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 respon sible for hypercalcemia of malignancy. PTHrP acts via the PTH/ PTHrP r eceptor, and therefore, PTH antagonists might be expected to reverse t he hypercalcemia in malignancy. In the present studies, the PTH antago nists Tyr(34)bovine (b) PTH-(7-34)NH2, D-Trp(12),Tyr(34)-bPTH-(7-3 4)NH2, or PTHrP-(7-34)NH2, were administered to hypercalcemic athymic nude mice bearing a human squamous cell carcinoma of the lung in 60- t o 500-fold molar excess of a dose of PTHrP-(1-34) known to produce hyp ercalcemia. The antagonists had no significant effect on serum calcium levels. In an adenylyl cyclase assay using the ROS 17/2.8 cells, a po tent PTH antagonist, Leu(11),D-Trp(12)PTHrP-(7-34)NH2 was rapidly in activated 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 demon strated that inactivation of the PTHrP antagonist was caused by a plas ma component with an apparent mol wt of 230,000 daltons. The knowledge of the structure of the PTH/PTHrP receptor combined with the identifi cation of a hormone-inactivating plasma factor should facilitate the d esign of PTH-antagonists that are effective in vivo.