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A New Bioactive Form of Human Calcitonin1

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A New Bioactive Form of Human Calcitonin1 [CANCER RESEARCH 43, 3793-3799, August 1983] A New Bioactive Form of Human Calcitonin1 Paul H. Tobler,2 Maximilian A. Dambacher, Walter Born, Philipp U. Heitz, RenéMaier, and Jan A. Fischer3 Research Laboratory for Calcium Metabolism, Departments of Orthopedic Surgery (Balgrist) and Medicine, University of Zurich, 8008 Zurich, Switzerland [P. H. T., M. A. D., W. B., J. A. F.]; and Department of Pathology, University of Basel [P. U. H.] and Pharmaceuticals Division, Ciba-Geigy, Ltd., 4002 Basel, Switzerland [R. M.] ABSTRACT cannot be identified. With the recent advent of HPLC analysis, hCT-(1-32) and its Distinct immunoreactive forms of calcitonin (CT), extracted sulfoxide form have been recognized in thyroid extracts and in with 2 M acetic acid from two pancreatic tumors, were charac the plasma of normal subjects and of patients with MTC (17,35, terized and identified by gel permeation chromatography and by 36). Moreover, large molecular weight (12 to 25 k dalton) com reverse-phase high-performance liquid chromatography. The ex ponents of CT have been detected in cell extracts and in the tracted CT forms were compared to CT obtained from medullary incubation medium of a CT-producing epidermoid bronchial car thyroid carcinoma and from normal thyroid glands, and were, cinoma cell line (21, 24). furthermore, analyzed in a rat hypocalcémiebioassay. On gel In the present report, we have for the first time recognized filtration analysis, two broad peaks coeluting with synthetic different CT forms in tissue extracts of patients with endocrine human CT-(1-32) and extracted dimeric CT, respectively, were pancreatic tumors and MTC by HPLC analysis, and have, fur found in variable amounts. An acetonitrile gradient high-perform thermore, detected a new biologically active CT-like peptide. ance liquid chromatography system revealed two to three pre dominant CT peaks. Biologically active monomeric and dimeric MATERIALS AND METHODS CT and the biologically inactive sulfoxide form of human CT-(1 - 32) have been identified. Moreover, we have detected for the Patients. Two female patients with endocrine pancreatic tumors se first time a new biologically active CT-like component which was creting CT ectopically, a 52-year-old with a benign tumor and a 74-year- most prominently recognized in a benign pancreatic tumor. old with a malignant tumor, were compared to 2 patients (a 32-year-old female and a 38-year-old male) with CT producing MTC. Plasma CT levels were raised in the patients with pancreatic tumors (27.0 and 97.4 INTRODUCTION ng equivalent/ml; normal range, <0.05 ng equivalent/ml) and with MTC hCT4 is a 32-amino acid polypeptide hormone (M, 3418) of the (2.0 and 2000 ng equivalent/ml). In the pancreatic tumor patients, plasma levels of calcium were increased (3.44 and 2.89 mmol/liter; normal range, thyroid gland that causes hypocalcemia by inhibition of the 2.07 to 2.42 mmol/liter) and those of parathyroid hormone, 5 and 18 ng release of calcium from bone (3, 23). Increased production of CT equivalent/ml, were in the normal range (6 to 40 ng equivalent/ml). The by medullary carcinoma of the thyroid has been amply docu benign pancreatic tumor was surgically removed, plasma levels of CT mented. In 1973, Sizemore ef al. (31) detected raised concentra became undetectable, and plasma calcium was normalized. The patient tions of immunoreactive CT in the plasma of 6 of 8 patients with with the malignant pancreatic tumor died of pulmonary embolism, and the Zollinger-Ellison syndrome and mentioned the possibility of the diagnosis was established at autopsy. ectopie CT secretion from non-0-islet cell tumors of the pancreas. In one of the MTC patients, plasma calcium (2.37 mmol/liter) was in the upper normal range, and parathyroid hormone (62 ng equivalent/ml) One of their patients showed no postmortem evidence of med was increased. This patient belonged to a kindred with multiple endocrine ullary carcinoma of the thyroid. Schwartz ef a/. (30) have found adenomatosis type 2 (32) and, moreover, presented hyperplastic para elevated plasma levels of CT in 42% of the patients with pan thyroid glands and pheochromocytomas. The other MTC patient was creatic tumors. Immunocytochemical examination of endocrine inoperable because of generalized métastasesas confirmed at autopsy. pancreatic tumors revealed the presence of CT among other Peptides. Synthetic hCT-(1-32) (monomeric form), extracted purified polypeptide hormones such as adrenocorticotropic hormone, dimeric hCT from MTC, and synthetic human parathyroid hormone-(1- gastrin, /3-endorphin, and somatostatin (25). The findings have 34) have been donated by W. Rittel, Ciba-Geigy AG, Basel, Switzerland; [3H]hCT-(1-32), by R. Wade, Ciba-Geigy, Ltd., Horsham, Great Britain been confirmed by other groups of investigators (2, 8,9,16,19). (6); and extracted bovine parathyroid hormone-(1-84), by the Medical Abe ef al. (1) demonstrated superimposable ¡mmunodilution curves of extracts of pancreatic tumors and of synthetic hCT-(1- Research Council, Great Britain. Bovine serum albumin was purchased from Sigma Chemical Co., St. Louis, Mo., and human serum albumin 32) suggesting immunological similarities. On gel permeation was from Behring Werke, Hoechst Pharma AG, Zurich, Switzerland. chromatography of tumor extracts (15) and plasma (10, 26, 29) Preparation of Tissues and Extraction. Tumor tissue obtained at of patients with pancreatic tumors, several immunoreactive CT surgery was, after determination of wet weight, snap-frozen in liquid components have been recognized. In view of the limited reso nitrogen shortly after excision and stored at -70° until extraction. The lution of peptides on gel filtration analysis, different CT forms frozen tissues were homogenized in 2 M acetic acid, and the clear supernatants of the centrifuged homogenates were extracted by adsorp tion of the peptides on octadecasilyl silica (C,e-Sep-Pak cartridges; ' This work was supported by the Swiss National Science Foundation Grants 3.941-0.78 and 3.813-0.81, the State of Zurich, and the Schweizerische Verein Waters Assoc., Milford, Mass.) according to a method described previ Balgrist. ously (36). Lyophilized extracts were dissolved in 1 ml 0.1 M acetic acid 2 In partial fulfillment of the requirements for a Dr.sc.nat. degree at the Federal for further analysis. In 5 individual extractions, the overall recovery of Institute of Technology, Zurich, Switzerland. [3H]hCT-(1-32) initially added to the frozen tissue amounted to 73.1 ± 3 To whom requests for reprints should be addressed, at Klinik Balgrist, Forch trasse 340, CH-8008 Zurich, Switzerland. 4.3% (S.E.) with a range of 62 to 84%. 'The abbreviations used are: hCT, human calcitonin; CT, calcitonin; HPLC, Gel Filtration. For gel filtration of tissue extracts, columns of Bio-Gel high-performance liquid chromatography; MTC, medullary thyroid carcinoma. P-150 (100 to 200 mesh; Bio-Rad Laboratories, Richmond Calif.), 1.6 x Received July 16, 1982; accepted May 9.1983. 100 cm, have been used by ascending flow (flow rate, 3.8 to 5.2 ml/hr) AUGUST 1983 3793 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1983 American Association for Cancer Research. P. H. Tabler et al. at 4°in0.2 Mammoniumacétate,pH4.7, containing 0.5 g bovine sérum 4.6 mm; Macherey-NagelGmbH, Duren, West Germany)columns under albumin per liter, and fractions were collected in 1.9- to 2.6-ml volumes. either isocratic conditions or by gradient elution as described previously The void volume(V0)was estimated by the elution position of the largest- (13, 36). Extracts containing 150 ng to 10 ßQimmunoreactiveCT and molecular-weightproteins determined spectrophotometrically at 280 nm tracer amounts of [3H]hCT-(1-32)and its sulfoxide (30,000 to 60,000 and the salt volume (Vs)was estimated with Na31l.The elution position dpm) not interfering in the radioimmunologicaldeterminations were in of CT components, designated ka,is defined as: jected in a volume of 0.5 ml. Fractionswere collected in siliconizedtubes; 0.2 to 0.3-ml aliquots were analyzed for 3Hradioactivity by liquid scintil (elution volume of the substance - V0) lation spectroscopy (Model MR 300; Kontron AG) in Rotiszint 22 (Carl (V, - Vo) Roth KG, Karlsruhe, West Germany). The remaining fractions were analyzed radioimmunologically.Peak fractions of several extractions of Tracer amounts of radioiodinatedhuman serum albumin,bovine parathy all numbered CT components (Charts 2 and 3) were pooled and recir- roid hormone-(1-84),humanparathyroidhormone-(1-34),hCT-(1-32),and culated in the same systems. The purified CT peptides were analyzedin Na'3'l were added to each extract as calibrating substances. Radioactiv the hypocalcémieratbioassay. The recoveries of immunoreactive hCT ity was measured in an automatic -y-wellspectrometer (Model MR 252; on HPLC were 63.7 ±7.2% (range, 36.7 to 105.0%) under isocratic «ontrónAG, Zurich, Switzerland). Recovery of immunoreactive CT conditionsand 80.9 ±4.2%(range,62.3 to 95.0%) in the gradient elution ranged from 60 to 80%. system. HPLC. The HPLC systemconsistedof a programmer(Model420; Radioimmunoassays.CT was determinedina homologoushCT-(1- Altex, Berkeley, Calif.)and 2 pumps (Model 110 A; Altex). Sampleswere 32) assay described previously (12, 13). The antibodies (goat-6A ob injected via a septumlessvalve(Model 7125; Rheodyne,Berkeley,Calif.) tained on Day 143) were used at a dilution of 1/100,000. They are fitted with a 0.5-ml injector loop. Acetonitrile (HPLC-gradeS), methanol predominantly directed to determinants located in the COOH-terminal (HPLC-grade),and trifluoroacetic and heptafluorobutyric acid (both se parts of the hCT-(1-32)molecule. The specificity of the antibodies used quencer grade) were obtained from Rathburn Chemicals (Walkerburn, has been studied previously(13). The CT-like structure of the corticotro- Great Britain).
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