistry. Both NCI-H82 and NCI-H345 demonstrated similar binding patterns with the V1 and V2 vasopressin-receptor antagonists, indicating the presence of both receptor subtypes. For the classical cell line (NCI-H345), vasopressin (1 microM) induced an increase in cytosolic free calcium, while the peptide was ineffective at increasing cytosolic calcium in the variant cell line (NCI-H82). However, vasopressin (0.1 or 1 microM) was unable to stimulate thymidine uptake in the classical (NCI-H345) or variant (NCI-H82) cell lines for the conditions used. These results indicate that both classical and variant SCCL produce vasopressin, and vasopressin V1a and V2 receptors. In the variant cell line, there appears to be a disruption in the activation cascade for V1a receptors as indicated by the lack of vasopressin-induced calcium mobilization.

Topics: Calcimycin; Calcium; Carcinoma, Small Cell; Cytosol; Humans; Lung Neoplasms; Receptors, Vasopressin; Thymidine; Tumor Cells, Cultured; Vasopressins

A new cancer cell line (Lu-165) producing a large amount of anti-diuretic hormone (ADH, 2.8 micrograms/g protein) was established from a 50-year-old small cell lung cancer patient presenting with a syndrome of inappropriate anti-diuretic hormone secretion. These cells grew well in serum-supplemented medium and during more than 100 passages they continued producing a large amount of this hormone. This cell line will be a useful tool for studies of the biochemistry and pathology of ADH-producing cancer.

Topics: Animals; Carcinoma, Small Cell; Cell Division; Cell Nucleus; Cytoplasm; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Microscopy, Electron; Middle Aged; Neoplasm Transplantation; Tumor Cells, Cultured; Vasopressins

Small-cell neuroendocrine carcinoma of the lung is known to express products related to the vasopressin gene, although these products have been reported to sometimes differ from those generated by neurones of the hypothalamo-neurohypophyseal system. To further investigate vasopressin gene expression in neuroendocrine carcinomas, we performed immunohistochemistry on 24 histologically classified small-cell carcinomas using antibodies directed against different regions of the vasopressin precursor. All of the tumours examined contained at least two parts of the vasopressin precursor, suggesting that vasopressin might have a biological role in these tumours and indicating a role for these products in tumour diagnosis and treatment. Sixty-seven per cent of the tumours contained immunoreactivity for all major regions of the precursor: vasopressin, vasopressin-associated human neurophysin, the bridging region between the hormone and the neurophysin, and vasopressin-associated human glycopeptide. However, 33% of the tumours examined appeared to express only part of the vasopressin precursor, as evidenced by the absence of immunoreactivity for the neurophysin and/or the glycopeptide. These results support the proposition that both normal and abnormal vasopressin gene expression occurs in small-cell carcinoma of the lung.

Topics: Carcinoma, Small Cell; Humans; Lung Neoplasms; Neurophysins; Protein Precursors; Vasopressins

Various polypeptide hormones including vasopressin (VP) and gastrin-releasing peptide (GRP) are produced by small cell lung carcinomas (SCLC). VP as well as GRP have mitogenic effects on several cell types and are proposed to be autocrine growth factors. In this study the presence of VP mRNA, oxytocin (OT) mRNA and GRP mRNA was investigated in cell lines derived from SCLCs. Out of 26 cell lines 3 contained low amounts of VP mRNA (GLC-8, SCLC-21H and NCI-H345) and 7 contained abundant GRP mRNA (GLC-16, GLC-1-M13, SCLC-22H, NCI-H249, NCI-H345, NCI-H449 and NCI-H450). The GRP mRNA-containing cell lines belong to the classic SCLC type, whereas VP mRNA was found in two classic and one variant cell line. None of the SCLC cell lines contained detectable levels of OT mRNA. Of the three VP-expressing SCLC cell lines, GLC-8 had the highest level of VP mRNA. Both the length of the transcript and the hybridization with different probes containing exons A and C of the VP gene suggest that the detected transcript is a normal VP messenger. SCLC GLC-8 contained low levels of VP immunoreactivity and VP receptors. In GLC-8 an autocrine role of VP may be suspected.

Topics: Base Sequence; Blotting, Northern; Carcinoma, Small Cell; DNA Probes; Gastrin-Releasing Peptide; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Molecular Sequence Data; Oxytocin; Peptide Biosynthesis; Peptides; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured; Vasopressins

Plasma antidiuretic hormone (ADH) was assayed before and after surgery for lung cancers. The results showed that the plasma ADH in the control group was 11.6 +/- 4.8 pg/ml in contrast to higher levels in the lung cancer patients. The ADH level was highest in patients with small cell anaplastic cancer (SCAC), and in decreasing order, adenocarcinoma, mixed cell type carcinoma and lowest in squamous cell carcinoma. The ADH levels in all patients were reduced postoperatively from one week to three months when they approached the control level. One year later, ADH became elevated again in those who developed recurrence as compared with those clinically free of the disease. The difference was most significant in patients suffering from SCAC (P < 0.05-0.001). The authors believe that ADH assay may be useful in the diagnosis, assessment of treatment and monitor or prognosis in lung cancers.

Topics: Adenocarcinoma; Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Period; Vasopressins

Analogues of the neurotransmitter substance P (SP) can interact with neuropeptide receptors, and are reported to inhibit growth of small cell lung cancer cell lines (SCLC CLs). We found [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P (D-Phe5SP) significantly inhibited DNA synthesis by 10/10 human tumour CLs; six SCLC, one N-SCLC (squamous), two ovarian and one squamous cervical carcinoma, with inhibition to 50% control levels (IC50) of 20-50 microM. There was dose dependent inhibition of colony forming efficiency (CFE) in 3/3 SCLC and 1/1 N-SCLC CL, IC50s of 0.5-6.5 microM in 5% serum. Exposure of SCLC CL HC12 to 100 microM D-Phe5SP for 1-4 h caused a progressive fall in viable cell number; surviving cells, grown in the absence of peptide, showed a decreased growth rate. During 1 week's exposure of two SCLC CLs to 20 microM D-Ph5SP, growth was slower than control cultures, while 50-100 microM completely inhibited growth. These inhibitory effects were partially reversed by increasing serum concentration from 5 to 20%, but not by SP, vasopressin, bombesin or insulin-like growth factor 1. There was some inhibition of CFE by 3/3 normal human bone marrows, IC50s of 30-80 microM, compared with 8 microM for HC12 in 20% FCS. Therefore D-Phe5SP appears to have more potent antiproliferative effects in tumour cells than normal cells, suggesting a role for this analogue in tumour treatment.

Topics: Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Bombesin; Bone Marrow; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Division; Cell Line; Colony-Forming Units Assay; DNA; Dose-Response Relationship, Drug; Female; Fibroblasts; Humans; In Vitro Techniques; Insulin-Like Growth Factor I; Lung Neoplasms; Ovarian Neoplasms; Substance P; Time Factors; Vasopressins

Vasopressin (VP) and oxytocin (OT) were evaluated as tumor markers for small cell carcinoma of the lung by measuring the concentrations of these hormones in plasma samples obtained from patients at the onset of therapy and during treatment. Patient levels of VP before treatment ranged from 0.9-116 pmol/L, and this hormone was elevated (greater than 2.4 times) in 37 of 80 patients (46%) when values were compared to those of 25 healthy volunteers (normal mean, 2.13 +/- 0.15 pmol/L). Seventeen patients with elevated arginine VP displayed symptoms of the syndrome of inappropriate secretion of antidiuretic hormone. Patient levels of OT ranged from 0.3-124 pmol/L, and OT was elevated (greater than 2.4 times) in 14 of 72 patients (19%) compared with values in normal subjects (normal mean, 2.23 +/- 0.34 pmol/L). Both hormones were elevated in 6 patients. A positive response to treatment (partial or complete remission) was associated with reductions of elevated VP to 34.6 +/- 4.0% and of elevated OT to 34.7 +/- 7.5%, of values before treatment. Relapse was associated with an increase to 334 +/- 93% of remission values for VP (6 patients) and to 307% for OT (1 patient). These results indicate that VP and OT may be suitable plasma markers for a majority of small cell tumors. In most cases, an elevated concentration of hormone was associated with an elevation of the biosynthetically related neurophysin and vice versa. However, there were a number of exceptions, so that an elevated plasma concentration of VP, OT, or a neurophysin was found for 88% of patients with extensive disease and 70% of patients with limited disease.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neuropeptides; Neurophysins; Oxytocin; Reference Values; Vasopressins

We tested whether Ca(2+)-mobilizing neuropeptides can function as growth factors for small cell lung carcinoma cells. The neuropeptides bradykinin, neurotensin, cholecystokinin, and vasopressin at nanomolar concentrations stimulated a rapid and transient increase in the intracellular concentration of Ca2+. Crucially, these peptides in the same concentration range also caused a marked increase in colony formation in semisolid medium in responsive small cell lung carcinoma cell lines. At optimal concentrations bradykinin, neurotensin, cholecystokinin, vasopressin, galanin, and gastrin-releasing peptide were equally effective in promoting clonal growth. These findings support the hypothesis that small cell lung carcinoma growth is sustained by an extensive network of autocrine and paracrine interactions involving multiple neuropeptides.

Topics: Bradykinin; Calcium; Carcinoma, Small Cell; Cell Division; Cholecystokinin; Galanin; Humans; In Vitro Techniques; Lung Neoplasms; Neuropeptides; Neurotensin; Peptides; Tumor Cells, Cultured; Tumor Stem Cell Assay; Vasopressins

The role of glucocorticoids and second messenger systems in the regulation of the vasopressin (VP) gene was studied in the human small cell lung carcinoma cell line GLC-8. Small cell lung carcinoma GLC-8 cells express VP mRNA and contain both glucocorticoid and mineralocorticoid receptors. Treatment with the synthetic glucocorticoid dexamethasone when added alone at 10(-8) M had no effect on the VP mRNA level and decreased the level by 30% at 10(-6) M. However, the effect of dexamethasone changed to positive when cells were simultaneously treated with cAMP-enhancing agents. VP mRNA levels, which were elevated by 1.5- to 2-fold by the cAMP-enhancing agents alone, increased a further 1.5- to 3-fold by dexamethasone. Thus, the combined effect of dexamethasone and cAMP stimulation was a 3- to 7.5-fold increase in VP mRNA levels. Long term treatment with the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) reduced the VP mRNA level by 75%. The TPA-suppressed VP mRNA levels could be up-regulated about 6-fold by simultaneous treatment with 8-bromo-cAMP. Dexamethasone did not alter the TPA-suppressed VP mRNA levels. These results indicate that both cAMP and protein kinase-C pathways as well as glucocorticoid receptors are involved in the regulation of VP mRNA levels and that these factors interact. This leads to a negative or positive response of VP gene expression to glucocorticoids in a state-dependent manner. The interactions may be of significance in a physiological context and relate to the different regulation of VP-expressing systems in the brain.

Topics: 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Aldosterone; Carcinoma, Small Cell; Cell Line; Cyclic AMP; Dexamethasone; Gene Expression Regulation, Neoplastic; Humans; Hydrocortisone; Lung Neoplasms; Receptors, Glucocorticoid; RNA, Messenger; Second Messenger Systems; Tetradecanoylphorbol Acetate; Transcription, Genetic; Vasopressins

In the search for novel antiproliferative agents for small cell lung cancer (SCLC), we found the neuropeptide antagonist [Arg6, D-Trp7,9,MePhe8]substance P(6-11) to be effective in vitro. In murine Swiss 3T3 cells [Arg6,D-Trp7,9,MePhe8]substance P(6-11) was identified as a potent inhibitor of vasopressin-stimulated DNA synthesis which also blocks [3H]vasopressin binding to specific cell-surface receptors. It was a less potent antagonist of gastrin-releasing peptide and bradykinin in these cells but did not block the effects of other mitogens. In SCLC cell lines, [Arg6,D-Trp7,9,MePhe8]substance P(6-11) inhibited colony-formation in soft agarose and growth in liquid culture in a dose-dependent manner. It also blocked receptor-mediated Ca2+ mobilization induced by vasopressin, bradykinin, cholecystokinin, galanin, gastrin-releasing peptide, and neurotensin. We suggest that broad-spectrum neuropeptide antagonists can block multiple autocrine and paracrine growth loops in SCLC and could be useful therapeutic agents.

Topics: Animals; Bradykinin; Calcium; Carcinoma, Small Cell; Cell Division; Cells, Cultured; DNA, Neoplasm; Drug Screening Assays, Antitumor; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Mice; Peptide Fragments; Peptides; Recombinant Proteins; Substance P; Tumor Cells, Cultured; Vasopressins

The possible role of cyclic AMP (cAMP) in the regulation of the vasopressin (VP) gene was tested in two cellular expression systems: one cell line with endogenous VP expression and the other which was transiently with a VP promoter-luciferase fusion gene. 8,Bromo-cAMP stimulated the VP mRNA content about 4-fold in the human VP-expressing small cell lung carcinoma cell line GLC-8. The luciferase activity in P19 embryonal carcinoma cells which were transiently transfected with -174 to +44 of the 5'-flanking region of the human VP gene linked to the firefly luciferase gene, was stimulated about 2-fold by the cAMP analogue. The results indicate that cAMP plays a role in the upregulation of the VP gene and hence point to several putative nucleotide motives in the promoter functionally conferring this response.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Actins; Animals; Base Sequence; Carcinoma, Small Cell; Cloning, Molecular; Cyclic AMP; DNA, Recombinant; Gene Expression Regulation; Humans; Luciferases; Lung Neoplasms; Mice; Molecular Sequence Data; Promoter Regions, Genetic; RNA, Messenger; Transfection; Tumor Cells, Cultured; Vasopressins

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.

Topics: Adenosine Diphosphate Ribose; Adenylyl Cyclases; Bombesin; Calcium; Carcinoma, Small Cell; Cell Division; Cell Membrane; Cholera Toxin; Colforsin; Dose-Response Relationship, Drug; G(M1) Ganglioside; Growth Inhibitors; GTP-Binding Proteins; Humans; In Vitro Techniques; Ionomycin; Mitogens; Receptors, Bombesin; Receptors, Neurotransmitter; Signal Transduction; Time Factors; Tumor Cells, Cultured; Vasopressins

The neuropeptides vasopressin, bradykinin, cholecystokinin, galanin, neurotensin and gastrin-releasing peptide stimulate rapid, transient increases in cytosolic Ca2+ in small cell lung cancer cell lines at nanomolar concentrations. Responsiveness to individual peptides is heterogeneous among the diverse cell lines, but the ability to respond to regulatory peptides is a general phenomenon. Peptide responses demonstrate homologous desensitisation and are blocked by ligand-specific antagonists, indicating that they are mediated by distinct receptors. Many neuropeptides are also secreted by small cell lung cancer. Here we suggest that multiple autocrine and paracrine interactions regulate its growth.

Topics: Bradykinin; Calcium; Carcinoma, Small Cell; Cholecystokinin; Galanin; Humans; Lung Neoplasms; Neuropeptides; Neurotensin; Peptides; Tumor Cells, Cultured; Vasopressins

A panel of human lung carcinoma lines was studied with respect to hormone production and intermediate filament expression to distinguish between endodermal and neuroendocrine differentiation. An index of the degree of neuroendocrine differentiation of each line was derived from the presence or absence of hormone production, cytokeratins, neurofilaments and an embryonic endodermal cell marker, which allowed identification of three groups showing high, intermediate or low neuroendocrine expression. This grouping correlated well with the in vitro radiosensitivity of the lines, those expressing pure neuroendocrine features being significantly more radiosensitive than those with an endodermal phenotype, with the intermediate group having intermediate sensitivity. Use of such an index might predict those patients likely to benefit from the use of radiotherapy in their management.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Line; Humans; Intermediate Filaments; Keratins; Lung Neoplasms; Radiation Tolerance; Vasopressins

In this study we have identified and characterized several vasopressin-like peptides in the plasma of a patient with the syndrome of inappropriate antidiuretic hormone secretion and oat cell carcinoma of the lung. Immunoreactive plasma vasopressin was measured after gel filtration (Sephadex G-25) or C-18 cartridge extraction using two different region-specific antisera: AS1 and AS2. Antiserum AS1 is more specifically directed towards the antigenic site of the hexapeptidic ring of arginine-vasopressin (AVP), whereas AS2 is more specifically directed towards the C-terminal region of AVP. Unexpectedly, the Sephadex G-25 gel filtration elution profile of the immunoreactive vasopressin was very heterogeneous, indicating the presence of several molecular species. After extraction of total AVP and AVP-like peptides of this plasma, an unusual AS1/AS2 ratio of immunoreactivity was observed, suggesting the presence of vasopressin-like peptides which differ from AVP in the C-terminus.

Topics: Aged; Arginine Vasopressin; Carcinoma, Small Cell; Chromatography, Gel; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Molecular Conformation; Radioimmunoassay; Trypsin; Vasopressins

Topics: Arginine Vasopressin; Atrial Natriuretic Factor; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Neurophysins; Oxytocin; Paraneoplastic Endocrine Syndromes; Protein Precursors; Vasopressins

Patients with small-cell lung cancer and hyponatremia were examined for the syndrome of inappropriate antidiuresis (SIAD). A comparison was made between the definition based on hyponatremia, serum hypoosmolality and urine hyperosmolality (classic SIAD, 12 patients) and a definition based on measurement of plasma ADH concentration by radioimmunoassay (RIA-SIAD, nine patients) and patients without SIAD (eight patients). A standard water load test was performed as a reference before initiation of cytostatic treatment. All tests were repeated if remission of the malignant disease occurred. RIA-SIAD patients were a subgroup of classic SIAD patients, with more pronounced homeostatic abnormalities. Biochemical abnormalities were reduced after tumor regression but a completely normal renal water handling was achieved in only few patients, even when complete remission of the tumor was achieved, presumably due to the persistence of subclinical disease. However, an effect of other yet unknown factors might be of influence.

Topics: Carcinoma, Small Cell; Female; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Osmolar Concentration; Radioimmunoassay; Remission Induction; Vasopressins

Topics: Bone Marrow Transplantation; Bronchial Neoplasms; Carcinoma, Small Cell; Cyclophosphamide; Dehydration; Diabetes Insipidus; Humans; Kidney Diseases; Liver Neoplasms; Male; Middle Aged; Vasopressins

The relationships between prognostic factors and duration of survival in small cell lung cancer were investigated in a consecutive series of 874 patients treated with combination chemotherapy with or without irradiation. The series included 443 patients with limited and 431 patients with extensive stage disease based on staging including bone marrow examination and peritoneoscopy with liver biopsy but no routine scans. The median durations of survival for the two disease categories were 48 and 30 weeks, respectively. The influence on survival of various pretreatment factors was investigated by use of univariate methods and Cox's multivariate regression model. Patients in each stage were treated according to one of three controlled trials. Variations among the applied treatment regimens did not result in significant differences in duration of survival among patients with limited disease. An alternating regimen was superior to continuous therapy in patients with extensive disease and raised serum lactate dehydrogenase. Prognosis was correlated with disease extent. Surgical resection as well as limited stage disease thus both contributed to survival. Poor performance status, reduced hemoglobin concentration, and raised values for serum lactate dehydrogenase were significantly associated with a reduced duration of survival in both stages. Females with limited disease lived significantly longer than males while advanced age was a negative prognostic factor in extensive disease. Plasma sodium and serum urate were both predictive of survival in limited disease. Proved metastatic disease affecting specific sites or total number of metastatic sites did not carry significant prognostic information in a model including a general variable characterizing stage of disease. Fifty of the 778 patients, on whom the multiple regression model was based, were alive and disease free 2 years after the start of the treatment. Two-year survival rates were strongly correlated to groupings based on prognostic factors, and information about disease extent was not mandatory for predicting the probability of long term disease-free survival.

Topics: Adult; Aged; Alkaline Phosphatase; Carcinoma, Small Cell; Combined Modality Therapy; Erythropoietin; Female; Hormones, Ectopic; Humans; L-Lactate Dehydrogenase; Lung Neoplasms; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Prognosis; Regression Analysis; Risk; Vasopressins

Review of clinical data from 350 patients with small-cell lung cancer (SCLC) revealed hyponatremia (sodium less than 130 mEq/L) attributable to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 40 patients (11%). Although hyponatremia was severe in most instances (median, sodium 117 mEq/L), symptoms attributable to water intoxication were identified in only 27% of hyponatremic episodes. Development of SIADH showed no correlation with clinical stage, distribution of metastatic sites, sex, or histologic subtype of small-cell carcinoma. SIADH occurred most often with initial presentation (33 of 40), and resolved promptly (less than 3 weeks) with initiation of combination chemotherapy in 80% of evaluable patients. The presence of SIADH did not influence response to chemotherapy or overall survival as an independent variable. However, in five patients profound hyponatremia developed immediately following primary cytotoxic therapy (range, one to five days). Despite initial control of SIADH, dilutional hyponatremia recurred in 70% of patients with tumor progression. Our findings suggest that development of clinically demonstrable SIADH in patients with SCLC is dependent on functional properties of the neoplastic cells, rather than tumor burden or metastatic site. The potential for development of clinically significant hyponatremia early in the course of cytotoxic therapy emphasizes the need to closely monitor patients, particularly those receiving chemotherapy regimens requiring substantial intravenous hydration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Female; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Staging; Osmolar Concentration; Paraneoplastic Endocrine Syndromes; Sodium; Vasopressins

The binding of a radiolabeled bombesin analogue to human small cell lung cancer (SCLC) cell lines was investigated. (125I-Tyr4)bombesin bound with high affinity (Kd = 0.5 nM) to a single class of sites (2,000/cell) using SCLC line NCI-H446. Binding was reversible, saturable and specific. The pharmacology of binding was investigated using NCI-H466 and SCLC line NCI-H345. Bombesin and structurally related peptides, such as gastrin releasing peptide (GRP), but not other peptides, such as substance P or vasopressin, inhibited high affinity (125I-Tyr4)BN binding activity. Finally, the putative receptor, a 78,000 dalton polypeptide, was identified by purifying radiolabeled cell lysates on bombesin or GRP affinity resins and then displaying the bound polypeptides on sodium dodecylsulfate polyacrylamide gels. Because SCLC both produces bombesin/GRP-like peptides and contains high affinity receptors for these peptides, they may function as important autocrine regulatory factors for human SCLC.

Topics: Bombesin; Carcinoma, Small Cell; Cell Line; Chromatography, Affinity; Gastrin-Releasing Peptide; Humans; Kinetics; Lung Neoplasms; Peptides; Receptors, Bombesin; Receptors, Cell Surface; Substance P; Vasopressins

Vasopressin (ADH) was measured in CSF and plasma in 75 evaluable patients with known or suspected CNS metastases from small-cell bronchogenic carcinoma (SCBC), and in 66 control patients having neither malignant disease nor organic CNS disease. The presence of CNS metastases was confirmed or excluded on the basis of computed tomographic scans, neurologic examination, and autopsy. Twenty-four of the 75 patients had no CNS metastases. Ten of the 51 patients with CNS metastases had leptomeningeal carcinomatosis (MC). CSF-ADH was significantly increased in patients with MC (P less than .05), but not in patients having exclusively parenchymatous CNS metastases. Taking 2 pg/mL (95th percentile of control patients) as the upper limit of normal, 15 SCBC patients had elevated CSF-ADH, including 12 patients with CNS metastases and six patients with MC. The CSF-ADH to plasma ADH ratio was significantly increased in patients with CNS metastases (P less than .05). Patients without CNS metastases had a ratio less than or equal to 0.8 whereas the ratio was greater than 0.8, in 21 of the 51 patients with CNS metastases. The positive and negative predictive values with 95% confidence limits were 84% to 100% and 31% to 59%, respectively. Patients with inappropriate secretion of ADH (SIADH) constituted a significantly greater proportion of patients with elevated CSF-ADH than of patients with normal CSF-ADH levels (P less than .05). In addition, patients with SIADH constituted a significantly greater proportion of patients with MC than of patients with parenchymatous metastases (P less than .05). The diagnostic application of these findings is limited because of the large number of false-negative results, but it may prove to be of value in conjunction with the measurement of other tumor markers.

Topics: Carcinoma, Bronchogenic; Carcinoma, Small Cell; Central Nervous System Diseases; Humans; Inappropriate ADH Syndrome; Intracranial Pressure; Lung Neoplasms; Meningeal Neoplasms; Neoplasm Metastasis; Vasopressins

To determine whether propressophysin (vasopressin-neurophysin precursor) is present in human plasma, the nature of the immunoreactive neurophysin was characterized by gel filtration. When plasma samples obtained from six patients with the syndrome of inappropriate antidiuretic hormone secretion due to central nervous system disease were fractionated on a column of Sephadex G-50 in 0.2 N acetic acid, virtually all of the nicotine-stimulated neurophysin (NSN) immunoreactivity coeluted with 125I-labeled NSN. In contrast, gel filtration of plasma from six patients with oat cell carcinoma of the lung with ectopic vasopressin production consistently demonstrated, in addition, a peak of a higher molecular weight (HMW) form of neurophysin. This HMW neurophysin represented 8.7-29.4% of the total NSN immunoreactivity in plasma and its elution profile was not changed when chromatographed after incubation in 6 M urea. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the HMW neurophysin ran in the 20,000-dalton area of the gel. A substantial portion of the HMW neurophysin appeared to be a glycoprotein judging from its binding to Concanavalin A. When the HMW neurophysin was incubated with trypsin, most of the immunoreactivity was converted into a smaller neurophysin which bound to a vasopressin-agarose column in a pH-dependent manner. Moreover, a definite peak of immunoreactive vasopressin appeared after the trypsin treatment. This peak coeluted with synthetic arginine vasopressin on gel filtration and had the characteristic affinity of vasopressin for neurophysin-agarose. These results indicate that propressophysin circulates in patients with oat cell carcinoma of the lung with ectopic vasopressin production and suggest that plasma propressophysin may be a marker for ectopic vasopressin production.

Topics: Adult; Aged; Arginine Vasopressin; Carcinoma, Small Cell; Chromatography, Affinity; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Humans; Lung Neoplasms; Middle Aged; Neurophysins; Oxytocin; Protein Precursors; Radioimmunoassay; Vasopressins

Although the syndrome of inappropriate ADH secretion (SIADH) has many causes, principally pulmonary, central nervous system or neoplastic disease, and drugs, patients may present with SIADH in whom the etiology is not readily evident. We measured serum ADH levels in such an individual in both the eunatremic and water-loaded states and found levels to be undetectable despite failure to dilute the urine. A small oat cell pulmonary carcinoma was ultimately diagnosed with lung tomograms and cytology. Following a partial response to water restriction, demeclocycline was effective in producing a water diuresis that restored the serum sodium concentration to normal. Patients with clinical SIADH but low serum ADH levels can harbor a malignant or benign process that, notwithstanding the low ADH levels, may still remain responsive to demeclocycline, suggesting either neoplastic production of a biologically-active, immunologically-inactive ADH-like peptide, or increased renal tubular sensitivity to ADH.

Topics: Carcinoma, Small Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Middle Aged; Vasopressins

We measured basal and dexamethasone-suppressed plasma ACTH in 246 patients with bronchogenic carcinoma (105 with small-cell carcinoma); in 138 of these patients (67 with small-cell carcinoma) basal and pentagastrin-stimulated serum calcitonin was also determined. In addition, in a subgroup of 120 patients (58 with small-cell carcinoma) plasma ADH with reference to plasma osmolality was also assayed. Non-suppressible plasma ACTH was found in 45% of patients with small-cell carcinoma but only in isolated cases of large-cell carcinoma, adenocarcinoma, and squamous-cell carcinoma. Serum calcitonin was increased in 28% of patients with small-cell carcinoma but only in few patients with other tumor types. Stimulation of calcitonin by pentagastrin was ineffective. Plasma ADH was inappropriately high in 47% of patients with small-cell carcinoma. Strikingly high also was the incidence of increased ADH concentrations in patients with large-cell (40%), adenocarcinoma (46%), and squamous-cell carcinoma (29%). By measuring plasma ACTH after dexamethasone suppression and ADH with reference to osmolality, the sensitivity of these tumor markers in detecting pathological hormone secretion is markedly increased. In small-cell carcinoma the simultaneous measurement of ACTH, ADH, and calcitonin gives a high yield of positive results (74%), indicating that this set of tumor markers is a promising aid in diagnosis and therapy control.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Dexamethasone; Humans; Kinetics; Lung Neoplasms; Pentagastrin; Vasopressins

From 1976 to 1980, 18 of the 250 patients (7%) seen with small cell carcinoma of the lung had clinically evident inappropriate secretion of antidiuretic hormone (ADH). Hyponatremia was usually severe (116 +/- 7 meq/l), and eight patients showed symptoms of water intoxication at the time of diagnosis. Of the eight patients who had plasma ADH measured at diagnosis, seven had elevated values (mean 52.0, range 16.1 - greater than 250 pg/ml). Intensive combination chemotherapy produced objective tumor responses in all patients, and syndrome of inappropriate ADH secretion (SIADH) resolved in 16 of 17 evaluable patients within three weeks of initiation of treatment. ADH values after therapy were normal, and all patients maintained a normal serum sodium during the period of tumor remission in spite of unrestricted fluid intake. All 17 evaluable patients have developed progressive cancer, but only 10 have manifested recurrent SIADH. Patient survival was similar to the overall population of small cell carcinoma patients without SIADH. The indirect methods of treatment for SIADH (fluid restriction, demeclocycline, lithium, urea) are frequently of transient value while awaiting a response to chemotherapy or in patients with resistant tumors. However, the initial treatment of choice for SIADH associated with small cell carcinoma of the lung is combination chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Small Cell; Drug Therapy, Combination; Female; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Middle Aged; Paraneoplastic Endocrine Syndromes; Recurrence; Retrospective Studies; Sodium; Uric Acid; Vasopressins

Topics: Carcinoma, Small Cell; Diabetes Insipidus; Humans; Lung Neoplasms; Radioimmunoassay; Vasopressins

We report a patient who had an oat cell bronchogenic carcinoma in association with the syndrome of inappropriate antidiuresis. There was an unusually long interval between the onset of hyponatraemia and clinically evident malignant disease. Dynamic testing of vasopressin secretion showed preservation of baroregulated, but not osmoregulated, vasopressin release. Immunoreactive vasopressin was detected in pleural fluid, which co-eluted with synthetic vasopressin on gel chromatography.

Topics: Carcinoma, Bronchogenic; Carcinoma, Small Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Middle Aged; Vasopressins

An electron microscopic study of 28 small cell carcinomas of the lung is presented. Cytoplasmic secretory granules, characteristic of endocrine cells of the human foetal lung were observed in a variable number of tumor cells. Two groups of tumors could be distinguished based on the morphology of the cytoplasmic secretory granules. Twenty-three tumors showed cells with granules resembling type 1 or P1 cells of the human fetal lung, and 5 tumors with granules resembling type 3 cells of the human fetal lung. No relationship was found between the light microscopic WHO classification of small cell carcinoma of the lung and the results obtained by electron microscopy. Increased serum calcitonin as well as inappropriate ADH secretion may be correlated with one of the two types of small cell carcinoma, but further investigations are needed.

Topics: Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Small Cell; Cytoplasmic Granules; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Skin Neoplasms; Vasopressins

At diagnosis, 65% of 103 patients with small cell carcinoma of the lung were found to have elevated plasma concentrations of vasopressin-associated human neurophysin (VP-HNP), oxytocin-associated human neurophysin (OT-HNP), or both, which were thought to be related to tumor secretion of these proteins. The remainder of patients were designated as nonsecretors (24%) or possible secretors (11%), depending upon plasma concentration of the neurophysins prior to therapy. There was a significantly higher percentage of secretors among patients with extensive disease (82%) than among those with limited disease (40%) (P = 0.001). However, within each stage group, there was no correlation between secretory status and response to therapy, survival, or histologic subtype. In addition, patients who initially were nonsecretors or possible secretors maintained this status throughout the course of disease remission and subsequent relapse. These findings suggest the possibility of biochemical differences between tumors which present as limited disease and those which present as extensive disease. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was infrequent in limited disease but was present in 33% of patients with extensive disease. SIADH was not seen without VP-HNP elevation; however, with extensive disease, 49% of patients with elevated VP-HNP had SIADH. In contrast, elevated plasma concentrations of the neurophysins were seen in only 19.6% of 56 patients with non-small cell carcinoma of the lung. The levels were in general lower than those in patients with small cell carcinoma and were seen at approximately equal frequencies in each major cellular subtype.

Topics: Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Neurophysins; Oxytocin; Prognosis; Vasopressins

The very rare occurrence of an ADH-producing small cell carcinoma of the lung in a 52 year old male patient with cranial diabetes insipidus since childhood is described. In this case diabetes insipidus disappeared concomitantly with development of lung cancer and re-appeared with shrinkage of the lung tumour by radiation therapy. Further progressive expansion of the primary and metastatic tumours induced the syndrome of inappropriate ADH secretion once again (SIADH). This deterioration in the clinical course was reflected in the plasma levels of ADH and neurophysins. The existence of vasopressin in the tumour tissue was also demonstrated by means of an immunohistochemical staining technique combined with anti-vasopressin serum.

Topics: Carcinoma, Small Cell; Diabetes Insipidus; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Middle Aged; Neurophysins; Remission, Spontaneous; Vasopressins

Transplantable human oat cell carcinoma cells of the lung with ectopic vasopressin production were incubated with labeled amino acids and immunoreactive neurophysins in cell extracts were analyzed by isoelectric focusing. When the cells were incubated with L-(35S)-cysteine for 20 h, one major peak (isoelectric point; pI=5.3) and several minor peaks (pI=6.1, 5.7, 5.1, 4.9 and 4.7) of labeled proteins were observed. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the relative molecular mass (Mr) of the pI 5.7 protein was estimated to be 20,000 and that of the pI 6.1 species to be 19,000, while the remainder had a Mr of approximately 10,000. The result of the pulse-labeling experiment has clearly shown that the pI 5.7 and 6.1 proteins, which have affinity for concanavalin A, are biosynthetic precursors for the smaller form of neurophysin with a pI 5.3. When subjected to limited proteolysis with trypsin, the pI 5.7 protein generated a Mr 10,000 protein and a smaller peptide. The Mr 10,000 protein thus produced was identified as neurophysin on the basis of its pH-dependent affinity for vasopressin and the migration pattern on isoelectric focusing. The smaller peptide coeluted with synthetic arginine vasopressin and bound to neurophysin suggesting that it possesses a cysteine-tyrosyl sequence at its N-terminus. Similarly, the pI 6.1 protein liberated neurophysin and vasopressin-like peptide after incubation with trypsin. These results suggests that the glycosylated protein with a pI of 5.7 and a Mr of 20,000 is the common precursor to vasopressin and neurophysin in human oat cell carcinoma of the lung with ectopic vasopressin production. The pI 6.1 protein may be an intermediate in the conversion of the precursor to vasopressin and neurophysin.

Topics: Carcinoma, Small Cell; Cysteine; Hormones, Ectopic; Humans; In Vitro Techniques; Inappropriate ADH Syndrome; Isoelectric Focusing; Lung Neoplasms; Male; Middle Aged; Molecular Weight; Neurophysins; Vasopressins

Previous studies have suggested that ectopic production of adrenocorticotropic hormone (ACTH) or antidiuretic hormone (ADH) may occur commonly in patients with small cell carcinoma of the lung (SCCL) and that evidence of such production may be elicited only by provocative tests of water excretion and adrenal function. We studied 28 patients with SCCL and 29 patients with other cancers. Adrenal function, assessed by measuring the 8 am plasma cortisol, the 8 am to 4 pm diurnal variation in plasma cortisol, and the suppressibility of the 8 am plasma cortisol following administration of 1 mg of dexamethasone, was found to be abnormal in 28.5, 71, and 25 percent, respectively, of the patients with SCCL, compared with 18, 65, and 29.5 percent in patients with other types of cancer (P greater than 0.3). The possibility of ectopic ADH secretion was assessed by a standard water loading test, which showed excretion impairment in 60 percent of patients with SCCL and 68 percent of patients with other cancers (P greater than 0.9). Neither the stage of neoplastic disease, sites of metastatic deposits, nor performance status of the patients correlated with abnormalities of water and cortisol metabolism, indicating that such abnormalities are common in patients with all types of cancer. These data do not suggest that subclinical disturbances of adrenal function or water excretion are characteristic of any histologic type of cancer. The precise mechanism(s) underlying these abnormalities are unknown.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Body Water; Carcinoma, Small Cell; Circadian Rhythm; Dexamethasone; Humans; Hydrocortisone; Lung Neoplasms; Middle Aged; Prognosis; Vasopressins

Antidiuretic hormone (ADH) was determined by radioimmunoassay in 139 patients with bronchial carcinoma. Serum ADH levels, compared with a control group, were increased in 30% of patients with small-cell and 21% of patients with large-cell bronchial carcinoma. Patients with squamous carcinoma or adenocarcinoma had normal ADH values. There was no correlation between serum ADH levels and stage of tumour. Serial ADH measurements during chemotherapy provided good correlation between ADH and response to treatment. ADH was also demonstrable by immunohistology in the tumour cells of one patient with increased serum levels.

Topics: Adenocarcinoma; Bronchial Neoplasms; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Lung Neoplasms; Neoplasm Staging; Radioimmunoassay; Vasopressins

The endocrine status of 106 patients with undifferentiated small cell carcinoma of the lung was evaluated before treatment was begun. Almost one half of the patients had evidence of abnormal control of the secretion of adrenal cortical steroids, manifested by loss of diurnal rhythmicity or dexamethasone suppressibility. Only two had the clinical syndrome of ectopic ACTH secretion. Evidence of inappropriate secretion of vasopressin was found in 38% of the patients, most of whom also had abnormalities of corticosteroid secretory pattern. About one half of the patients had evidence of abnormal glucose tolerance, and many also had a paradoxical rise of plasma growth hormone concentration after glucose administration. The levels of the other hormones studies were normal. The pattern of hormone abnormality observed in these patients appears to be relatively specific for small cell undifferentiated carcinoma, and is different from that observed in other pulmonary tumors. Patients with abnormal control of plasma cortisol had a worse prognosis than those with normal adrenal function, largely because of decreased response rates to chemotherapy. Other endocrine abnormalities were of no prognostic significance.

Topics: 11-Hydroxycorticosteroids; Adrenal Cortex; Adrenocorticotropic Hormone; Blood Glucose; Carcinoma, Small Cell; Cyclophosphamide; Female; Humans; Hydrocortisone; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Methotrexate; Middle Aged; Prognosis; Sodium; Vasopressins

Two cases of Schwartz-Bartter syndrome are reported. Both were due to malignant anaplasic tumours of the APUD type with multiple abnormal endocrine secretion, and both were accompanied with hypouricaemia of uncertain significance. The authors believe that the association of hypernatraemia with hypouricaemia should alert clinicians to the possibility of a syndrome of inappropriate antidiuretic hormone secretion (SIADH) of malignant origin.

Topics: Apudoma; Carcinoma, Small Cell; Female; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Middle Aged; Uric Acid; Vasopressins

A case is described of a patient with an oat cell carcinoma of the bronchus with moderately elevated levels of plasma corticotrophin (ACTH) and antidiuretic hormone (ADH). Ectopic secretion of ACTH induced severe hypokalaemia and concealed the effects of concomitant ADH secretion on renal function. Normal renal responsiveness was restored following correction of hypokalaemia. The hypokalaemia was associated with evidence of a marked increase in corticosteroid secretion but plasma ACTH concentrations did not show a proportionate elevation. Chromatographic studies on tumour extracts suggest that the presence of a large fraction of high molecular weight ACTH in plasma could explain this discrepancy.

Topics: Adrenocorticotropic Hormone; Aged; Carcinoma, Small Cell; Electrolytes; Female; Humans; Hypokalemia; Lung Neoplasms; Syndrome; Vasopressins

A 58-year-old man with bronchogenic oat cell carcinoma developed a typical syndrome of inappropriate secretion of antidiuretic hormone. The tumor tissue obtained at autopsy had been serially transplanted in nude mice for more than four years with 20 passages. The levels of vasopressin were remarkably increased in the plasma of nude mice bearing this tumor [24.4 +/- 18.3 (S.D.) pg/ml, n = 3] as well as in the tumor tissues ]134.3 +/- 72.2 ng/g, n = 3]. Furthermore, human nicotine-stimulated neurophysin was detected in both plasma and tumor tissues (7.4 +/- 3.7 ng/ml, n = 3, and 2.28 +/- 0.90 micrograms/g, n = 3, respectively). On ad libitum intake of water, nude mice bearing this tumor excreted significantly less urine with higher sodium concentration than did controls, but serum sodium concentrations did not differ from those of controls. When tumor-bearing mice were hydrated with 2 ml of water twice a day i.p., their diuretic response was found to be suppressed in parallel with the tumor size. However, these mice did not become hyponatremic because they drank less water. When a larger amount of water was loaded which could not be compensated by restriction of water drinking, serum sodium concentrations were markedly decreased. On the basis of these results, the lung cancer, when transplanted into nude mice, produced and secreted its own antidiuretic hormone, which induced inappropriate secretion of antidiuretic hormone in the mice. These mice may provide a useful experimental model for the study of excessive secretion of antidiuretic hormone and associated pathophysiological disorders.

Topics: Animals; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Drinking; Female; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Natriuresis; Neoplasm Transplantation; Sodium; Transplantation, Heterologous; Vasopressins

Hypouricaemia has been observed in patients with the syndrome of inappropriate secretion of antidiuretic hormone (IADH). Accordingly, 69 patients with untreated bronchogenic small cell carcinoma were examined for IADH. Serum urate was also measured. IADH was proven in 25 (35%) of the 69 patients. The median serum concentration of urate in these patients was 0.26 mmol/l (range 0.13-0.50), compared to 0.36 mmol/l (0.21-0.60) in the 44 patients without IADH. The difference is statistically significant (p less than 0.01), but serum urate--when used alone--is lacking in both sensitivity and specificity for the diagnosis of IADH.

Topics: Carcinoma, Bronchogenic; Carcinoma, Small Cell; Female; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Uric Acid; Vasopressins

Topics: Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Humans; Lung Neoplasms; Prognosis; Vasopressins

The incorporation of labeled compounds into neurophysins of a transplantable human oat cell carcinoma of the lung with ectopic vasopressin production was studied in vitro. Neurophysins in cell extracts and in incubation media were isolated by immunoprecipitation and analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. When cells were incubated with L-[35S]cysteine for 12 h, SDS-polyacrylamide gel electrophoresis of the immunoprecipitates from cell extract and medium resolved two forms of neurophysins with apparent molecular mass of 10,000 (10K) and 20,000 (20K). Both forms of [35S]-neurophysins were completely displaced from the immunoprecipitates by excess human neurophysin. Incubation of cells with L-[35S]cysteine and D-[3H]-glucosamine hydrochloride revealed that glucosamine was incorporated into the 20K neurophysin region, but not into 10K species. To observe the kinetics of labeling of the two forms of neurophysins, cells were incubated with L[35S]cysteine for varying periods of time. After short labeling periods, most of the radioactivity resided in 20K species, which plateaued after 1 h, whereas 10K neurophysin progressively increased in its height. When cells were chased with unlabeled cysteine after the exposure to a short pulse of labeling, 20K neurophysin peak gradually decreased with an apparent initial half-life of 1 h. In contrast, the label in 10K neurophysin steadily increased, which exceeded the former by 3 h of chase. Analysis of 20K neurophysin in cell extract by isoelectric focusing on polyacrylamide gel demonstrated that it was principally composed of a protein with an apparent isoelectric point (pI) of 5.7. These results suggest that neurophysin is synthesized in ectopic vasopressin-producing tumors by post-translational processing from a glycosylated proneurophysin with an apparent molecular mass of 20,000 daltons and a pI of 5.7.

Topics: Animals; Carcinoma, Small Cell; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Hormones, Ectopic; Humans; Kinetics; Lung Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Molecular Weight; Neoplasm Transplantation; Neoplasms, Experimental; Neurophysins; Vasopressins

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; Aged; Carcinoma, Small Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Paraneoplastic Endocrine Syndromes; Vasopressins

Topics: Adrenocorticotropic Hormone; Adult; Aged; Calcitonin; Carcinoma, Small Cell; Female; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Vasopressins

Antidiuretic hormone (ADH) immunoactivity (28--164 pg/mg wet weight) was detected in the tumour tissue of only three out of thirty-two patients with carcinoma of the bronchus. All three patients had small oat-cell tumours and two had persistent hyponatraemia prior to death. Serum sodium was not obtained in the third patient. Serum sodium was normal in the remaining twenty-nine patients with undetectable ADH immunoactivity.

Topics: Adenocarcinoma; Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Hyponatremia; Lung Neoplasms; Male; Middle Aged; Radioimmunoassay; Vasopressins

Topics: Calcitonin; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Oxytocin; Peritoneal Neoplasms; Vasopressins

A study of 61 patients with small cell carcinoma of the lung using specific RIAs for 2 human neurophysins (HNPs) has revealed that plasma levels of 1 or both HNPs are substantially elevated (> 3 times) in 62% of the patients before the commencement of therapy. These elevated HNPs may be a consequence of production/release by tumor. Eighteen patients with elevated plasma HNPs and 14 with normal values were followed during therapy. All of the patients with normal pre-therapy levels maintained these normal levels regardless of the course of their disease. For all patients with elevated HNP levels before therapy, there was good agreement between changes in these elevated values and clinically assessed responses. Partial or complete remission (12 patients) was associated with a 2- to 30-fold reduction in HNP levels, progressive disease (6 patients) was associated with a rise in HNP levels, and relapse after a previous objective response (6 patients) was associated with an increase in plasma HNPs over values found during remission. For many of the patients in clinical remission, HNPs remained elevated above normal values, and RIA data seem to forecast recurrent disease several weeks before clinical recognition. These data provide good evidence that our RIAs for HNPs can provide a valuable guide to therapeutic management of small cell carcinoma of the lung.

Topics: Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Neurophysins; Oxytocin; Radioimmunoassay; Vasopressins

The ectopically produced polypeptide hormones ACTH, ADH, and calcitonin were investigated as tumor markers in patients with small-cell carcinoma of the lung (SCC). Plasma ADH concentrations were evaluated separately as well as in relation to concomitantly obtained plasma osmolality levels. No significant nor consistent changes of marker concentrations caused by lysis of tumor cells were found immediately after administration of cytotoxic drugs. After tumor regression, plasma ACTH and serum calcitonin concentrations and inappropriate ADH secretion (plasma ADH levels inappropriately high compared with plasma osmolality) became normal in most cases; however, progressive disease was not followed consistently by changes in plasma ACTH concentrations and occurrence of inappropriate ADH secretion. Contrary to this, among 12 patients with disease progression, serum calcitonin levels increased in ten patients and plasma ADH levels increased in 11 patients. In most cases, however, these changes were only moderate, and serum calcitonin concentrations were found to be increased after tumor regression in patients who had normal pretreatment levels. It is concluded that decisions on treatment of patients with SCC cannot exclusively be based on changes in the concentrations of the polypeptide hormones that might be of ectopic origin.

Topics: Adrenocorticotropic Hormone; Amine Oxidase (Copper-Containing); Calcitonin; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Prognosis; Vasopressins

Topics: ACTH Syndrome, Ectopic; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Middle Aged; Muscular Diseases; Paraneoplastic Endocrine Syndromes; Vasopressins

Topics: Adrenocorticotropic Hormone; Carcinoma, Small Cell; Female; Hormones, Ectopic; Humans; Lung Neoplasms; Middle Aged; Vasopressins

Topics: Bronchial Neoplasms; Calcitonin; Carcinoma, Small Cell; Hormones; Humans; Hydrocortisone; Lung Neoplasms; Male; Melanocyte-Stimulating Hormones; Middle Aged; Peptide Biosynthesis; Vasopressins

Topics: Antineoplastic Agents; Carcinoma, Small Cell; Demeclocycline; Humans; Lung Neoplasms; Syndrome; Vasopressins

Immunoactive antidiuretic hormone (ADH) was measured by radioimmunoassay in the plasma, lung tumours and metastatic tumours of nineteen patients with bronchogenic carcinoma. Ten patients had hyponatraemia and carcinoma of the small oat cell type. Plasma ADH measured in nine of these patients ranged from 11--270 pg/ml and was elevated above the normal range (4.6--6.2 pg/ml) in all subjects. ADH-immunoreactive material was detectable in all primary lung tumours (range 9--1080 pg/mg wet weight, n = 7) and metastases (range 5--63 pg/mg wet weight, n = 9) obtained from the hyponatraemic patients. A statistical relationship existed between plasma and tumour ADH concentration in six patients where both measurements were performed. Three patients had small cell carcinomas (two oat cell and one anaplastic) without overt hyponatraemia. ADH-like material was detectable in the lung tumours (18 and 1.1 pg/mg wet weight) and liver metastases (4 and 1.0 pg/mg wet weight) of two patients but not in the third. Four of the remaining patients had squamous cell carcinomas and two had adenocarcinomas. None had hyponatraemia. ADH-like material was undetectable in all lung tumours, metastatic tumours and uninvolved tissue from these patients. ADH extracted from the pituitaries of four patients ranged from 6400--13200 pg/mg wet weight. ADH immunoreactive extracts of six lung tumours and nine metastases (all oat cell) showed the same pattern on elution from a Sephadex G-25 column. A large peak, which made up 65% of the total activity, was eluted in the same position as synthetic arginine vasopressin and contained comparable amounts of immunoreactive and bioactive ADH. Two smaller peaks (8 and 27% of total activity) were eluted in positions of higher molecular weight and contained more immunoreactive than bioactive ADH. In contrast, three of four pituitary extracts showed only a single peak which eluted in the same position as marker vasopressin.

Topics: Carcinoma, Bronchogenic; Carcinoma, Small Cell; Chromatography, Affinity; Chromatography, Gel; Female; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Sodium; Vasopressins

A 61 year old woman presented with profound hyponatremia and markedly low serum osmolality. Urine osmolality was greater than the serum osmolality, an abnormality that was corrected by water restriction, suggesting inappropriate ADH secretion. Although there were no physical signs of Cushing's syndrome, her serum potassium level was low and markedly elevated levels of plasma and urine corticosteroids were not altered by the administration of large amounts of dexamethasone, suggesting the ectopic ACTH-MSH syndrome. Plasma levels of immunoreactive ACTH and beta-MSH were elevated. At autopsy, a metastastic oat cell carcinoma of the lung, not detected antemortem by chest roentgenograms and bronchoscopy, was found. Immunoreactive ADH, ACTH and beta-MSH were detected in the primary tumor and in metastases to the liver. beta-MSH was also detected in the spleen, in which metastases were observed. This is the first documented case of the simultaneous production of ADH, ACTH and beta-MSH by neoplastic tissue associated with clinical manifestations of the syndrome of inappropriate ADH secretion and the ectopic ACTH-MSH syndrome.

Topics: Adrenocorticotropic Hormone; Carcinoma, Small Cell; Female; Humans; Liver Neoplasms; Lung Neoplasms; Melanocyte-Stimulating Hormones; Middle Aged; Neoplasm Metastasis; Splenic Neoplasms; Vasopressins

A continuous cell culture line was established from a bone marrow metastasis of small cell anaplastic carcinoma of the lung. The cultures were characterized by light and electron microscopy, and an unusual concentric arrangement of cells was observed, both in sectioned material from the patient's tumor and from the cell cultures. The cells had two types of specialized cell junctions and contained secretory-like granules of the type described in neuroendocrine cells. Lactic dehydrogenase isozyme patterns were the same as those observed in normal human serum, and the karyotype revealed the presence of several marker chromosomes. Vasopressin was present in the cells and secreted into the culture medium in the absence of neurophysin, as shown by the immunoperoxidase technique and radioimmunoassay. Oxytocin was also absent from cells.

Topics: Carcinoma, Small Cell; Cell Division; Cell Line; Chromosome Aberrations; Hormones, Ectopic; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lung Neoplasms; Neurophysins; Vasopressins

The efficacy of demeclocycline hydrochloride in suppressing the tubular action of tumoral antidiuretic products was tested in seven patients with the syndrome of inappropriate antidiuretic hormone secretion. In all patients, demeclocycline hydrochloride (1,200 mg/day) induced production of hypotonic urine and corrected hyponatremia despite large fluid intakes. Comparison of the response to a standard water load before and during treatment showed a notable improvement in the response to water ingestion. Even though demeclocycline moderately impairs renal function, it appears to be the treatment of choice in the chronic form of the syndrome.

Topics: Administration, Oral; Aged; Carcinoma, Small Cell; Chronic Disease; Demeclocycline; Depression, Chemical; Dose-Response Relationship, Drug; Humans; Hyponatremia; Kidney Concentrating Ability; Lung Neoplasms; Male; Middle Aged; Syndrome; Vasopressins

Daily arginine-vasopressin (AVP) excretion was determined by radioimmunoassay in 60 consecutive cases of untreated lung carcinoma. Control excretion was 61 +/- 34 (SD) in 41 healthy subjects and 50 +/- 38 ng/24 h in 10 patients with chronic lung diseases. Overall 20 out of the 60 cases of lung carcinoma presented with abnormally elevated urinary AVP; In the group with anaplastic oat-cell carcinoma, 15 of 23 had elevated urinary AVP with a mean of 370 +/- 331 (SD) ng/24 h if 2 cases with extremely high values of 11 100 and 55 300 ng/24 h respectively are excluded. None of the 9 patients with large-cell carcinoma had elevated urinary AVP, while only 3 of the 19 cases of epidermoid carcinoma and 2 of the 9 cases of adenocarcinoma had high urinary AVP, with means of 127 +/- 8 and 125 +/- 12 ng/24 h respectively. Plasma osmolality and sodium correlated inversely with AVP excretion. However, only 10 of 23 patients with increased urinary AVP had decreased plasma sodium, although one became hyponatremic 9 weeks later. In one patient AVP excretion normalized after radiotherapy. Plasma renin activity and urinary aldosterone were usually low when urinary AVP was high. Two cases with elevated plasma luteotrophic hormone and another with elevated plasma ACTH, all three presenting with oat-cell carcinoma, were found;

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Aldosterone; Bronchial Neoplasms; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Luteinizing Hormone; Renin; Sodium; Vasopressins

Topics: Carcinoma, Small Cell; Demeclocycline; Humans; Hyponatremia; Lung Neoplasms; Male; Middle Aged; Paraneoplastic Endocrine Syndromes; Phosphorus; Uric Acid; Vasopressins

Topics: Aged; Carcinoma, Small Cell; Humans; Lung Neoplasms; Male; Myasthenia Gravis; Syndrome; Vasopressins

Topics: Carcinoma, Small Cell; Humans; Lung Neoplasms; Male; Middle Aged; Vasopressins

Topics: Adult; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Vasopressins

Two cases of small cell carcinoma of the lung associated with the ectopic production of multiple hormones are reported. Both tumors were shown to contain significant amounts of ADH, ACTH, and beta-MSH. Biologic, immunologic, and gel chromatographic properties of these ectopic hormones were found to be very similar to those of pituitary origin. The effect of excessive secretion of antidiuretic hormone (ADH) dominated the clinical manifestations in both cases, i.e., syndrome of inappropriate secretion of ADH (SIADH). The clinical manifestations of the ectopic ACTH-MSH syndrome were minimal. These data suggest that multiple hormone production without clinically overt sequelae of excess hormone is not uncommon in small cell (oat cell) carcinoma of the lung.

Topics: Adrenocorticotropic Hormone; Aged; Carcinoma, Small Cell; Female; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Melanocyte-Stimulating Hormones; Middle Aged; Molecular Weight; Radioimmunoassay; Vasopressins

Among the malignant tumors of nonendocrine origin that are capable of producing polypeptide hormones and of manifesting as different endocrine syndromes discussed here are ectopic ACTH syndrome, SIADH, and ectopic gonadotropin-producing tumors.

Topics: Adrenocorticotropic Hormone; Carcinoma, Hepatocellular; Carcinoma, Small Cell; Chorionic Gonadotropin; Cushing Syndrome; Diagnosis, Differential; Erythropoietin; Follicle Stimulating Hormone; Gynecomastia; Hormones, Ectopic; Humans; Hyperthyroidism; Hypoglycemia; Hyponatremia; Liver Neoplasms; Lung Neoplasms; Luteinizing Hormone; Male; Paraneoplastic Endocrine Syndromes; Polycythemia; Puberty, Precocious; Thyrotropin; Vasopressins; Water Intoxication

A radioimmunoassay has been developed for plasma arginine-vasopressin in man and dog. The mean recovery of added arginine-vasopressin (AVP) was 60 +/-6.9 (S.D.)% and the lower threshold of detection 2.0 pmol/1. A close correlation was found between concurrent radioimmunoassay and bioassay values. The mean concentration found in peripheral venous blood in healthy men after overnight fasting was 5.3 pmol/1 (range 4.6-6.2 pmol/1.) In man, significant increases in plasma AVP occurred after dehydration (5-9-9-5 pmol/1) and significant decreases after oral water-loading (5.9-9.5 pmol/1). During i.v. infusion of graded doses of synthetic AVP in normal men, plasma levels were closely correlated with infusion rate. On stopping the infusion, plasma vasopressin fell exponentially with a half-life of between 7 and 8 min. In man, plasma AVP was unaffected by tilting head-up for 2 h, or by a non-hypotensive bleeding of 500 ml in 10 min. In the dog, haemorrhage of 5 ml/kg and over caused proportionate increases in AVP in the circulation. In normal men, plasma vasopressin was significantly correlated with concurrent urinary osmolality. Five patients with oat-cell bronchial carcinoma and hyponatraemia showed a marked increase of plasma vasopressin. Five patients with diabetes insipidus had significantly reduced, but detectable, levels of plasma AVP. The plasma concentration in these patients did not increase after water restriction.

Topics: Adult; Animals; Arginine Vasopressin; Biological Assay; Blood Volume; Bronchial Neoplasms; Carcinoma, Small Cell; Dehydration; Diabetes Insipidus; Dogs; Half-Life; Hemorrhage; Humans; Male; Osmolar Concentration; Posture; Radioimmunoassay; Urine; Vasopressins; Water; Water Deprivation

Topics: Carcinoma, Small Cell; Demeclocycline; Diuresis; Humans; Hyponatremia; Lung Neoplasms; Male; Middle Aged; Syndrome; Vasopressins

We have studied the effects of demeclocycline on the water metabolism of a patient with the syndrome of inappropriate antidiuretic hormone (ADH) secretion who presented with a serum sodium concentration of 110 meq/litre. Free water clearance was studied before, during, and after treatment with demeclocycline. This study shows that demeclocycline (900 mg/day) can at least partially inhibit the action of ADH in the setting of tumor-induced ADH secretion, with the production of a reversible, partial nephrogenic diabetes insipidus, and with few or no side effects. Demeclocycline may be useful in the treatment of chronic inappropriate ADH secretion.

Topics: Carcinoma, Small Cell; Demeclocycline; Diabetes Insipidus; Humans; Hyponatremia; Kidney Diseases; Lung Neoplasms; Male; Middle Aged; Osmolar Concentration; Syndrome; Urine; Vasopressins

Topics: Calcitonin; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Hyponatremia; Lung Neoplasms; Male; Middle Aged; Osmolar Concentration; Paraneoplastic Endocrine Syndromes; Sodium; Syndrome; Vasopressins

Topics: Adrenocorticotropic Hormone; Bone Neoplasms; Bronchial Neoplasms; Carcinoma, Small Cell; Corticotropin-Releasing Hormone; Female; Genes, Regulator; Genetic Code; Hormones, Ectopic; Humans; Hypercalcemia; Hyperthyroidism; Male; Neoplasm Metastasis; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Thyrotropin; Vasopressins

Topics: Adrenocorticotropic Hormone; Alkalosis; Bicarbonates; Breast Neoplasms; Calcium; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Female; Gentamicins; Hodgkin Disease; Hormones, Ectopic; Humans; Hydrocortisone; Hyponatremia; Hypothalamus; Lung Neoplasms; Paraneoplastic Endocrine Syndromes; Phosphates; Potassium; Vasopressins

Topics: Adrenocorticotropic Hormone; Aminoglutethimide; Carcinoma, Small Cell; Cells, Cultured; Female; Humans; Insulin; Lung Neoplasms; Melanocyte-Stimulating Hormones; Microscopy, Electron; Middle Aged; Neurophysins; Oxytocin; Peptides; Prolactin; Vasopressins

Topics: Carcinoma, Small Cell; Electrophoresis; Gels; Hormones, Ectopic; Humans; Lung Neoplasms; Neurophysins; Oxytocin; Pituitary Gland, Posterior; Protein Binding; Radioimmunoassay; Starch; Vasopressins

Topics: Aged; Alcohol Drinking; Beer; Carcinoma, Small Cell; Coma; Hormones, Ectopic; Humans; Hyponatremia; Lung Neoplasms; Male; Middle Aged; Osmolar Concentration; Paraneoplastic Endocrine Syndromes; Sodium; Vasopressins

Topics: Aged; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Male; Vasopressins

Topics: Adrenal Gland Neoplasms; Autopsy; Bone Neoplasms; Bronchial Neoplasms; Calcitonin; Carcinoma; Carcinoma, Small Cell; Humans; Hyponatremia; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Osmolar Concentration; Paraneoplastic Endocrine Syndromes; Syndrome; Vasopressins

Topics: Bronchial Neoplasms; Carcinoma, Small Cell; Diabetes Insipidus; Humans; Hyponatremia; Iodine Isotopes; Radioimmunoassay; Vasopressins; Water; Water Deprivation

Topics: Autopsy; Brain Neoplasms; Bronchial Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Humans; Hypopituitarism; Hypothalamus; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Paraneoplastic Endocrine Syndromes; Pituitary Gland; Pituitary Neoplasms; Vasopressins

Topics: Adolescent; Adult; Arginine; Blood; Carcinoma, Small Cell; Cyclophosphamide; Humans; Leukemia, Lymphoid; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Osmolar Concentration; Peripheral Nervous System Diseases; Prednisone; Radioimmunoassay; Sodium; Urine; Vasopressins; Vincristine

Topics: Adult; Aged; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Diuresis; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neurophysins; Protein Binding; Radioimmunoassay; Syndrome; Tongue Neoplasms; Vasopressins

Topics: Carcinoma, Small Cell; Diabetes Insipidus; Hormones, Ectopic; Humans; Hyponatremia; Lung Neoplasms; Osmolar Concentration; Plasma Volume; Polyuria; Radioimmunoassay; Syndrome; Vasopressins

Topics: Adult; Autopsy; Bicarbonates; Bronchial Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Chlorides; Cyclophosphamide; Hormones, Ectopic; Humans; Hyponatremia; Injections, Intravenous; Male; Osmolar Concentration; Sodium; Urea; Vasopressins

Ectopic production of polypeptide hormones by tumors of nonendocrine tissues can serve as a clue to diagnosis of the tumor and as a focus for management of the patient with cancer. In the differential diagnosis of syndromes of endocrine hyperfunction, the ectopic hormone syndromes have achieved an increasingly prominent position. Available evidence on the properties of ectopic ACTH, MSH, parathyroid hormone, erythropoietin, gonadotropins, and thyrotropin is consistent with the unifying hypothesis of genetic derepression.

Topics: Abdominal Neoplasms; Adenocarcinoma; Adrenocortical Hyperfunction; Brain Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Hepatocellular; Carcinoma, Small Cell; Cysts; Diagnosis, Differential; Fibroma; Hemangiosarcoma; Humans; Hyperparathyroidism; Hypoglycemia; Kidney Diseases; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Paraneoplastic Endocrine Syndromes; Pheochromocytoma; Polycythemia; Sarcoma; Thoracic Neoplasms; Vasopressins

Topics: Addison Disease; Arginine Vasopressin; Avena; Bronchial Neoplasms; Carcinoma, Small Cell; Cushing Syndrome; Gynecomastia; Humans; Hypercalcemia; Hyperthyroidism; Hyponatremia; Hypotension; Liver Cirrhosis; Male; Metabolism; Pathology; Physiology; Small Cell Lung Carcinoma; Sodium; Vasopressins

Topics: Arginine Vasopressin; Blood Chemical Analysis; Carcinoma; Carcinoma, Small Cell; Geriatrics; Humans; Hyponatremia; Lung Neoplasms; Vasopressins