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)

A serially transplantable perianal gland carcinoma (CAC-9) was developed in nude mice from a hypercalcemic dog that has been maintained through passage 20. Tumor doubling rate of CAC-9 was 3.1 +/- 0.4 days. Mithramycin (MMC) injected intraperitoneally (8 mg/kg) into nude mice bearing CAC-9 markedly decreased the tumor volume 2 weeks post-injection. MMC returned the elevated serum and urine calcium levels in mice with CAC-9 back to similar values as controls. The few remaining viable tumor cells after MMC were large and had numerous aggregations of intermediate filaments that displaced cytoplasmic organelles. Histomorphometric evaluation of lumbar vertebrae reveled no significant differences in bone resorption of nude mice bearing CAC-9 compared to saline-treated controls. This rapidly growing tumor line in nude mice associated with mild hypercalcemia will be a useful animal model to evaluate combinations of chemotherapy for cancer-associated hypercalcemia.
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PMID:Effects of mithramycin on transplantable canine perianal gland carcinoma (CAC-9) in nude mice: biochemical, histomorphometric, and ultrastructural investigations. 294 19

The effect of a low calcium diet, mithramycin, or dichlorodimethylene bisphosphonate were evaluated in nude mice with humoral hypercalcemia of malignancy associated with the transplanted canine adenocarcinoma (CAC-8). Low calcium (0.01%) diet significantly reduced serum calcium levels in hypercalcemic nude mice and reduced urine calcium excretion to control levels. Mithramycin (8 mg/kg) decreased serum calcium concentration and urine calcium excretion to the range of control non-tumor-bearing nude mice at day 5 after a single injection, but there was no change in the number of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from CAC 8-bearing nude mice after mithramycin administration were decreased in size, had small ruffled borders, and increased relative size of clear zones. Dichlorodimethylene bisphosphonate (Cl2MDP) (45 mg/kg) partially reduced serum calcium concentration of hypercalcemic tumor-bearing nude mice, decreased urine calcium excretion to control levels, and markedly reduced the numbers of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from Cl2MDP-treated nude mice were smaller and had a reduced frequency of ruffled borders than saline-treated hypercalcemic nude mice. In vitro bone resorption induced by CAC-8 extract was significantly reduced by Cl2MDP and mithramycin. The results of these investigations suggest that the hypercalcemia and hypercalciuria associated with HHM in nude mice with CAC-8 are the combined result of altered calcium homeostasis in the bone, kidney, and intestine. Chemotherapeutic agents that specifically affect only bone or feeding a low calcium diet alone may not completely ameliorate the hypercalcemia of HHM.
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PMID:The effect of low calcium diet, mithramycin, and dichlorodimethylene bisphosphonate on humoral hypercalcemia of malignancy in nude mice transplanted with the canine adenocarcinoma tumor line (CAC-8). 297 5

Mithramycin (Mithracin(R)) rapidly controlled the hypercalcemia of malignant disease in every patient. This control was temporary, and intermittent administration of the antibiotic was required.Hypercalcemia frequently responds to non-toxic maneuvers such as hydration and moderate doses of corticoids. Until the mechanism of action of Mithramycin in hypercalcemia is better understood, caution should be urged in its prolonged use for this purpose.
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PMID:Mithramycin for hypercalcemia of malignant disease. 425 88

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.
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PMID:Therapy of malignancy-associated hypercalcemia: 1983. 621 80

Mithramycin given as a single dose for the treatment of hypercalcemia has not been reported to cause renal dysfunction. A case is presented of nephrotoxicity following a single 25 micrograms/kg dose in a patient with underlying squamous cell carcinoma, obstructive uropathy, and hypercalcemia. Underlying renal impairment may magnify the nephrotoxicity of mithramycin.
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PMID:Nephrotoxicity following single dose mithramycin therapy. 622 49

Four patients with parathyroid carcinoma operated on at the Karolinska Hospital were reviewed. In three patients the parathyroid carcinoma was suspected at the primary operation and successfully treated with excision of the tumour and ipsilateral hemithyroidectomy. In one patient the diagnosis was made only after local recurrence of the tumour and the appearance of lung metastasis. Although removal of local recurrence and distant metastasis was not curative, the patient improved for a long period of time. When surgical resection did not successfully control the hypercalcemia, Mithramycin, 12.5 micrograms/kg intravenous daily was given for five days. With two days interruption the treatment was repeated. The hypercalcemia could in this manner be controlled for almost one and a half years. It is concluded that parathyroid carcinoma is a relatively rare endocrine tumour which may be cured by adequate initial operation. When surgery is not feasible to control hypercalcemia, Mithramycin seems to be the drug of choice even for long-term therapy.
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PMID:Parathyroid carcinoma--problems in diagnosis and treatment. 623 Nov 53

It is proposed that this review will adopt the following format: establishment of hypercalcemia. This demands a discussion of the problem of normal ranges, the usage of either total calcium or ionized calcium in making this decision and where total calcium is used whether adjustment of this value for serum protein concentration should be used and if so, the formulae which have been cited to perform this. Having established hypercalcemia why is it necessary to differentiate this? This will involve reviewing those clinical situations in which differentiation of hypercalcemia has been attempted and will include an attempt to produce an up to date indication of conditions in which hypercalcemia has been described. When hypercalcemia has been established the laboratory tests which have been further used to discriminate will be divided into single tests such as N- or C- terminal parathormone, 1,25- dihydroxycholecalciferol, cyclic AMP; the combination tests which have been used including phosphate clearance, chloride vs. bicarbonate etc. proceeding to those groups which have used discriminant function to help in the decision making; dynamic testing will also be discussed particularly with reference to steroid suppression but will also include other known suppressants such as Mithramycin and Calcitonin. A final section will be included attempting to assess overall the present state of art in differentiating laboratory diagnosis of hypercalcemia and will also attempt to highlight those areas which appear to be most fruitful areas of progress in the future.
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PMID:Differential laboratory diagnosis of hypercalcemia. 638 33

In order to define the relative importance of renal failure and increased bone resorption in the hypercalcaemia of myelomatosis 22 untreated patients were studied, of whom 12 were hypercalcaemic. Most patients had malabsorption of radiocalcium from the gastrointestinal tract and evidence of increased bone resorption as assessed by fasting urinary hydroxyproline/creatinine ratio. The mean OHPr/Cr ratio, however, was similar in patients with and without hypercalcaemia. Renal failure and Bence Jones proteinuria occurred more frequently in the hypercalcaemic patients. In four patients with hypercalcaemia there was an increase in OHPr/Cr after saline infusion accompanied by an improvement in renal function and hypercalcaemia. Mithramycin given to the same patients further reduced hypercalcaemia, presumably by inhibiting bone resorption. It was concluded that the hypercalcaemia of myelomatosis is due to the combination of renal failure and increased bone resorption, but that the OHPr/Cr ratio in the untreated state is a poor indicator of the degree of bone resorption in hypercalcaemic patients.
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PMID:Relative importance of renal failure and increased bone resorption in the hypercalcaemia of myelomatosis. 645 Jul 79

Within a recent one-year period, 3 patients in the accelerated phase of chronic myelogenous leukemia were admitted to our medical center with severe hypercalcemia. Simultaneous determinations of ionized calcium and parathyroid hormone levels in 2 of the patients confirmed the hypercalcemia and revealed suppression of parathyroid hormone. We conclude that hypercalcemia in the accelerated phase of chronic myelogeneous leukemia may be more common than previously described and is not mediated by parathyroid hormone. An elevated parathyroid hormone level accompanying hypercalcemia in these patients should suggest the additional diagnosis of primary hyperparathyroidism. Mithramycin was necessary for control in 2 of our cases as well as in others reported in the medical literature and should be an early therapeutic consideration whenever saline diuresis is inadequate.
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PMID:Hypercalcemia in the accelerated phase of chronic myelogenous leukemia. 645 95

Mithramycin is an mRNA synthesis inhibitor that has been used to decrease bone resorption in patients with humoral hypercalcemia and Paget's disease. During studies on the mechanism of action of mithramycin it became clear that the compound has a direct inhibitory effect on osteoclastic bone resorption in the in vitro bone slice assay. At concentrations of 0.1-100 nM mithramycin directly inhibited osteoclastic bone resorption dose-dependently up to 66 +/- 5% at 100 nM (mean +/- SEM, 3 expts.). Another mRNA synthesis inhibitor, actinomycin D (0.1-100 nM) and the protein synthesis inhibitor, cycloheximide (0.1-10 microM), also dose-dependently inhibited osteoclastic bone resorption by 78 +/- 7% at 100 nM and 76 +/- 7% at 10 microM, respectively. Mithramycin and actinomycin D at 100 nM did not affect osteoclast survival on bone slices and were therefore not cytotoxic at the concentrations used. Mithramycin (100 nM) and cycloheximide (10 microM) both slightly decreased osteoclast cytoplasmic spreading. Addition of 100 nM mithramycin 6 hr after osteoclast adhesion to bone slices still inhibited subsequent resorption by 50%, indicating a continued but lesser requirement for mRNA synthesis during bone resorption. These results show that approximately 75% of osteoclasts obtained from neonatal rat long bones are activated by adhesion to mineralized bone surfaces and require mRNA and protein synthesis in order to resorb bone in vitro.
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PMID:The majority of osteoclasts require mRNA and protein synthesis for bone resorption in vitro. 821 56


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