Nephrogenous Cyclic AMP, Adenylate Cyclase-Stimulating Activity, and the Humoral Hypercalcemia of Malignancy

Abstract

Publisher Summary This chapter discusses nephrogenous cyclic AMP (NcAMP), adenylate cyclase-stimulating activity (ACSA), and the humoral hypercalcemia of malignancy (HHM). Clinical HHM is a pathophysiologic syndrome which can be readily distinguished from 1°HPT group and local osteolytic hypercalcemia. Human HHM and animal models of HHM are associated with increases in NcAMP or UcAMP excretion. In contrast, NcAMP or UcAMP excretion is normal in humans and animals with HHM. These observations, and the findings that humans with MAHC can be divided into clinically and pathophysiologically distinct groups based upon NcAMP excretion, lead inescapably to the conclusion that the observed elevations in NcAMP are related mechanistically to hypercalcemia in patients with HHM. The ACSA that is present in human and animal HHM-associated tumors is not typically present in tumors derived from normocalcemic patients or animals. This ACSA can be prepared in highly purified form from human and animal tumors and can be shown to result from a basic protein with a molecular weight of approximately 30,000. This highly purified material contains potent in vitro bone-resorbing activity. These observations provide strong evidence that this PTH-like ACSA is related mechanistically to HHM. Human and animal HHM-associated tumors contain mRNA which encodes for a secretary protein which is closely related or identical to the ACSA found in tumor extracts.