oxytocin and Lung-Neoplasms

Topics: Arginine Vasopressin; Biomarkers, Tumor; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neurophysins; Oxytocin; Protein Precursors

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

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

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Arginine Vasopressin; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chorionic Gonadotropin; Growth Hormone; Hormones, Ectopic; Humans; Lung Neoplasms; Neurophysins; Oxytocin; Parathyroid Hormone

Topics: Adrenocorticotropic Hormone; Arginine Vasopressin; beta-Lipotropin; Calcitonin; Gastrointestinal Hormones; Gonadotropins; Growth Hormone; Hormones, Ectopic; Humans; Hypercalcemia; Insulin; Insulin Secretion; Lung Neoplasms; Melanocyte-Stimulating Hormones; Neoplasm Proteins; Neoplasms; Neurophysins; Osteomalacia; Oxytocin; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Phosphates; Placental Lactogen; Prolactin; Thyrotropin; Vasopressins

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

Gastrin-releasing peptide (GRP) is a growth factor for small cell lung cancer (SCLC). GRP belongs to the bombesin peptide family and has significant homology to bombesin. We constructed a bispecific molecule, OKT3xAntag2, by conjugating a monoclonal antibody OKT3 (anti-CD3) with a bombesin/GRP antagonist (Antag2) and evaluated cytotoxicity against SCLC cells.. We tested binding of the bispecific molecule to SCLC cell lines and T cells by flow cytometry, antibody-dependent cellular cytotoxicity (ADCC) of SCLC cells in vitro and in a murine SCLC xenograft model. We studied SCLC apoptosis and necrosis during ADCC and the activity and cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP).. The bispecific molecule functions as a cross-linker between T cells and SCLC cells, induces T cell activation, and mediates ADCC of SCLC cells; 40% to 80% growth inhibition of SCLC cells mediated by the bispecific molecule at low effector to target cell ratios was achieved. Activation of T cells by the bispecific molecule resulted in significant increases in IFNgamma production and apoptosis and necrosis of SCLC cells associated with cleavage of PARP and caspase-3. Targeted immunotherapy with the bispecific molecule-armed human T cells significantly reduced SCLC tumor burdens in a mouse model.. The bispecific molecule OKT3xAntag2 mediates growth inhibition and apoptosis of SCLC cells by activated T cells through activation and cleavage of caspase-3 and PARP in vitro and in vivo. Clinical trials of this bispecific molecule through adoptive transfer of ex vivo activated T cells in GRP receptor-positive tumors, such as SCLC, are warranted.

Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Binding Sites; Carcinoma, Small Cell; Cell Line, Tumor; Cell Proliferation; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Humans; Immunoconjugates; Immunotherapy; Interferon-gamma; Lung Neoplasms; Mice; Mice, Inbred NOD; Muromonab-CD3; Oxytocin; Receptors, Bombesin; Structure-Activity Relationship; T-Lymphocytes; Transplantation, Heterologous; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The human testicular receptor 4 (TR4) shares structural homology with members of the nuclear receptor superfamily. Some other members of this superfamily were able to regulate the transcriptional activity of the human oxytocin (OXT) promoter by binding to the first DR0 regulatory site. However, little investigation was conducted systematically in the study of the second dDR4 site of OXT proximal promoter, and the relationship between the first and the second sites of OXT promoter. Here, we demonstrated for the first time that TR4 could increase the proximal promoter activity of the human OXT gene via DR0, dDR4, and OXT (both DR0 and dDR4) elements, respectively. TR4 might induce OXT gene expression through the OXT element in a dose-dependent manner. However, there is no synergistic effect between DR0 and dDR4 elements during TR4 transactivation. Taken together, these results suggested that TR4 should be one of important regulators of OXT gene expression.

Topics: Adenocarcinoma; Cell Line, Tumor; Humans; Lung Neoplasms; Nuclear Proteins; Oxytocin; Promoter Regions, Genetic; Repressor Proteins; Transcriptional Activation

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

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

Paraneoplastic secretion of the lactation-inducing hormone oxytocin (OT) has been reported in about 30% of cases of small cell carcinoma of the lung (SCCL). In order to investigate the role of OT in the biology of SCCL tumours, a specific enzyme-immunoassay (EIA) for OT, which can be applied to both human plasma and culture medium, has been developed. OT EIA is performed on 96-well microtiter plates coated with a rabbit polyclonal antibody (Ab) anti-OT (04). This antibody does not exhibit any significant cross-reactivity either with vasopressin (VP) or with vasotocin (VT). The immunological reaction involving Ab anti-OT is a competition between the tracer (biotinylated OT) and synthetic OT (standard curve) or OT present in biological samples. In order to limit interference induced by plasma proteins, plasma samples are filtrated by a one-step centrifugation on centricon YM-3 (cut-off 3000 Da). After plasma filtration, 90.7 +/- 5.1 (SD) % (n = 22) immunoreactive (IR) OT is recovered. The sensitivity of OT EIA is 1 pmol/L, while intra- and inter-assay coefficients of variation (CV) are around 3.41% and 2.84%, respectively. In healthy volunteers, plasma IR OT is 7.28 +/- 4.49 (SD) pmol/L (n = 32) with no gender difference. As shown by the data both from plasma of SCCL patients and from supernatants and cell contents of SCCL cell lines, this EIA procedure offers a novel, reproducible, specific and sensitive method for the measurement of IR OT.

Topics: Adult; Animals; Antibody Specificity; Binding, Competitive; Biotinylation; Carcinoma, Small Cell; Centrifugation; Culture Media, Conditioned; Female; Filtration; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Middle Aged; Oxytocin; Rabbits; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Tumor Cells, Cultured

In previous studies we have demonstrated the high incidence of vasopressin gene expression as a characteristic feature of small-cell carcinoma of the lung. In the present study we examined expression of this gene in non-neuroendocrine tumors to determine if vasopressin production is a common feature of all lung tumors. We carried out the immunohistochemical evaluation of 22 non-neuroendocrine tumors (12 adenocarcinomas and 10 squamous-cell carcinomas) with antibodies to vasopressin, to oxytocin, and to their related neurophysins. The antibody preparations directed against vasopressin, oxytocin, or oxytocin-associated human neurophysin did not react with any of the tumors examined. Of two monoclonal antibodies to vasopressin-associated human neurophysin used, one did not react with any of the tumors, while the other stained neoplastic cells in only one adenocarcinoma and one squamous-cell carcinoma. These findings, taken with previous reports, indicate that among lung carcinomas, a high incidence of vasopressin/oxytocin gene expression is confined to neuroendocrine tumors.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Gene Expression; Humans; Immunoenzyme Techniques; Lung Neoplasms; Neurophysins; Oxytocin; 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

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

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

The human genes for prepro-arginine-vasopressin-neurophysin II (prepro-AVP-NPII) and prepro-oxytocin-neurophysin I (prepro-OT-NPI) were cloned from a human genomic library and the nucleotide sequence of both genes was determined. The two genes are similar in their intron-exon structure, linked together with 12 kilobases intervening, and transcribed from opposite DNA strands. A human small cell lung cancer cell line, H378, produces significant quantities of pre-pro-AVP-NPII mRNA using a transcription unit predicted from the genomic DNA sequence. Despite the proximity of the actively transcribed prepro-AVP-NPII gene, transcription of prepro-OT-NPI is not detected in this cell line.

Topics: Amino Acid Sequence; Arginine Vasopressin; Base Sequence; Cell Line; Cloning, Molecular; DNA Restriction Enzymes; Genes; Genetic Linkage; Genetic Vectors; Humans; Lung Neoplasms; Neurophysins; Oxytocin; Protein Precursors; 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

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

In an attempt to delineate the nature of the immunoreactive neurophysins in oat cell carcinomas of the lung with ectopic vasopressin production, tumor neurophysins were characterized by gel filtration and by electrophoresis. In all of the five tumor tissues, activities of both vasopressin and nicotine-stimulated neurophysin (NSN) determined by radioimmunoassay were demonstrated. A small amount of oxytocin as well as estrogen-stimulated neurophysin was detected in three of the tissues. When tissue extract was subjected to Sephadex G-50 gel filtration in 0.2 N acetic acid, the major portion of immunoreactive NSN emerged in the fractions corresponding to the molecular size of 10,000. The migration pattern of NSN in these fractions on electrophoresis was qualitatively the same as that of NSN extracted from human posterior pituitary glands. In addition to this major neurophysin, immunoreactive NSN with the molecular size of 20,000 was consistently demonstrated in three tumor extracts. This high molecular weight form of neurophysin represented 6.5--8.7% of total NSN immunoactivities in each tumor extract and its elution profile was not changed when analyzed under denaturating conditions in 6 M guanidine hydrochloride. On electrophoresis, it migrated near the gamma globulin region; however, the peak was broad suggesting that it consists of more than two different molecular populations. A substantial portion of the high molecular weight NSN appears to be a glycoprotein judging from its binding to concanavalin A. When the high molecular weight from of neurophysin was incubated with trypsin, essentially all of the activities were converted into NSN with the molecular size of 10,000. Moreover, an equimolar amount of vasopressin was liberated after the treatment, the elution pattern of which closely resembled that of synthetic arginine vasopressin. When a lower concentration of trypsin was used, some of the 20,000-dalton neurophysin exhibited activities of both NSN and vasopressin. Since the antivasopressin serum used in this study appeared to be directed toward the ring portion side of vasopressin, these results suggest that this 20,000-dalton neurophysin is, in all probability, a common precursor to vasopressin and neurophysin, and that vasopressin may be located in the middle of the precursor molecule.

Topics: Aged; Arginine Vasopressin; Carcinoma, Small Cell; Hormones, Ectopic; Humans; Lung Neoplasms; Middle Aged; Molecular Weight; Neurophysins; Oxytocin; Paraneoplastic Endocrine Syndromes; Protein Precursors

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

Topics: Carcinoma, Bronchogenic; Hormones, Ectopic; Humans; Lung Neoplasms; Molecular Weight; Oxytocin; 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: Adenocarcinoma; Animals; Carcinoma, Bronchogenic; Choriocarcinoma; Culture Media; Diuresis; Female; In Vitro Techniques; Liver; Liver Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Oxytocin; Pancreatic Neoplasms; Pregnancy; Rats; Recurrence; Uterine Neoplasms; Vasopressins

Topics: Adenocarcinoma; Animals; Biological Assay; Carcinoma, Bronchogenic; Chickens; Humans; Hyponatremia; Lung Neoplasms; Male; Methods; Middle Aged; Neoplasm Metastasis; Neoplasms, Multiple Primary; Osmolar Concentration; Oxytocin; Pancreatic Neoplasms; Pneumonectomy; Rabbits; Radioimmunoassay; Rats; Vasopressins