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Inactivation by plasma may be responsible for lack of efficacy of parathyroid hormone antagonists in hypercalcemia of malignancy.

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.