Abstract |
PTH-related protein ( PTHrP) has been shown to be a major factor responsible for hypercalcemia of malignancy. PTHrP acts via the PTH/PTHrP receptor, and therefore, PTH antagonists might be expected to reverse the hypercalcemia in malignancy. In the present studies, the PTH antagonists [Tyr34]bovine (b) PTH-(7-34)NH2, [D-Trp12,Tyr34]- bPTH-(7-34)NH2, or PTHrP-(7-34)NH2, were administered to hypercalcemic athymic nude mice bearing a human squamous cell carcinoma of the lung in 60- to 500-fold molar excess of a dose of PTHrP-(1-34) known to produce hypercalcemia. The antagonists had no significant effect on serum calcium levels. In an adenylyl cyclase assay using the ROS 17/2.8 cells, a potent PTH antagonist, [Leu11,D-Trp12] PTHrP-(7-34)NH2 was rapidly inactivated in the presence of rat or human plasma. This inactivation by plasma was not blocked by common inhibitors of proteolysis ( aprotinin, soybean trypsin inhibitor, and leupeptin). Preliminary studies demonstrated that inactivation of the PTHrP antagonist was caused by a plasma component with an apparent mol wt of 230,000 daltons. The knowledge of the structure of the PTH/PTHrP receptor combined with the identification of a hormone-inactivating plasma factor should facilitate the design of PTH-antagonists that are effective in vivo.
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Authors | S C Kukreja, J J D'Anza, S A Wimbiscus, J E Fisher, R L McKee, M P Caulfield, M Rosenblatt |
Journal | Endocrinology
(Endocrinology)
Vol. 134
Issue 5
Pg. 2184-8
(May 1994)
ISSN: 0013-7227 [Print] United States |
PMID | 8156920
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Parathyroid Hormone
- Peptide Fragments
- Protease Inhibitors
- Proteins
- parathyroid hormone-related protein (7-34)amide
- parathyroid hormone (7-34)amide, Tyr(34)-
- Calcium
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Topics |
- Animals
- Blood
- Calcium
(blood)
- Carcinoma, Squamous Cell
(complications)
- Humans
- Hypercalcemia
(etiology, metabolism)
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Parathyroid Hormone
(antagonists & inhibitors, pharmacology)
- Peptide Fragments
(pharmacology)
- Protease Inhibitors
(pharmacology)
- Proteins
(pharmacology)
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