Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.
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PMID:The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications. 1577 88

Newer-generation intravenous bisphosphonates have resulted in the reduction of skeletal-related complications, i.e. skeletal-related events (SREs) such as pain, hypercalcemia, pathologic fractures and spinal cord and nerve compression, as well as improvements in the quality of life in patients with metastatic bone disease who are likely to have a prolonged clinical course. Highly potent, nitrogen-containing bisphosphonates such as zoledronic acid reduce SREs in patients with bone metastases from other solid tumors (including lung cancer). Part one of our review discussed the mechanisms of action by bisphosphonates as well as potential roles for bone markers and imaging in lung cancer. In this article, part two of our review, we examine the economic and clinical impact of bisphosphonates in lung cancer, with a focus on the potential role of newer-generation bisphosphonates in the management of advanced, metastatic bone disease of lung cancer.
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PMID:The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 2: Clinical studies and economic analyses. 1577 89

Nude rats bearing the LC-6-JCK human lung cancer xenograft displayed cancer-associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL-6, leukemia-inducing factor, IL-8, IL-5 and IL-11, were secreted to the bloodstream. Proinflammatory cytokines induce acute-phase reactions, as evidenced by a decrease of serum albumin and an increase in alpha1-acid glycoprotein. Tumor resection abolished the production of proinflammatory cytokines and improved acute-phase reactions, whereas anti-PTHrP antibody affected neither proinflammatory cytokine production nor acute-phase reactions. Nevertheless, tumor resection and administration of anti-PTHrP antibody similarly and markedly attenuated not only hypercalcemia but also loss of fat, muscle and body weight. Body weight gain by anti-PTHrP antibody was associated with increased food consumption; increased body weight from anti-PTHrP antibody was observed when animals were freely fed but not when they were given the same feeding as those that received only vehicle. Furthermore, nude rats bearing LC-6-JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti-PTHrP antibody restored them. Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level. These results indicate that PTHrP represses physical activity and energy metabolism independently of hypercalcemia and proinflammatory cytokine actions and that deregulation of such physiologic activities and functions by PTHrP is at least in part involved in PTHrP-induced wasting syndrome.
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PMID:Parathyroid hormone-related protein (PTHrP) as a causative factor of cancer-associated wasting: possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts. 1580 Sep 41

Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-beta that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.
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PMID:Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. 1617 92

We have previously demonstrated that parathyroid hormone-related protein (PTHrP) is a cachexia inducer, but it is still not known what PTHrP effects on target tissues induce the cachexia. Therefore, we examined the effects of anti-PTHrP antibody and osteoprotegerin (OPG) on PTHrP-producing tumor-induced cachexia. Nude mice bearing PTHrP-producing human lung cancer cells (HARA-B) exhibited cachexia with hypercalcemia 3-4 weeks after inoculation, accompanied by losses in body, adipose tissue, and muscle weight. OPG ameliorated hypercalcemia, as did neutralization of PTHrP with antibody; and it increased both body and adipose tissue weights. These increases in body and adipose tissue weight, however, were significantly less than those in mice treated with anti-PTHrP antibody. Simultaneous administration of OPG and anti-PTHrP antibody caused significant increases in body, adipose tissue, and muscle weight, along with an immediate decrease in blood ionized calcium levels. The increase in body weight was similar to that observed in mice treated with anti-PTHrP antibody alone, and the decrease in the blood ionized calcium levels was significantly greater than that in mice treated with OPG or anti-PTHrP antibody alone. These results suggest that an effect of PTHrP on target tissues other than hypercalcemia is involved in the development of cachexia. Expression of cachexia-inducing proinflammatory cytokines (interleukin-6 and leukemia inhibitory factor) is stimulated by PTHrP. This might be a mechanism by which PTHrP produces tumor-induced cachexia. It is also suggested that OPG and anti-PTHrP antibody synergistically act to ameliorate hypercalcemia, although the mechanism responsible for this is unclear.
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PMID:Effects of anti-parathyroid hormone-related protein monoclonal antibody and osteoprotegerin on PTHrP-producing tumor-induced cachexia in nude mice. 1636 93

While 1,25 dihydroxycholecalciferol (calcitriol) is best recognized for its effects on bone and mineral metabolism, epidemiological data indicate that low vitamin D levels may play a role in the genesis and progression of breast, lung, colorectal and prostate cancer, as well as malignant lymphoma and melanoma. Calcitriol has strong antiproliferative effects in prostate, breast, colorectal, head/neck and lung cancer, as well as lymphoma, leukemia and myeloma model systems. Antiproliferative effects are seen in vitro and in vivo. The mechanisms of these effects are associated with G0/G1 arrest, induction of apoptosis, differentiation and modulation of growth factor-mediated signaling in tumor cells. In addition to the direct effects on tumor cells, recent data strongly support the hypothesis that the stromal effects of vitamin D analogs (e.g., direct effects on tumor vasculature) are also important in the antiproliferative effects. Antitumor effects are seen in a wide variety of tumor types and there are few data to suggest that vitamin D-based approaches are more effective in any one tumor type. Glucocorticoids potentiate the antitumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In addition, calcitriol potentiates the antitumor effects of many cytotoxic agents. Preclinical data indicate that maximal antitumor effects are seen with pharmacological doses of calcitriol and that such exposure can be safely achieved in animals using a high dose, intermittent schedule of administration. AUC and C(max) calcitriol concentrations of 32 ng.h/ml and 9.2 ng/ml are associated with striking antitumor effects in a murine squamous cell carcinoma model and there is increasing evidence from clinical trials that such exposures can be safely attained in patients. Another approach to maximizing intra-tumoral exposure to vitamin D analogs is to inhibit their catabolism. The data clearly indicate that agents which inhibit the major vitamin D catabolizing enzyme, CYP24 (24 hydroxylase), potentiate calcitriol killing of prostate tumor cells in vitro and in vivo. Phase I and II trials of calcitriol, either alone or in combination with carboplatin, taxanes or dexamethasone, as well as the non-specific CYP24 inhibitor, ketoconazole, have been initiated in patients with androgen-dependent and -independent prostate cancer and other advanced cancers. The data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered, but the optimal dose and schedule remain to be delineated. Clinical responses have been seen with the combination of high-dose calcitriol + dexamethasone in androgen-independent prostate cancer (AIPC) and, in a large randomized trial in men with AIPC, potentiation of the antitumor effects of docetaxel were seen.
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PMID:Vitamin D compounds: clinical development as cancer therapy and prevention agents. 1688 63

Hypercalcemia is commonly associated with cancer, occurring in around 10-20% of cancer patients. Hypercalcemia is usually related to solid and non-solid malignancies specifically breast cancer, lung cancer and multiple myeloma. Hypercalcemia has been reported to occur in association with astrocytomas, and uncommonly in gliomas. We report a case of a previously healthy man presenting with glioblastoma multiforme . He was found to have persistently elevated serum calcium and calcitriol with normal parathyroid function. This is the first reported case of hypercalcemia associated with glioblastoma multiforme.
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PMID:Hypercalcemia in glioblastoma multiforme. 1689 4

Bone metastases are a common occurrence in patients with breast cancer, lung cancer and prostate cancer. Bone metastases cause considerable morbidity including pain, impaired mobility, pathologic fracture, spinal cord or nerve root compression, bone marrow infiltration and hypercalcemia of malignancy. These complications result from the derangement of normal bone metabolism that arise from interactions between factors originating in tumor cells and others originating in the microenvironment of the bone. Fortunately, there is an increasing array of treatment options for the skeletal complications associated with bone metastases arising from breast, lung, and prostate cancer. The goals of treatment for such skeletal complications are to relieve pain and reduce the risk of fracture. Traditional therapies to treat skeletal malignancies include radiation, surgery, and chemotherapy. In recent years, bisphosphonates have become the treatment of choice because of their ability to reduce bone resorption, leading to decreases in hypercalcemia, new osteolytic lesions, and fractures, thereby ameliorating pain and improving quality of life.
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PMID:Managing bone complications of solid tumors. 1696 20

The skeleton is the most common organ to be affected by metastatic cancer and the site of disease that produces the greatest morbidity. Skeletal morbidity includes pain that requires radiotherapy, hypercalcemia, pathologic fracture, and spinal cord or nerve root compression. From randomized trials in advanced cancer, it can be seen that one of these major skeletal events occurs on average every 3 to 6 months. Additionally, metastatic disease may remain confined to the skeleton with the decline in quality of life and eventual death almost entirely due to skeletal complications and their treatment. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years compared with lung cancer, where the average survival is only a matter of months. Additionally, the presence of extraosseous disease and the extent and tempo of the bone disease are powerful predictors of outcome. The latter is best estimated by measurement of bone-specific markers, and recent studies have shown a strong correlation between the rate of bone resorption and clinical outcome, both in terms of skeletal morbidity and progression of the underlying disease or death. Our improved understanding of prognostic and predictive factors may enable delivery of a more personalized treatment for the individual patient and a more cost-effective use of health care resources.
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PMID:Clinical features of metastatic bone disease and risk of skeletal morbidity. 1706 8

Metastatic spread to bones frequently occurs in several types of cancer diseases, in particular breast, prostate, and lung cancer. Infiltration of bone by tumour cells is a source of several complications including severe bone pain, spinal cord compression, hypercalcemia, pathologic fractures, all reducing quality of life and worsening prognosis. Therefore, early recognition of bone metastases is among the highest priorities in the clinical management of cancer disease. Currently, detection and staging relies on radiological imaging techniques (scintigraphy, radiography, computer tomography, etc.). Due to their limited sensitivity and/or inconveniences, irradiation, and considerable costs related to serial use, they are not suited for close monitoring of cancer patients to capture skeletal spread in an early stage or to follow-up on therapeutical responses. Interaction of tumour cells with surrounding bone cells leads to enhanced bone resorption and/or bone formation. These cellular processes result in the release of numerous epitopes that, if detected by immunoassays, can reflect the changes of the rate of bone turnover and the occurrence of metastatic spread to bone. Numerous studies reported elevated levels of bone turnover markers in patients with bone metastases proportionally to the extent of skeletal involvement. Furthermore, preliminary data suggest that biomarkers can predict skeletal-related events (SREs), disease progression, and even cancer-related death. The present review intends to summarize the list of emerged biomarkers, major studies assessing their relative utility for detection of bone metastases in different types of cancer disease, and discuss their potentials for becoming part of screening protocols for improving our success rate in the early detection of metastatic bone disease.
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PMID:Biochemical approach to the detection and monitoring of metastatic bone disease: What do we know and what questions need answers? 1716 May 57


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