HYPOCALCEMIC AND PTH-INHIBITORY MECHANISMS OF WR2721

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The aim of this research project will be to investigate in a systematic manner the basis for the hypocalcemia and reduction in PTH secretion which we have found in preliminary studies following the administration of WR2721, S-2-(3-aminopropylaminoethyl) phosphorothioic acid. This compound is an organic thiophosphate derivative which in animals selectively protects normal tissues against the toxicity of radiation and alkylating agent chemotheraphy. In Phase I clinical trials of this compound, one patient developed hypocalcemia. Subsequently serial calcium measurements in eight patients demonstrated both a consistent fall in serum calcium from 9.48 to 7.44 mg/dl and a concomitant fall in serum PTH levels in every patient studied from a average of 4.75 to 1.6 pL-Eq/ml. We therefore plan to extend these preliminary observations to identify the mechanism by which WR2721 reduces the serum calcium level as well as reduces the level of parathyroid hormone released. We will utilize three experimental techniques in order to achieve this aim. First we will do a large series of clearance and metabolic balance studies in intact dogs and rats to demonstrate the in vivo characteristics of WR2721 hypocalcemic action. These studies will be devoted to identifying the relative contributions of changing PTH release and other components of calcium homeostasis to the observed hypocalcemia. They also will be devoted to examining the clinical utility of WR2721 as an inhibitor of PTH release and as a hypocalcemi agent. The second series of experiments will utilize the dispersed bovine parathyroid cell preparation to identify the effects and mechanism of WR2721 in a highly sensitive model system to detect changes in PTH release. The third experimental technique will be to attempt to identify the changes in whole animal as well as single cell calcium kinetics which may underlie the effects of WR2721 to alter the serum calcium level in vivo. There are currently no effective tools for the regulation of parathyroid hormone secretion. Thus if WR2721 fulfills its early promise as being an agent effective in lowering serum calcium with virtually no other toxic effects as well as capable of inhibiting PTH release, it may achieve wide clinical use as a therapeutic tool in a variety of conditions.