Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6-phosphate dehydrogenase-stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy.

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Abstract
Humoral hypercalcemia of malignancy (HHM) most commonly results from secretion by tumors of an unidentified circulating calcemic factor that appears in clinical studies to stimulate both a parathyroid hormone (PTH)-sensitive proximal tubular adenylate cyclase and a distinct PTH-sensitive renal tubular G-6-P dehydrogenase complex. In the study, 8 M urea extracts of tumors from patients with HHM contained both in vitro adenylate cyclase-stimulating activity and G-6-P dehydrogenase-stimulating activity as detected in a sensitive cytochemical bioassay. Both the adenylate cyclase-stimulating activity and cytochemical bioactivity are due to specific binding of a substance in the tumor extracts to renal PTH receptors, as demonstrated by competitive inhibition studies using the bovine PTH [bPTH] fragment analog [Nle8,18, Tyr34]bPTH-(3-34) amide. Preincubation with an antiserum to PTH results in no loss of activity in the tumor extract, and the activity appears both on gel filtration and ultrafiltration to be far larger than PTH (estimated MW 70,000). Extracts of tumors from patients with HHM contain a substance that binds to the PTH receptors in the nephron responsible for activation of both the PTH-sensitive G-6-P dehydrogenase and the PTH-sensitive adenylate cyclase. This substance is chromatographically and immunologically distinct from PTH. Its role in the genesis of HHM requires further study.