scholarly journals Cinacalcet for the Treatment of Humoral Hypercalcemia of Malignancy: An Introductory Case Report with a Pathophysiologic and Therapeutic Review

2020 ◽  
Vol 13 (1) ◽  
pp. 321-329 ◽  
Author(s):  
Michael Sheehan ◽  
Sabo Tanimu ◽  
Yusuf Tanimu ◽  
Jessica Engel ◽  
Adedayo Onitilo
Keyword(s):  
Potential Effect ◽  
Calcium Excretion ◽  
Intravenous Fluids ◽  
Related Protein ◽  
Small Cell Lung ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Intravenous Bisphosphonates

Hypercalcemia is an ominous development in the course of malignancy associated with a mean survival of only several months. A majority of cases of hypercalcemia are related to humoral hypercalcemia of malignancy (HHM), where hypercalcemia is caused by increased levels of circulating parathyroid hormone-related protein (PTHrP). Mainstay treatments in the management of HHM are intravenous fluids, intravenous bisphosphonates, and subcutaneous denosumab, although hypercalcemia oftentimes recurs despite these efforts. We present a case of advanced non-small cell lung cancer with PTHrP-mediated hypercalcemia that proved resistant to standard therapy. A trial of oral cinacalcet was initiated and improved calcium levels for 2 months despite a progressive rise in PTHrP and prior to subsequent disease progression. Based on the current body of literature, we propose that this calcium-lowering effect of cinacalcet occurs due to a potential effect on renal calcium excretion.

Defining the roles of parathyroid hormone-related protein in normal physiology

1996 ◽  
Vol 76 (1) ◽  
pp. 127-173 ◽  
Author(s):  
W. M. Philbrick ◽  
J. J. Wysolmerski ◽  
S. Galbraith ◽  
E. Holt ◽  
J. J. Orloff ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Fetal Life ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Physiological Functions ◽  
Hypercalcemia Of Malignancy ◽  
Normal Tissues ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Differentiation And Proliferation

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.

scholarly journals Parathyroid Hormone-Related Protein-(1–36) Is Biologically Active When Administered Subcutaneously to Humans1

1997 ◽  
Vol 82 (3) ◽  
pp. 900-906
Author(s):  
Jean G. Henry ◽  
Maryann Mitnick ◽  
Pamela R. Dann ◽  
Andrew F. Stewart
Keyword(s):  
Biologically Active ◽  
Dose Finding ◽  
Calcium Excretion ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Dihydroxyvitamin D ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Finding Study ◽  
Normal Women

Abstract PTH-related protein (PTHrP) is responsible for most cases of humoral hypercalcemia of malignancy (HHM). It mimics the actions of PTH as a result of its structural homology with PTH and its ability to bind to and signal via the PTH/PTHrP receptor in bone and kidney. PTHrP-(1–36) appears to be one of several secretory forms of PTHrP. This peptide has been administered iv to normal volunteers previously and has been shown to produce effects that are qualitatively and quantitatively the same as those produced by PTH-(1–34). To determine whether PTHrP-(1–36) could be used sc in humans as a diagnostic reagent for elucidating the differences between HHM and hyperparathyroidism, we performed a 12-h dose-finding study examining whether sc PTHrP-(1–36) could elicit effects on mineral homeostasis. PTHrP-(1–36) administered sc in three doses (0.82, 1.64, and 3.28μ g/kg) to 21 normal women produced increases in circulating PTHrP-(1–36), reductions in serum phosphorus and the renal phosphorus threshold, increments in fractional calcium excretion and nephrogenous cAMP excretion, and increases in plasma 1,25-dihydroxyvitamin D. These changes were highly significant in statistical terms and were observed at doses that had no effect on serum calcium or endogenous PTH. These studies demonstrate the feasibility of using PTHrP-(1–36) as a diagnostic probe for future studies aimed at elucidating the differing pathophysiologies of HHM and hyperparathyroidism.

Parathyroid Hormone-Related Protein: Structure, Function, and Measurement

1992 ◽  
Vol 38 (11) ◽  
pp. 2171-2183 ◽  
Author(s):  
W J Burtis
Keyword(s):  
Parathyroid Hormone ◽  
Amino Acid ◽  
Amino Acid Sequences ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Physiological Importance ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Order Of Magnitude

Abstract Parathyroid hormone-related protein (PTHRP) is a 139- to 173-amino-acid protein with N-terminal homology to parathyroid hormone (PTH). Initially isolated from tumors from patients with humoral hypercalcemia of malignancy, PTHRP appears to be of far more widespread physiological importance. Its complex gene is expressed in a surprising diversity of tissues. The primary amino acid sequences of both the PTH-like and non-PTH-like regions of the protein are highly conserved across species. In addition to classical and nonclassical PTH-like activities of the N-terminal region, other biological functions have been ascribed, including augmentation of calcium transport by midregion PTHRP and potent inhibition of bone resorption by a C-terminal peptide. There is emerging evidence that the protein undergoes extensive processing, including glycosylation and defined proteolytic cleavages. Several region-specific immunoassays are now capable of measuring circulating concentrations of PTHRP in patients with humoral hypercalcemia of malignancy. Molar concentrations of different regions may differ by more than an order of magnitude, reflecting diversity in processing and (or) metabolism. By analyzing the results of these assays, taking into account the specificities of known endoproteases, one can hypothesize about some of the endoproteolytic cleavages that occur in PTHRP metabolism. Clinically, selected PTHRP assays can be very helpful in diagnosing PTHRP-mediated hypercalcemia, but are not yet sufficiently sensitive to accurately measure normal concentrations of the protein.

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