Humoral hypercalcemia of malignancy

May be superior to bisphosphonates for humoral hypercalcemia of malignancy (PTHrp)... 

Sanders, JL, Chattopadhyay, N, Kifor, O, Yamaguchi, T and Brown, EM, 2000, Extracellular calciumsensing receptor (CaR) expression and its potential role in parathyroid hormone-related peptide (PTHrP) secretion in the H-500 rat Ley dig cell model of humoral hypercalcemia of malignancy, Biochem Biophys Res Commun 269 127 132... 

Hypercalcemia occurs in 10% to 20% of individuals with cancer. Tumors most commonly cause hypercalcemia by producing PTHrP, which is secreted into the circulation and stimulates bone resorptions and/or by invasion of the bone by metastatic tumor, which produces local factors that stimulate bone resorption. PTHrP binds to the PTH receptor and is the principal mediator of humoral hypercalcemia of malignancy (HHM). Cytokines such as lymphotoxin, interleukin-1, tumor necrosis factor, and PTHrP appear to be important mediators of hypercalcemia in multiple myeloma and other hematological malignancies. Some lymphomas associated with acquired immunodeficiency syndrome or HTLV [ infections cause hypercalcemia by producing 1,25(0H)2D. It is estimated that 5% of patients with hypercalcemic cancer have coexisting primary hyperparathyroidism. 

Parathyroid Hormone-Related Protein PTHrP was discovered in 1987 by investigators studying the mechanism by which certain cancers produce humoral hypercalcemia of malignancy (HHM). ... 

Blind E. Humoral hypercalcemia of malignancy role of parathyi oid hormone-related protein. Recent Results Cancer Res 1994 137 20-43. 

Tsuchihashi T, Yamaguchi K, Miyake Y, Otsubo K, Nagasaki K, Honda S, et al. Parathyroid hormone-related protein in tumor tissues obtained from patients with humoral hypercalcemia of malignancy. JNCI 1990 82 40-4. 

Complexity is seen in different models. Parathyroid hormone-related protein and Ca have conflicting actions in a nude rat model of humoral hypercalcemia of malignancy. In differentiated Caco cells, there is upregulation of P450 27B1 expression by la,25-dihydroxyvita-min Dj and epidermal growth factor, but down-regulation in less differentiated Caco cell lines . 

Michigami, X, H. Yamato, H. Suzuki, Y. Nagai-Itagaki, K. Sato, and K. Ozono (2001). Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin Dj-la-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy. J. Endocrinol. 171, 249-257. 

The humoral hypercalcemia of malignancy hypothesis states that an osteolytic non-PTH substance is secreted by certain tumors and, in an endocrine manner, is transported from tumor to bone through the bloodstream. The evidence for this hypothesis is that 1) bone destruction occurs in patients without bone metastases, 2) serum PTH levels in these patients were usually normal, 3) PTH mRNA was absent in tumors (27), and 4) tumor extracts from hypercalcemic patients enhanced bone cell adenylate cyclase activity and phosphate transport in kidney epithelial cells (28-30). 

Morony S et al The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia and malignancy. Endocrinology 2005 146 3235. [PMID 15845617]... 

Hypercalcemia of malignancy is a common occurrence in solid tumors of the lung and breast as well as multiple myeloma and adult T-cell lymphoma/leukemia (26). The hypercalcemia associated with breast cancer is usually seen in late stages of the disease in patients with extensive bone metastases. In squamous cell carcinoma of the lung or kidney, however, hypercalcemia is not correlated with disease stage and is not necessarily associated with bone metastases. The hypercalcemia results from increased bone resorption, decreased bone formation and increased renal tubular calcium reabsorption. These findings suggest that some tumors may secrete humoral factors with PTH-like actions. 

In hospitalized patients, hypercalcemia of malignancy is the major cause of hypercalcemia (26,, , 54). In two separate studies, 9X of all cancer patients had hypercalcemia of malignancy (. 56). Hypercalcemia of malignancy is most common in solid tumors such as carcinomas of the lung, breast, kidney, pancreas and ovary, but also occurs with multiple myeloma and adult T-cell lymphoma/ leukemia. It has been estimated that there is approximately an equal distribution between humoral factors and metastatic bone tumors for causing hypercalcemia of malignancy (26,57,58). 

Hypercalcemia in hospitalized patients is caused most often by a malignancy, either with or without bone metastases. The degree of hypercalcemia here often exceeds considerably that seen with primary hyperparathyroidism (often >13 mg/dL) and lethargy, weakness, and volume depletion may be profound. PTH-related peptide, which is produced by squamous cell and other tumors, can interact with the PTH receptor to cause humoral hypercalcemia. An assay for PTH-related peptide is often diagnostic in these patients, while the PTH level is suppressed due to feedback by the elevated serum CcP. ... 

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