The synthetic human parathyroid hormone-related protein is inhibited by a parathyroid hormone antagonist in rats in vivo

Horiuchi, Noboru; Hongo, Takashi; Clemens, Thomas L.

doi:10.1002/jbmr.5650050603

Cited by 7 publications

(1 citation statement)

References 23 publications

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“…A fourth hormone, namely parathyroid hormone‐related protein (PTHrp), has been demonstrated to play an important role in calcium metabolism, particularly in malignant conditions in human beings and dogs (Burtis and others 1990, Rosol and others 1992, Ikeda and others 1994, Firkin and others 1996, Mellanby and others 2006a). PTHrp has a similar structure and function to parathyroid hormone and causes hypercalcaemia by increasing bone resorption and renal tubular resorption of calcium (Horiuchi and others 1990, Strewler 2000).…”

Section: Introductionmentioning

confidence: 99%

Calcium metabolism in eight dogs with hypoadrenocorticism

Gow¹,

Gow²,

Bell³

et al. 2009

J of Small Animal Practice

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Hypoadrenocorticism is a well-described endocrinopathy in dogs that results from deficient production and secretion of glucocorticoids and/or mineralocorticoids. Although hyperkalaemia, hyponatraemia and hypochloraemia are the most common electrolyte disturbances, hypercalcaemia also occurs in approximately 30 per cent of cases. The pathogenesis of hypercalcaemia in dogs with hypoadrenocorticism is unknown. This case series reports ionised calcium, parathyroid hormone, parathyroid hormone-related protein and vitamin D metabolite concentrations that were measured in eight dogs with concurrent hypercalcaemia and hypoadrenocorticism. Ionised calcium was increased in five of seven dogs with hypercalcaemia associated with hypoadrenocorticism. Parathyroid hormone, parathyroid hormone-related protein and 1,25 dihydroxyvitamin D concentrations were within their reference ranges in seven of eight dogs, six of seven cases and six of seven dogs, respectively. This case series highlights that hypercalcaemia associated with hypoadrenocorticism is rarely associated with increases in plasma parathyroid hormone, parathyroid hormone-related protein or serum 1,25 dihydroxyvitamin D concentrations.

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Section: Introductionmentioning

confidence: 99%

Calcium metabolism in eight dogs with hypoadrenocorticism

Gow¹,

Gow²,

Bell³

et al. 2009

J of Small Animal Practice

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Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Sato

Yamakawa

Shizume

et al. 1993

Journal of Bone and Mineral Research

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Malignancy-associated hypercalcemia is mainly caused by excessive production of parathyroid hormone-related protein (PTHrP) by the tumor. Using anti-PTHrP-(1-34) monoclonal murine antibody (anti-PTHrP MoAb), we studied whether repeated injection of the homologous antibody would continuously decrease the serum calcium concentration in hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors, leading to prolongation of their survival time. Daily SC injections of anti-PTHrP MoAb decreased the serum calcium concentration almost to within the normal range in nude mice bearing transplanted human PTHrP-producing tumors (T3M-1, EC-GI, PC-3, and FA-6) but not in a nude mouse bearing a transplanted parathyroid carcinoma. The antibody did not affect FA-6 tumor growth either in vitro or in vivo. Pancreatic carcinoma cells (FA-6), which caused the most severe hypercalcemia, were inoculated into 6-week-old nude mice. When severe hypercalcemia (approximately 19 mg/dl) had developed, daily SC injection of anti-PTHrP MoAb was started. Within 18 days of this time point, all untreated tumor-bearing mice (n = 10) died of hypercalcemia and cachexia, whereas all the treated mice (n = 10) showed an increase in body weight and survived for at least 25 days. Histologic examination of the treated mice revealed a marked decrease in osteoclastic bone resorption, without toxicologic findings in the kidney and liver. These results suggest that passive immunization against PTHrP can continuously ameliorate the hypercalcemia and markedly prolong the survival time of severely hypercalcemic, tumor-bearing mice. If a human monoclonal antibody against PTHrP-(1-34) could be developed, then passive immunization would be potentially one of the most effective therapies for patients with malignancy-associated hypercalcemia due to excessive production of PTHrP.

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Evaluation in vivo of a potent parathyroid hormone antagonist: [Nle8,18, D-Trp12, Tyr34]bPTH(7–34)NH2

Dresner–Pollak

Yang

Behar

et al. 1996

Journal of Bone and Mineral Research

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In an effort to design and select potent parathyroid hormone (PTH) antagonists suitable for clinical utility, a PTH analog was evaluated in vivo in an animal model to assess its properties in preparation for human studies. The previously described PTH antagonist, [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2, which is highly active in vitro, was documented in these studies to be an effective antagonist of the PTH-stimulated calcemic response in vivo. In thyroparathyroidectomized (TPTX) rats, the efficacy of the antagonist was demonstrated to be dose-dependent. Inhibition was demonstrated when intravenous administration of antagonist started 1 h prior to coinfusion with the PTH agonist [Nle8,18,Tyr34]bPTH(1-34)NH2. Maximal inhibition by antagonist (an 84% decline in serum calcium levels compared with agonist alone) of the calcemic response was observed when a 200-fold molar excess of antagonist (12 nmol/h) was administered. At dose ratios of antagonist:agonist as low as 10:1, a 40-50% inhibition of PTH-stimulated calcemic response is evident, provided a longer (2 h) lead time for antagonist infusion is allowed. Based on these and related studies, the antagonist [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2 has displayed sufficient potency to obtain approval from the appropriate institutional and regulatory agencies for clinical trials in hypercalcemic states of parathyroid and tumor origin.

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The synthetic human parathyroid hormone-related protein is inhibited by a parathyroid hormone antagonist in rats in vivo

Cited by 7 publications

References 23 publications

Calcium metabolism in eight dogs with hypoadrenocorticism

Calcium metabolism in eight dogs with hypoadrenocorticism

Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Evaluation in vivo of a potent parathyroid hormone antagonist: [Nle8,18, D-Trp12, Tyr34]bPTH(7–34)NH2

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