Immunochemical studies on rabbit calcitonin.
Cross reaction studies using radioimmunoassays specific for human and porcine calcitonin showed that rabbit calcitonin is structurally more closely related to human than to porcine calcitonin.
Biomedical subjects
Publications and source records attributed to C Calmettes.
Cross reaction studies using radioimmunoassays specific for human and porcine calcitonin showed that rabbit calcitonin is structurally more closely related to human than to porcine calcitonin.
Radioimmunological assays of peptidic hormone levels is now an essential procedure for the diagnosis of polyadenomatosis. The diversity of pathological associations found in polyadenomatosis cannot be completely explained by the unitary theories that have been proposed. Neither the APUD system, nor the common embryonic origin, nor the reduction in calcitonin excretion can fully explain the clinical picture: a logical explanation has still to be discovered. In practice, ectopic secretions are frequent in type 2 polyadenomatosis (medullary cancer, pheochromocytoma, neurofibroma, Marfan's syndrome, hyperparathyroidism) contrary to what is observed in type 1 cases (pituitary, parathyroid, pancreas).
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Hypercalcaemia always results in serious clinical sequalae and, if not treated, carries a most unfavourable prognosis. The clinician will gain major diagnostic help from an evaluation of the calcitonin and parathyroid hormone blood levels. With regard to parathyroid hormone we have developed, for the first time, a radioimmunoassay which is specific for the estimation of biologically active hormone in the circulation. We are dealing here with an unusual radioimmunological situation as the immunochemical sites are generally quite distinct from those associated with hormonal activity. We are presenting in this first paper the normal values and also the variations that occur in different types of hypercalcaemia. The comparison of these results with those obtained by the usual methods of estimation for parathyroid hormone assay lacking in biological activity shows the value of this new technique.
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The localization of intracellular calcitonin has been achieved by immunofluorescence in the cytoplasm of all cells forming the epithelium of the ultimobranchial body of eels, using a human antiserum against synthetic Salmon calcitonin I. The specificity of the reaction is demonstrated by inhibition with synthetic salmon calcitonin (S.C.T.); the fluorescence is not inhibited by synthetic human calcitonin (H.C.T.).
We have detected high values of carcinoembryonic antigen in the blood of patients suffering from medullary carcinoma of the thyroid (MCT). Levels of the antigen and calcitonin, the hormone which is specifically secreted by these tumours, are positively correlated. Stimulation of calcitonin secretion has no effect on carcinoembryonic antigen levels. Though the antigen assay is non specific for MCT, it may improve the diagnosis and follow-up of MCT-patients.
The authors report a case of probably ectopic secretion of calcitonin in a 35 year old woman suffering from a malignant tumour in a double intra- and extra-spinal form. Hormone levels returned to normal after complete excision of the tumour, in which it was impossible to demonstrate the presence of calcitonin despite a very marked secretory appearance by electron microscopy. Study of the literature concerning the secretion of calcitonin by malignant tumours indicates the high degree of contradiction concerning the origin and the significance of increased radio-immunological levels of this hormone, which it is not possible to use without criticism as a "marker" of carcinomas.
The detection of high circulating levels of calcitonin is a most valuable procedure to diagnose advanced cases of medullary carcinoma of the thyroid. However, the diagnosis of a primitive tumor in the early stages of development (as in cases of the familial form of the disease) or of a metastasis following ablation of the tumor is more difficult. In the latter cases, the levels of circulating calcitonin may be within normal limits, and for diagnosis one must then resort to tests to stimulate the secretion of calcitonin. We are reporting from our personal experiences the advantages, disadvantages and inconveniences of the three most well-known tests. All patients responded positively to administration of calcium or pentagastrin. The alcohol test, however, produced inconsistent results.
Chromatographic analysis of plasma, urine and tumour tissues extracted from medullary cancer patients demonstrates the existence of immunoreactive calcitonins with higher molecular weight than that of the monomer hormone.
Plasma from patients with medullary carcinoma containing very high levels of immunoreactive calcitonin were fractionated by filtration on Sephadex gel. In all cases the elution gave four immunoreactive fractions. Two of these fractions correspond to the volume of elution of the monomere and of the dimere of human calcitonin. The two other fractions emerge at an elution volume corresponding to much higher molecular weights. After stimulation of calcitonin secretion in vivo, by dynamic tests, the fractions corresponding to the monomere and dimere increase more strongly than the two other fractions. Preliminary studies of secretion, in vitro, of calcitonin by medullary carcinoma tissue, show the presence in the incubate of four immunoreactive forms having the same elution characteristics as those found in the plasma. The significance of these results is discussed.
Multiple endocrine neoplasia type 2 (MEN 2) is transmitted as an autosomal dominant trait, with 3 different forms. MEN 2a consists of medullary thyroid carcinoma, phaeochromocytoma(s) and hyperparathyroidism. In MEN 2b, parathyroid hyperplasia is absent, but a Marfan-like syndrome and neuromas of the mucosae are present. In some families, the only manifestation of MEN 2 is a medullary thyroid carcinoma. These 3 forms seem to related to one or several gene(s) located in the pericentromeric region of chromosome 10. The histological lesions of MEN 2a are multifocal, bilateral and associated with hyperplasia (which affects C-cells in the thyroid gland). Screening for familial medullary thyroid carcinoma is based upon plasma calcitonin levels measured before and after a pentagastrin stimulation test. The demonstration of DNA markers near the gene(s) of the disease in chromosome 10 pericentromeric region makes it possible to identify, with good probability, the subjects at risk for the disease. It is only by determining the responsible gene(s) that subjects carrying the hereditary anomaly will be identified directly, without marker assays.
We have discussed in an earlier paper the value of estimating the circulating levels of biologically active parathyroid hormone. We consider here the importance of an evaluation of circulating calcitonin by showing the frequency of raised calcitonin secretion in hypercalcaemia of different origins. These results lead one to attribute to calcitonin a role which goes beyond the regulation of phospho-calcium metabolism and which in fact is that of a particularly sensitive indicator of tumours.
We have recently studied a kindred in which there have been 2 proven and 2 probable cases of medullary thyroid carcinoma without pheochromocytoma, hyperparathyroidism or Cushing's disease. Four other members suffered from intestinal occlusion and death occurred in three of them. The family has been traced through 4 generations (80 members) and 47 members could be examined; circulating calcitonin and carcinoembryonic antigen levels were measured. This study leads to two conclusions: 1) Medullary thyroid carcinoma is transmitted as an autosomal dominant trait with a high degree of penetrance. 2) Carcinoembryonic antigen is a valuable tumour marker particularly if no calcitonin radioimmunoassay is avialable for the diagnosis of M.C.T.