title: Cinacalcet attenuates hypercalcemia observed in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors.
abstract: Excessive secretion of parathyroid hormone-related protein (PTHrP) by tumors stimulates bone resorption and increases renal tubular reabsorption of calcium, resulting in hypercalcemia of malignancy. We investigated the ability of cinacalcet, an allosteric modulator of the calcium-sensing receptor, to attenuate hypercalcemia by assessing its effects on blood ionized calcium, serum PTHrP, and calcium-sensing receptor mRNA in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors. Cinacalcet effectively decreased hypercalcemia in a dose- and enantiomer-dependent manner; furthermore, cinacalcet normalized phosphorus levels, but did not affect serum PTHrP. Ribonuclease protection assay results demonstrated presence of PTHrP receptor, but not calcium-sensing receptor mRNA in C26-DCT tumors. The mechanism by which cinacalcet lowered serum calcium was investigated in parathyroidectomized rats (i.e., without PTH) made hypercalcemic by PTHrP. Cinacalcet attenuated PTHrP-mediated elevations in blood ionized calcium, which were accompanied by increased plasma calcitonin. Taken together these results suggest that the cinacalcet-mediated decrease in serum calcium is not the result of a direct effect on tumor cells, but rather is the result of increased calcitonin release. In summary, cinacalcet effectively reduced tumor-mediated hypercalcemia and corrected hypophosphatemia in mice. Further investigation of cinacalcet for treatment of hypercalcemia of malignancy is warranted.
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Colloton
authors.forename: Edward
authors.initials: E
authors.lastname: Shatzen
authors.forename: Bernadette
authors.initials: B
authors.lastname: Wiemann
authors.forename: Charlie
authors.initials: C
authors.lastname: Starnes
authors.forename: Sheila
authors.initials: S
authors.lastname: Scully
authors.forename: Charles
authors.initials: C
authors.lastname: Henley
authors.forename: David
authors.initials: D
authors.lastname: Martin
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000378:metabolism; D002118:Calcium / Q000097:blood / Q000378:metabolism; D045744:Cell Line, Tumor; D000069449:Cinacalcet; D003110:Colonic Neoplasms / Q000150:complications / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007984:Leydig Cell Tumor / Q000150:complications / Q000473:pathology*; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000235:genetics
chemical_list: D009281:Naphthalenes; D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing; D002116:Calcitonin; D002118:Calcium; D000069449:Cinacalcet