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)

Gallium nitrate, the nitrate salt of the "near-metal" element gallium, is highly effective in the treatment of cancer-related hypercalcemia. Unlike bisphosphonates, gallium nitrate is effective in both parathyroid hormone-related protein-mediated and non-parathyroid hormone-related protein-mediated hypercalcemia. Gallium nitrate's effects on bone are clearly different from those of bisphosphonates. Gallium nitrate enhances calcium and phosphate content of bone and has direct, noncytotoxic effects on osteoclasts at markedly lower doses than those used for the treatment of cancer-related hypercalcemia. The drug may have clinical application in a variety of disorders associated with accelerated bone loss, including multiple myeloma. Gallium nitrate was originally evaluated as an antitumor agent. Its antitumor activity occurs at somewhat higher doses than those used in the treatment of cancer-related hypercalcemia. Gallium nitrate has substantial single-agent activity in the treatment of advanced lymphoma, particularly diffuse large cell lymphoma, small lymphocytic lymphoma, and follicular lymphoma. Because of its profile, including a different mechanism of action and minimal myelosuppression, the drug merits further evaluation in the treatment of advanced lymphoma. Gallium nitrate also has activity in advanced bladder cancer and may be useful in patients with metastatic or unresectable disease failing first-line chemotherapy regimens. Gallium nitrate exhibits a range of dose-dependent pharmacologic actions that provide a basis for its therapeutic potential in a variety of diseases and warrants further investigational evaluation as an antiresorptive and antitumor agent.
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PMID:Gallium nitrate revisited. 1277 53

Gallium nitrate has been shown to be an effective treatment for patients with cancer-related hypercalcemia. Clinical studies have also suggested the drug may have considerably broader use in other diseases associated with accelerated bone loss including multiple myeloma, bone metastases, Paget's disease, and osteoporosis. The actions of gallium nitrate on bone are quite distinct from those of bisphosphonates. Preclinical studies show that gallium preferentially accumulates in trace amounts in metabolically active regions of bone. When present, gallium favorably alters the mineral properties to enhance hydroxyapatite crystallization and reduce mineral solubility. The drug also acts on the cellular components of bone to reduce bone resorption by decreasing acid secretion by osteoclasts. This effect appears to be mediated by inhibition of the ATPase-dependent proton pump of the osteoclast's ruffled membrane. Gallium does not inhibit the development or recruitment of osteoclasts to bone tissue, unlike many bisphosphonates that may induce osteoclast apoptosis. Together, these pharmacologic actions may yield a skeletal system with increased calcium and phosphate content and improved biomechanical strength. Gallium nitrate has potent antiresorptive effects on bone that can be achieved at considerably lower doses than are currently used for cancer-related hypercalcemia. Parenteral and oral formulations of gallium appear to have high activity in bone resorptive disorders, and thus development should be vigorously pursued in these diseases.
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PMID:The effects of gallium nitrate on bone resorption. 1277 54

Hypercalcemia is a common, life-threatening metabolic disorder that can be associated with cancer. Its pathophysiology includes enhanced osteoclastic bone resorption and decreased renal excretion of extracellular calcium. Symptoms of hypercalcemia include nausea, vomiting, bone pain, polyuria, renal insufficiency, bradycardia, and arrhythmia. The goals of medical therapy are to inhibit bone resorption and promote renal calcium excretion. Hydration is the first step in management. Treatments for hypercalcemia include phosphates, calcitonin, bisphosphonates, and gallium nitrate. Although intravenous phosphates prevent intestinal calcium absorption and inhibit mineral and bone matrix resorption, serious adverse events include renal failure, hypotension, extraskeletal calcification, and severe hypocalcemia. Calcitonin has a rapid onset of action and can lower serum calcium concentrations within hours, but its usefulness is limited by its short duration of effect and the development of tachyphylaxis. Bisphosphonates are effective inhibitors of bone resorption but appear to have decreased response rates in hypercalcemic patients with high levels of parathyroid-related protein. Gallium nitrate, an antitumor agent noncytotoxic to osteoclasts and bone cells, appears to be more effective than pamidronate, etidronate, and calcitonin in the treatment of cancer-related hypercalcemia. Importantly, unlike bisphosphonates, gallium nitrate is effective in both parathyroid-related protein-mediated and non-parathyroid-related protein-mediated hypercalcemia.
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PMID:Treatment of cancer-related hypercalcemia: the role of gallium nitrate. 1277 55

Multiple myeloma is characterized by bone destruction mediated by osteoclastic bone resorption. Skeletal complications of myeloma, including bone pain, fractures, spinal cord compression and hypercalcemia, result in significant morbidity. Gallium nitrate was shown in a small, randomized trial to attenuate the rate of bone loss in patients with myeloma treated with chemotherapy. In a retrospective analysis, we found that patients with advanced multiple myeloma treated with chemotherapy plus gallium nitrate had markedly prolonged median survival compared with similar patients treated with chemotherapy alone (87+ months v 48 months, respectively). These data suggest that gallium nitrate may have a positive, indirect benefit on survival in myeloma by decreasing the rate of bone resorption. Further evaluation of gallium nitrate to attenuate progression of disease in patients with multiple myeloma is warranted.
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PMID:Gallium nitrate in multiple myeloma: prolonged survival in a cohort of patients with advanced-stage disease. 1277 56

Gallium nitrate is effective and well tolerated for the treatment of cancer-related hypercalcemia. At somewhat higher doses, gallium nitrate also has cytotoxic activity against a variety of cancers. The probable mechanism is inhibition of both ribonucleotide reductase and a protein tyrosine phosphatase. Radioactive gallium ((67)Ga) is concentrated at sites of malignant lymphoma, Hodgkin's disease, and other tumors. Gallium nitrate has substantial single-agent activity in the treatment of patients with advanced lymphoma and has also shown activity when used in combination with other agents. Significant response rates have been observed in patients with diffuse large cell lymphoma, small lymphocytic lymphoma, and follicular lymphoma. Because of its unique mechanism of action, gallium nitrate could be non-cross-resistant with many of the cytotoxic agents used as standard chemotherapy for non-Hodgkin's lymphoma. Nephrotoxicity, the most frequent adverse event associated with gallium nitrate, can generally be minimized by ensuring adequate oral hydration and avoiding concomitant use of other nephrotoxic drugs. Gallium nitrate causes little myelosuppression and is therefore well tolerated by patients with advanced disease who have received extensive prior therapy. Given its unique mechanism of action, the high level of single-agent activity in published clinical trials, the absence of significant myelosuppression, and the potential lack of cross-resistance, further clinical study of gallium nitrate both alone and in combination with other active agents is warranted.
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PMID:Gallium nitrate in the treatment of lymphoma. 1277 57

Mortality from non-Hodgkin's lymphoma (NHL) is high, thus defining the need for additional therapeutic agents for this disease. Gallium nitrate is a metal compound that is presently approved for the treatment of hypercalcaemia associated with malignancy. In clinical trials first conducted over two decades ago, this drug was found to have antineoplastic activity in NHL. However, its development as an antineoplastic agent for the treatment of NHL was never rigorously pursued. Gallium has unique mechanisms of action that include its binding to transferrin in the circulation and targeting transferrin receptors present on lymphoma cells. As it shares chemical properties with iron, gallium can disrupt critical steps in iron homeostasis that are essential for tumour cell viability and growth and can inhibit the iron-dependent activity of ribonucleotide reductase. The drug may also target other cellular processes unrelated to iron. Phase I/II studies have shown that gallium nitrate displays the most efficacy and lowest toxicity in NHL when administered as a continuous intravenous infusion, producing response rates of 43% in patients with relapsed or refractory NHL. It does not suppress the white blood cells or platelets and does not share cross-resistance with other chemotherapeutic drugs. These characteristics make it particularly attractive for the treatment of myelosuppressed patients and for incorporation into combination therapy. Multi-institutional Phase II clinical trials are in progress to evaluate gallium nitrate as a single agent or in combination. These studies will help define its role in the current treatment of NHL.
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PMID:Gallium nitrate for the treatment of non-Hodgkin's lymphoma. 1515 28

Gallium nitrate is an approved therapy for symptomatic, cancer-related hypercalcemia unresponsive to adequate hydration, the most common life-threatening metabolic disorder of cancer. Initially developed because of its antineoplastic properties, gallium nitrate demonstrated the ability to reduce serum calcium levels in early trials. Although the mechanism by which gallium nitrate corrects hypercalcemia is not fully understood, it appears to involve multiple effects (inhibition of osteoclast-mediated bone resorption, stimulation of bone formation, and alteration of the mineral composition and properties of bone); however, gallium nitrate is not cytotoxic to bone cells. In randomized trials for moderate-to-severe cancer-related hypercalcemia, gallium nitrate was well tolerated and produced a higher rate and longer duration of normocalcemia relative to calcitonin and the bisphosphonates etidronate and pamidronate. Gallium nitrate induced normocalcemia in 72% to 82% of patients; in contrast to the comparator agents, it was effective regardless of epidermoid tumor status. Epidermoid tumors are associated with high levels of parathyroid hormone-related protein (PTHrP), the principal mediator of cancer-related hypercalcemia in solid tumors. High levels of PTHrP appear to adversely impact the calcium-lowering potential of bisphosphonates. The recommended schedule of gallium nitrate for the treatment of cancer-related hypercalcemia is 200 mg/m2 per day as a 5-day continuous intravenous infusion, administered with adequate hydration and close monitoring of renal function. Gallium nitrate is an effective treatment option for moderate-to-severe cancer-related hypercalcemia, a setting in which morbidity and mortality are high.
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PMID:Treating cancer-related hypercalcemia with gallium nitrate. 1632 18

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease. Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with primary hyperparathyroidism who present with clinical symptoms due to their hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of bisphosphonates are recommended in the literature. Calcium receptor agonists (calcimimetic agents) are at the present time only available for use within clinical trials. Cancer patients usually present with symptoms of hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of bisphosphonates are the treatment mainstays in hypercalcemia of malignancy. Five bisphosphonates are currently licensed in Europe for treatment of tumor-associated hypercalcemia: etidronate, clodronate, pamidronate, ibandronate, and zoledronate. In the US, pamidronate and zoledronate are licensed for use in this indication. Bisphosphonates containing nitrogen atoms (e.g. pamidronate, ibandronate, and zoledronate) are more potent than those without (e.g. etidronate, clodronate, and tiludronate). In patients with malignant hypercalcemia, the efficacy of the individual bisphosphonate depends on dose administered and initial serum calcium concentration. At present, pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum calcium concentration. More recently, one study reported that pamidronate was inferior to zoledronate. In this study, the duration of response was also longer in the two zoledronate groups (30 and 40 days) than in the pamidronate group (17 days). The most serious adverse events of bisphosphonates concern renal function. Increases in serum creatinine levels have been more frequently reported following treatment of tumor-associated hypercalcemia with etidronate (8%) and clodronate (5%) than with the nitrogen-containing bisphosphonates pamidronate (2%) and ibandronate (1%). The frequency of increases in serum creatinine levels following treatment with zoledronate is difficult to estimate. Administration of the nitrogen-containing bisphosphonates has been associated with transient (usually mild) fever, lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare. The toxicity and low efficacy of plicamycin (mithramycin) mean that use of this agent should be restricted to patients with hypercalcemia of malignancy who fail to respond to IV bisphosphonates. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of bisphosphonates. Combination calcitonin and bisphosphonate treatment may therefore be of value when rapid reduction of serum calcium is warranted. Gallium nitrate may be a valuable treatment for hypercalcemia of malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.
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PMID:Current management strategies for hypercalcemia. 1596 62

Widespread antimicrobial resistance encourages repurposing/refining of non-antimicrobial drugs for antimicrobial indications. Gallium nitrate (GaNt), an FDA-approved medication for cancer-related hypercalcemia, recently showed good activity against several clinically significant bacteria. However, the mechanism of GaNt antibacterial action is still poorly understood. In the present work, resistant and tolerant mutants of Escherichia coli were sought via multiple rounds of killing by GaNt. Multi-round-enrichment yielded no resistant mutant; whole-genome sequencing of one representative GaNt-tolerant mutant uncovered mutations in three genes (evgS, arpA, kdpD) potentially linked to protection from GaNt-mediated killing. Subsequent genetic analysis ruled out a role for arpA and kdpD, but two gain-of-function mutations in evgS conferred tolerance. The evgS mutation-mediated GaNt tolerance depended on EvgS to EvgA phosphor-transfer; EvgA-mediated up-regulation of GadE. YdeO, and SarfA also contributed to tolerance, the latter two likely through their regulation of GadE. GaNt-mediated killing of wild-type cells correlated with increased intracellular ROS accumulation that was abolished by the evgS-tolerant mutation. Moreover, GaNt-mediated killing was mitigated by dimethyl sulfoxide, and the evgS-tolerant mutation upregulated genes encoding enzymes involved in ROS detoxification and in the glyoxylate shunt of the TCA cycle. Collectively, these findings indicate that GaNt kills bacteria through elevation of ROS; gain-of-function mutations in evgS confer tolerance by constitutively activating the EvgA-YdeO/GadE cascade of acid-resistance pathways and by preventing GaNt-stimulated ROS accumulation by upregulating ROS detoxification and shifting TCA cycle carbon flux. The striking lethal activity of GaNt suggests that clinical use of the agent may not quickly lead to resistance.
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PMID:Gain-of-function mutations in acid stress response (evgS) protect Escherichia coli from killing by gallium nitrate, an antimicrobial candidate. 3325 48


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