In 50 consecutive patients with cancer-associated hypercalcemia, we measured nephrogenous cyclic AMP, tubular phosphorus threshold, fasting calcium excretion, plasma 1,25-dihydroxyvitamin D, and immunoreactive parathyroid hormone as determined by four region-specific antiserums. Nephrogenous cyclic AMP excretion was elevated in 41 patients and suppressed in nine (means, 5.85 vs. 0.51 nmol per 100 ml of glomerular filtrate). There was no overlap between these groups. When compared with 15 patients with primary hyperparathyroidism, the group with increased cyclic AMP excretion had similar reductions in tubular phosphorus threshold; higher fasting calcium excretion (means, 0.66 vs. 0.25 mg per 100 ml of glomerular filtrate, P < 0.01); marked reductions in 1,25-dihydroxyvitamin D (means, 20 vs. 83 pg per milliliter, P < 0.001); and lower levels of immunoreactive parathyroid hormone in all four assays. The data suggest that elevated excretion of nephrogenous cyclic AMP may be a useful marker of humorally mediated cancer-associated hypercalcemia, that this type of hypercalcemia is common, that the humoral factor responsible for this syndrome is not native 1-84 parathyroid hormone, and that the various subtypes of cancer-associated hypercalcemia are biochemically distinguishable from primary hyperparathyroidism.

Chromogranin A, the protein that is co-stored and co-released with catecholamines from the adrenal medulla, has recently been identified in a variety of human endocrine tissues, both normal and neoplastic. We investigated the secretion of chromogranin A by peptide hormone-producing human tumors in studies of patients with the following neoplastic disorders: pheochromocytoma, parathyroid adenoma, primary parathyroid hyperplasia, medullary thyroid carcinoma, thyroidal C-cell hyperplasia, carcinoid tumor, oat-cell lung carcinoma, pancreatic islet-cell tumor, and aortic-body tumor. All these patient groups had elevated concentrations of plasma chromogranin A. We distinguished different forms of immunoreactive plasma chromogranin A by size with the use of gel filtration. Plasma chromogranin A levels were not elevated in patients with diverse "control" conditions--both benign and malignant and both endocrine and nonendocrine--in which peptide hormones are not produced. The sensitivity and specificity of plasma chromogranin A elevations in the diagnosis of peptide-producing endocrine neoplasms were 81 and 100 percent, respectively. The elevation of plasma chromogranin A in our subjects suggests that their neoplasms co-release chromogranin A along with the usual resident hormone of the tumor, that these neoplasms could be characterized as "chromograninomas," and that measurement of plasma chromogranin A may be a useful diagnostic procedure in subjects with endocrine tumors, especially multiple endocrine neoplasia.

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We evaluated the pattern of osteoporosis after spinal cord injury, determined the time-frame of the changes, and elucidated the relationship among parathyroid hormone levels, biochemical markers of bone formation, and the pattern of bone mass loss. We included 176 subjects with spinal cord injury and 62 subjects without spinal cord injury as controls in the study. Bone mineral density of the spine and the proximal femur was measured. The participants' age, level of injury, and length of time since injury were compared with the nonspinal cord-injured controls and with each other. Serum levels of calcium, calcitonin, biochemical markers of bone formation, and parathyroid hormone were determined. Our results revealed that bone mineral density of the proximal femur declined and reached fracture threshold at one to five years after injury. The decline was detected at 12 months after injury in all age groups. Spinal bone mineral density neither declined significantly nor reached fracture threshold. Parathyroid hormone levels declined before the end of the first year postinjury and increased at one to nine years postinjury in the 20- to 39-year age group. The increase correlated with the initial decline of bone mineral density of the proximal femur. Our studies in spinal cord-injured subjects revealed a pattern of osteoporosis similar to age and parathyroid dysfunction-related osteoporosis. No other correlation was detected between indexes of bone metabolism and bone mineral density measurements.

Determination of the amino acid sequence of bovine parathyroid hormone has led to the synthesis of a tetratriacontapeptide corresponding to the aminoterminal 1-34 residues of the native molecule. The specific biological effects of this synthetic peptide on bone and kidney are qualitatively identical to those of the native hormone in classical bioassays in vivo and in several systems in vitro. Potency of the synthetic peptide equals or exceeds that of a biologically active fragment of comparable size isolated from the native hormone; the synthetic and natural peptides show complete immunological crossreactivity. Thus, essential requirements for the physiological actions of the peptide on both skeletal and renal tissue are contained within the 34 amino-terminal amino acids. The potency of the synthetic peptide, relative to that of the native (84-amino acid) polypeptide, is greater in vitro than in vivo; this suggests that the carboxyl terminal two-thirds of the native hormone may protect the circulating polypeptide from rapid metabolic degradation.

Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.

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A B S T R A C T The cause for the intestinal hyperabsorption of calcium (Ca) in various forms of hypercalciurias was explored by a careful measurement of plasma la,25-dihydroxycholecalciferol [la,25-(OH)2D] and by an assessment of intestinal Ca absorption and of parathyroid function. In 18 cases of primary hyperparathyroidism (PHPT), the mean plasma concentration of la,25-(OH)2D was significantly increased (4.9+2.2 SD ng/dl vs. 3.4+0.9 ngldl for the control group), and was significantly correlated with fractional Ca absorption (a) (r = 0.80, P < 0.001). Plasma la,25-(OH)2D was also correlated with urinary Ca (P < 0.05), but not with serum Ca or phosphorus (P), P clearance, urinary cyclic AMP, or serum immunoreactive parathyroid hormone. In 21 cases of absorptive hypercalciuria (AH), plasma la,25-(OH)2D was elevated in onethird of cases, and the mean value of 4.5±+1.1 ng/dl was significantly higher than that of the control group (P < 0.01). Since relative hypoparathyroidism may be present, the normal absolute value of plasma la,25-(OH)2D, found in two-thirds of cases of AH, may be considered to be inappropriately high. Moreover, in the majority of cases of AH, the data points relating plasma la,25-(OH)2D and a fell within 95% confidence limits of values found in non-AH groups (including PHPT). The results suggest that the intestinal hyperabsorption of Ca in PHPT and AH may be vitamin D dependent. However, the disturbance in vitamin D metabolism may not be the sole cause for the high Ca absorption in AH, since in some patients with AH, the intestinal Ca absorption appears to be