Nephrogenous cyclic AMP, adenylate cyclase-stimulating activity, and the humoral hypercalcemia of malignancy.
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Adenylyl Cyclases↗
Biomedical subjects
A F Stewart
Publications and source records attributed to A F Stewart.
Detection of the hypercalcemic hormone of malignancy in an adrenal cortical carcinoma.
We report a case of an adrenal cortical carcinoma associated with hypercalcemia. Tumor extracts showed significant activity in an in vitro assay that detects the existence of a hypercalcemic substance distinct from parathyroid hormone. Calcium studies revealed no other obvious cause of hypercalcemia in this patient, and serum calcium returned to normal after the tumor was removed.
Adrenal Cortex Neoplasms↗
Two species of adenylate cyclase-stimulating activity in a murine squamous carcinoma model of humoral hypercalcemia of malignancy.
PTH receptor-stimulating proteins may be a common mediator of humoral hypercalcemia of malignancy (HHM). Such proteins exhibit adenylate cyclase-stimulating activity (ACSA) in PTH-sensitive assays, and ACSA has been used to follow their purification. Acid/urea tumor extracts from a murine squamous carcinoma model of HHM were previously shown to have very high ACSA, which was partially, but incompletely, inhibited by the PTH antagonist Nle8,18,Tyr34-bovine PTH-(3-34) amide. ACSA from murine tumor extracts has now been further purified using solvent fractionation and reverse phase HPLC. Approximately half of the ACSA is attributable to a family of three proteins (peaks IA, IB, and IC) with properties characteristic of the PTH receptor-stimulating protein extracted from rat Leydig cell and human HHM tumors. The ACSA in these three peaks of murine tumor extract elutes in the same region as human tumor ACSA on reverse phase HPLC, has a dose-response curve parallel to that of PTH, and is fully inhibited by the PTH-(3-34) antagonist in both the renal cortical and rat osteosarcoma (ROS) adenylate cyclase assays. The remaining half of the ACSA from murine tumor extracts elutes as a single peak (peak II) at a higher acetonitrile concentration on reverse phase HPLC. In the renal cortical assay, its dose-response curve differs from that of PTH, its ACSA is not affected by the PTH-(3-34) antagonist, and it potentiates PTH- or peak I-stimulated adenylate cyclase activity. In the PTH-sensitive intact cell ROS assay, peak II exhibits no ACSA. We conclude that the potent ACSA of murine tumor acid/urea extract results in large part from amplification of the PTH-specific ACSA (peak I) by peak II. Peak II is a distinct protein, not previously reported in tumor extracts, that may act as a postreceptor step in the adenylate cyclase system.
Adenylyl Cyclases↗
Magnesium homeostasis following chemotherapy with cisplatin: a prospective study.
Retrospective studies suggest that cisplatin chemotherapy regularly leads to hypomagnesemia and occasionally hypocalcemia. The hypomagnesemia has been attributed to renal magnesium wasting. We examined prospectively the incidence of hypomagnesemia, magnesuria, and hypocalcemia in 17 patients receiving chemotherapy with cisplatin. Hypomagnesemia was found in 53% to 88% of patients, depending on the definition of hypomagnesemia. All displayed inappropriate renal excretion of magnesium. Hypocalcemia occurred in one of the 17 prospectively studied patients (5.8%) and in three additional retrospective patients. Hypocalcemic patients demonstrated lower serum magnesium values, higher fractional magnesium excretion, and evidence for reduced intestinal magnesium absorption. We conclude that hypomagnesemia, renal magnesium wasting, and hypocalcemia occur frequently among patients receiving cisplatin. Hypocalcemia occurs in those patients who have the severest renal magnesium wasting, the severest hypomagnesemia, and inadequate intestinal magnesium absorption.
Cisplatin↗
Sensitivity of the parathyroid hormone-1,25-dihydroxyvitamin D axis to variations in calcium intake in patients with primary hyperparathyroidism.
Previous studies have demonstrated a spectrum of parathyroid responsivity to alterations in the extracellular calcium concentration in patients with primary hyperparathyroidism, but studies employing physiologic amounts of calcium have not, to our knowledge, been reported. We studied 18 unselected patients with primary hyperparathyroidism at the lower (400 mg) and upper (1000 mg) limits of a normal dietary intake of calcium. The diet containing high-normal amounts of calcium induced only a slight increase in 24-hour calcium excretion (from 281 to 337 mg per day) yet was associated with significant reductions in fasting serum levels of immunoreactive parathyroid hormone (from 60 to 50 nleq per milliliter; P less than 0.001), nephrogenous cyclic AMP (from 3.52 to 2.63 nmol per deciliter of glomerular filtrate; P less than 0.001), and plasma levels of 1,25-dihydroxyvitamin D (from 74 to 58 pg per milliliter; P less than 0.001). A wide spectrum of responses was observed, with some patients appearing to have essentially autonomous parathyroid function and others having marked suppressibility (up to 50 per cent) of the parathyroid hormone-vitamin D axis. We conclude that parathyroid function may be suppressed by dietary calcium in some patients with primary hyperparathyroidism.
Adult↗
Calcium metabolism without anguish. Understanding the body's homeostatic 'black box'.
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Bone and Bones↗
Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia.
Three patients with hypercalcemia associated with malignant lymphoma and elevations in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] are described. In addition to the elevation of circulating 1,25-(OH)2D, these three patients were characterized by suppressed immunoreactive PTH levels and urinary cAMP excretion, elevated fasting urinary excretion of calcium, and absence of adenylate cyclase-stimulating activity in the tumor extracts. Bone marrow biopsy and skeletal radionuclide scans were negative for lymphoma in two patients. Surgical excision of a solitary splenic lymphoma in one patient and medical therapy in another patient resulted in rapid normalization of the serum calcium and plasma 1,25-(OH)2D levels. These findings confirm an earlier observation that elevated plasma levels of 1,25-(OH)2D may occur in certain patients with lymphoma and suggest that this vitamin D metabolite may act as a humoral or systemic mediator of hypercalcemia. Proof that this is the case and identification of the source of 1,25-(OH)2D production will require further study.
Aged↗
Hypercalcemia in pheochromocytoma. Evidence for a novel mechanism.
A child with a pheochromocytoma had hypercalcemia but no evidence for excessive parathyroid hormone secretion from the parathyroid glands or the pheochromocytoma. Therapy with the catecholamine synthesis inhibitor metyrosine (alpha-methyltyrosine) reversed the catecholamine excess but had no effect on the hypercalcemia. Adrenalectomy promptly reversed the hypercalcemia. Extracts of the tumor contained a substance(s) that produced both potent in-vitro bone resorption and striking adenylate-cyclase-stimulating activity in renal cortical membranes. This stimulating activity was due to activation of the parathyroid hormone receptor/adenylate cyclase complex but was not due to parathyroid hormone. Our findings document hypercalcemia in association with pheochromocytoma and show that hypercalcemia occurred in the absence of previously proposed mechanisms. We also provide preliminary characterization of the presumed responsible substance(s) and suggest that this substance(s) may be related to that associated with the humoral hypercalcemia of malignancy.
Adenylyl Cyclases↗
Nucleotide sequences of bovine alpha S1- and kappa-casein cDNAs.
The nucleotide sequences corresponding to bovine alpha S1- and kappa-casein mRNAs are presented. An unusual alpha S1-casein cDNA has been characterised whose 5' end commences upstream from its putative TATA box. The alpha S1-casein mRNA is compared to rat alpha-casein mRNA and two components of divergence are identified. Firstly, the two sequences have diverged at a high point mutation rate and the rate of amino acid replacement by this mechanism is at least as great as the rate of divergence of any other part of the mRNAs. Secondly, the protein coding sequence has been subjected to several insertion/deletion events, one of which may be an example of exon shuffling . The kappa-casein mRNA sequence verifies the proposition that it has arisen from a different ancestral gene to the other caseins.
Animals↗
Hypercalcemia in small cell carcinoma of the pancreas.
Although small cell carcinoma of the lung has a high incidence of skeletal metastasis and is frequently associated with paraneoplastic syndromes, it is only rarely associated with hypercalcemia. Similarly, the more unusual small cell carcinoma of the pancreas has not been associated with hypercalcemia. The authors describe the first such patient with small cell carcinoma of the pancreas and hypercalcemia. Comprehensive metabolic measurements (fasting calcium excretion, renal phosphorus threshold, 1,25 dihydroxyvitamin D, 25 hydroxyvitamin D levels, nephrogenous cyclic AMP and immunoreactive PTH levels) suggest that although bone metastases were present, the hypercalcemia may have been caused in part by humoral mechanisms.
Aged↗
Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy.
Humoral hypercalcemia of malignancy is a common but incompletely understood syndrome in humans. In an effort to define an animal model of this syndrome, we studied the transplantable Rice-500 Leydig cell tumor in male Fisher rats. Animals were studied 4-9, 10-12, and 13-14 days after tumor transplantation. By days 13-14, tumor-bearing animals were significantly hypercalcemic, hypercalciuric, and hyperphosphaturic compared to control animals. Fractional phosphorus excretion was elevated 4-fold in the tumor-bearing group despite hypophosphatemia. Mean nephrogenous cAMP in the tumor-bearing animals was 5 times the value in controls at days 13-14, while simultaneous immunoreactive PTH levels were undetectable. Plasma 1,25-dihydroxyvitamin D was significantly elevated in the tumor-bearing animals on day 14. Quantitative bone histomorphometry showed uncoupling of bone cell function in the tumor group, with marked suppression of bone formation, while indices of bone resorption were more than 2-fold elevated. Conditioned medium from tumor cells grown in culture consistently showed activity in a fetal bone-resorbing assay. This activity was heat stable and had an estimated mol wt of 30,000-50,000 daltons. Incubation of cells with indomethacin had no effect on bone-resorbing activity. These data indicate that the mediator in the model shares some of the actions of PTH, but is clearly distinct from native PTH. The findings exactly parallel those in human humoral hypercalcemia of malignancy, with the elevated 1,25-dihydroxyvitamin D values being the sole exception. The demonstration of in vitro bone-resorbing activity will aid in further characterization of the mediator.
Animals↗
Squamous carcinoma model of humoral hypercalcemia of malignancy.
Squamous carcinomas are the most common cause of humoral hypercalcemia of malignancy (HHM) in humans. To develop an animal model of this syndrome, CD-1 female mice were painted with dimethylbenzanthracene, which produced cutaneous squamous carcinomas in the majority of those painted. Greater than 90% of tumor-bearing mice developed a syndrome of hypercalcemia, hypophosphatemia, hypercalciuria, elevated plasma 1,25-dihydroxyvitamin D, normal immunoreactive PTH, elevated urinary cAMP, and accelerated bone resorption compared to control mice. Tumor excision reversed the hypercalcemia and hypophosphatemia, and autopsies revealed no evidence of skeletal or other metastases. Dietary calcium restriction did not affect the hypercalcemia in tumor-bearing mice. Extracts of tumor tissue contained potent bioactivity paralleling that of bovine (b) PTH in a PTH-sensitive canine renal cortical adenylate cyclase assay. The activity was trypsin sensitive and partially inhibitable by Nle, Tyr bPTH amide. The activity coeluted with chymotrypsinogen (mol wt, 25,700) on Sephacryl S-200 chromatography, well ahead of bPTH. This is the first description of an animal squamous carcinoma that produces HHM. With the exception of elevated plasma 1,25-dihydroxyvitamin D levels, the syndrome precisely mimics that seen in human HHM. The presence of a biologically active protein larger than PTH in tumor extracts, similar to that extracted from human tumors, suggests a common mode of pathogenesis. This model should be useful in further studying the pathophysiology of HHM.
Animals↗
Hypocalcemia-induced pustular psoriasis of von Zumbusch. New experience with an old syndrome.
Hypocalcemia occurs in patients with psoriasis vulgaris, pustular psoriasis of von Zumbusch, and impetigo herpetiformis. In most cases hypocalcemia is caused by accompanying hypoalbuminemia, yet reductions in ionized serum calcium concentrations due to hypoparathyroidism or malabsorption have been reported. We report the case of a patient with surgical hypoparathyroidism in whom hypocalcemia precipitated typical pustular psoriasis of von Zumbusch. The psoriasis rapidly cleared on two occasions when the patient's serum calcium was corrected by therapy with oral calcium and vitamin D or its analogues, and reappeared when treatment was discontinued. The patient's psoriasis cleared on a third occasion when her serum calcium level returned to normal with a calcium infusion. Hypocalcemia can precipitate pustular psoriasis of von Zumbusch in susceptible persons. These psoriatic flares are due not to abnormal circulating levels of parathyroid hormone or vitamin D metabolites but to hypocalcemia.
Calcitriol↗
Therapy of malignancy-associated hypercalcemia: 1983.
Hypercalcemia is common among patients with cancer and may be due to secretion by tumors of a humoral, calcemic, bone-resorbing factor or, alternatively, to skeletal metastases. In each case, hypercalcemia ultimately results from osteoclastic bone resorption. Therapy should be aimed at (1) reducing or eliminating tumor burden, (2) increasing renal calcium clearance, and (3) inhibiting osteoclastic bone resorption. Hydration with saline infusion and augmentation of calciuresis with furosemide should be the initial modes of therapy in most patients. Oral phosphorus should be used in hypophosphatemic patients. Glucocorticoids, calcitonin, and prostaglandin synthetase inhibitors may be effective in reducing bone resorption in selected patients. Mithramycin reliably induces a fall in serum calcium but long-term use is usually complicated by toxicity. A new class of drugs that inhibit osteoclastic bone resorption, the diphosphonates, is being employed in clinical trials in patients with malignancy-associated hypercalcemia. Results have been particularly promising with dichloromethylene diphosphonate.
Administration, Oral↗
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.
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 glucose-6-phosphate dehydrogenase complex. In the present study, 8 M urea extracts of tumors from patients with HHM have been shown to contain both in vitro adenylate cyclase-stimulating activity and glucose-6-phosphate 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 fragment analogue [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 Mr 70,000). These studies demonstrate that 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 glucose-6-phosphate 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.
Adenylyl Cyclases↗
Hypercalcaemia complicating acute myelogenous leukaemia: a syndrome of multiple aetiologies.
Hypercalcaemia complicating acute myelogenous leukaemia is a rare but well-recognized phenomenon. In most cases the pathogenetic mechanism causing the hypercalcaemia remains poorly understood. We recently studied in detail two patients with acute myelogenous leukaemia who developed hypercalcaemia during the course of their illness. The results of these studies conclusively excluded primary hyperparathyroidism or ectopic parathyroid hormone production as causes of the patients' hypercalcaemia. In vitro studies carried out on short-term suspension cultures of one patient's peripheral blood blast cells demonstrated production of a factor with potent bone resorbing activity, distinct from parathyroid hormone (iPTH) and prostaglandin E2 (PGE2). Further characterization of the bone resorbing factor suggested that it bore some similarity to osteoclast activating factor (OAF). Hypercalcaemia in the other case appeared to be due to a combination of skeletal invasion by malignant cells, and to ectopic secretion of an unidentified humoral factor with bone resorbing activity. These two cases demonstrate that the hypercalcaemia complicating acute myelogenous leukaemia may be due to a variety of mechanisms distinct from parathyroid hormone production.
Aged↗
Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells.
The culture media of three cell lines, a human prostate carcinoma (PC3), a rat Leydig cell tumor (Rice-500), and a rat carcinosarcoma (WRC-256), that were derived from tumors associated with humoral hypercalcemia of malignancy (HHM), were examined for stimulation of adenylate cyclase in ROS 17/2.8 osteoblastic cells and for bone resorptive activity in culture. Cells from a nonhypercalcemic variant of the WRC256 tumor served as control. Extracts from three solid human tumors, a lung adenocarcinoma from a patient with HHM and two adenocarcinoma from normocalcemic patients (lung and colon), were also examined for adenylate cyclase stimulation. We found excellent correlation between stimulation of cyclic AMP accumulation in ROS 17/2.8 cells and bone resorbing activity in culture, or production of HHM in vivo. Stimulation of adenylate cyclase by HHM factors was inhibited by the parathyroid hormone competitive inhibitor, [8norleucyl, 18norleucyl, 34tyrosinyl] bovine parathyroid hormone (3-34) amide.
Adenylyl Cyclases↗
Hypercalcemia associated with gynecologic malignancies: biochemical characterization.
Fasting calcium excretion, renal phosphorus threshold, plasma 1,25 dihydroxyvitamin D, immunoreactive PTH, nephrogenous cyclic AMP excretion, and tumor burden were assessed in nine patients with gynecologic neoplasms and hypercalcemia. Gynecologic neoplasms were responsible for hypercalcemia in seven of 34 (20.5%) consecutive patients with malignancy-associated hypercalcemia. The tumor burden in each patient was large. Three of four endometrial carcinomas contained squamous elements. All patients displayed biochemical evidence of nonparathyroid humorally mediated hypercalcemia (bone resorption). Treatment of hypercalcemia did not appear to diminish production of the humoral calcemic factor but eradication of tumor eliminated biochemical evidence of the humoral syndrome. It can be concluded that (1) gynecologic neoplasms are a frequent cause of malignancy-associated hypercalcemia, (2) humoral mechanisms appeared to be responsible for the hypercalcemia in 100% of the patients in this series, (3) squamous features occur with unexpected frequency in hypercalcemic endometrial carcinoma, (4) the presence of hypercalcemia connotes a large tumor burden, and (5) treatment directed at the neoplasm (but not treatment directed at hypercalcemia) may eliminate evidence of ectopic calcemic hormone production.
Adolescent↗