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)

Although 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been shown to inhibit the growth of certain malignant cells, its hypercalcemic effect has prevented clinical application. We have recently developed a novel vitamin D3 analog, 22-oxa-1,25-(OH)2D3 (OCT), that is capable of promoting differentiation and inhibiting proliferation without inducing hypercalcemia. The present study was undertaken to determine whether OCT could be applied for the treatment of breast cancer with or without estrogen receptor (ER). OCT inhibited the proliferation of both ER-positive (MCF-7, T-47D, and ZR-75-1) and ER-negative breast cancer cells (MDA-MB-231 and BT-20) in vitro in a time- and dose-dependent manner, as determined by cell number and [3H]thymidine uptake. The antiproliferative effect was observed with a concentration as low as 10(-11) M OCT, and treatment of MCF-7 cells with 10(-8) M OCT for 8 days caused more than a 50% reduction in cell number compared with that of vehicle-treated cells. OCT was approximately 1 order of magnitude more potent than 1,25-(OH)2D3 in inhibiting the proliferation of MCF-7 cells. The in vivo effect of OCT was examined in athymic mice implanted with ER-negative MX-1 tumor, which was established as the xenograft derived from human breast carcinoma. Intratumor administration of OCT three times a week remarkably delayed the growth of MX-1 tumor in a time- and dose-dependent manner. The antitumor effect of 1 microgram/kg BW OCT was greater than that of 500 microgram/kg BW adriamycin, and the relative tumor weights in each group on day 26 were 29.7% and 50.5% of that in the vehicle-treated group, respectively. The effects of OCT and adriamycin were additive, and the relative tumor weight after 26 days of combined treatment was 21.7% of that in the vehicle-treated group. Oral administration of OCT was also effective, and the relative tumor weight in the OCT-treated group (1 microgram/kg BW) was 54.6 +/- 0.1% (mean +/- SEM) of that in the vehicle-treated group. Neither intratumor nor oral administration of OCT raised the serum calcium level in these animals. These results demonstrate that OCT is a potent inhibitor of the proliferation of breast cancer cells with or without ER and that OCT inhibits the growth of breast cancer in vivo without inducing hypercalcemia. We suggest that OCT may provide a new strategy for the treatment of breast carcinoma regardless of ER status.
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PMID:A novel vitamin D3 analog, 22-oxa-1,25-dihydroxyvitamin D3, inhibits the growth of human breast cancer in vitro and in vivo without causing hypercalcemia. 185 78

169 postmenopausal women and 84 male patients aged over 59 years from the outpatient consultations of 32 general practitioners were examined. The most frequently encountered risk factors for osteoporosis were low physical activity (41% of women, 27% of men), low intake of dairy products (37%/21%), smoking (11%/22%), while the particularly relevant risk factors were more rare, such as corticotherapy (7%/9%) and early menopause (17%). The risk factors were not more frequent than in 550 persons of the same age screened among the Swiss general population in another study. The same group of persons also yielded reference values for urinary calcium and hydroxyproline in the fasting urine, which are both considered as markers of bone turnover and as potential tools for screening osteoporosis. The urinary values were independent of age, body mass index, calcium intake, and the duration of the postmenopausal period. They were different from those found in 38 patients with Paget's disease, 66 patients with malignant hypercalcemia and 25 with bone metastasis from breast cancer. Calcium and hydroxyproline excretion are expressed as a ratio of urinary creatinine. Percentiles 10 and 90 of urinary calcium are 0.058 and 0.363 mmol/mmol (male) and 0.062 and 0.523 mmol/mmol (women). Percentiles 10 and 90 for urinary hydroxyproline are 0.006 and 0.024 mmol/mmol (male) and 0.010 and 0.025 mmol/mmol (women).
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PMID:[Prevalence of risk factors for osteoporosis and distribution of calciuria and hydroxyprolinuria in an elderly population of a general practice. Results of a survey among 32 practitioners of the Vaud and Fribourg districts]. 192 67

Tumours which involve the skeleton do so by producing humoral factors which increase osteoclast and osteoblast activity. Increases in osteoclast activity lead to osteolytic bone destruction and sometimes to hypercalcaemia. Osteolytic metastases are common, and are found most often in patients with lung and breast cancer and in myeloma. The tumour-associated factors responsible are multiple and probably different in each case. Osteoblastic metastases occur most frequently in metastatic cancer of the prostate, and are due to osteoblast stimulating factors released by the tumour cells which have not, as yet, been identified. Agents such as bisphosphonates which inhibit osteoclastic bone resorption are useful in the prevention and treatment of patients with osteolytic metastases, although the precise mechanisms by which these agents work are not yet understood.
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PMID:Mechanisms of osteolytic bone destruction. 195 46

Neoplasia affecting the skeleton is an important cause of morbidity, which includes hypercalcaemia, bone pain and fracture. In most instances these events are mediated by an increase in the resorption of bone which decreases bone density and disrupts skeletal architecture, either at focal sites or generally throughout the skeleton. Neoplastic activation of bone resorption in heterogeneous, but there is now good evidence that this is due to the increased activation of osteoclasts, the cells which mediate bone resorption in health. Bisphosphonates are specific inhibitors of osteoclast-mediated bone resorption and are capable of inhibiting osteoclastic activation independent of the mechanism of its stimulation. This provides the rationale for the use of bisphosphonates in the hypercalcaemia of malignancy. Despite refinements in the use of endocrine therapy, chemotherapy and radiotherapy these interventions have had relatively little impact on the skeletal morbidity or mortality of common malignancies affecting the skeleton, particularly breast cancer and myelomatosis. In addition, there is good evidence that skeletal disease is progressive in many patients despite the use of chemotherapy and radiotherapy. Since accelerated bone resorption can be inhibited by long-term treatment with bisphosphonates, their use is likely to decrease skeletal complications such as bone pain and fracture. The bisphosphonates, therefore, hold great promise as agents to improve the quality of life of such patients.
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PMID:Rationale for the use of bisphosphonates in bone metastases. 195 47

A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against synthetic PTHrP-(1-40) and recombinant PTHrP-(1-84) as standard. The detection limit is 2 pmol/L, and intra- and interassay coefficients of variation are 4.8% and 13.6%, respectively. This assay does not detect PTH even at concentrations of up to 2000 pmol/L. Cross-reactivity studies using various synthetic PTHrP peptides localize the antibody-binding epitope between residues 20 and 29. Hypercalcemic patients with a range of solid tumors and no evidence of bone metastases on radionuclide scanning (n = 27) all had detectable PTHrP levels (range, 2.8-51.2 pmol/L). Of 17 patients with solid tumors (other than breast) and bone metastases, 11 (64%) also had detectable PTHrP levels (range, 4.9-47.5 pmol/L). Twenty samples from breast cancer patients with hypercalcemia, 19 with evidence of bone metastases, and 1 with a negative bone scan were assayed, and detectable PTHrP levels were found in 13 (65%; range, 3.8-61.6 pmol/L). Patients with squamous cell carcinomata and normal serum calcium levels (n = 11) had no detectable PTHrP or levels close to the detection limit of the assay (range, less than 2 to 3.7 pmol/L). Plasma levels in normal volunteers were below the detection limit of the assay in all but 1 of 38 normal subjects. Patients with chronic renal failure on hemodialysis (n = 18) and patients with primary hyperparathyroidism (n = 14) all had undetectable PTHrP in this assay. This assay allows positive identification of patients with PTHrP-mediated hypercalcemia and, therefore, should be useful in the clinical investigation of the hypercalcemic patient. Furthermore, it has allowed detection of circulating PTHrP in hypercalcemic breast cancer patients with bone metastases, indicating a significant role for PTHrP in this disease.
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PMID:Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. 195 13

The mechanisms of hypercalcaemia were assessed in 20 hypercalcaemic patients with breast cancer. Abnormalities suggestive of a PTH-related peptide (PTHrP) mechanism were observed in up to 60% of cases; urinary cyclic adenosine monophosphate (UcAMP) was elevated in nine patients (45%), renal tubular reabsorption of calcium (RTRCa) was elevated in nine (45%) and the renal tubular threshold for phosphate reabsorption (TmPO4) depressed in 12 (60%). While TmPO4 was lower in patients with high UcAMP, there was no consistent relationship between RTRCa and UcAMP or UcAMP and the extent of bone metastases. In a control group of nine normocalcaemic breast cancer patients, bone resorption as assessed by urinary calcium/creatinine ratio was slightly increased but UcAMP, RTRCa and TmPO4 were generally normal. These observations indicate that a PTHrP-mediated mechanism of hypercalcaemia may be operative in up to 60% of patients with breast cancer, irrespective of the presence or extent of bone metastases.
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PMID:Breast cancer-associated hypercalcaemia: a reassessment of renal calcium and phosphate handling. 196 70

Holter's test was performed in eight patients with advanced breast cancer and paraneoplastic hypercalcemia. In spite of several reports of cardiac arrhythmias, none were found in these patients.
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PMID:[Hypercalcemia and changes in cardiac rythm]. 204 15

Tubular reabsorption of calcium (Ca) is becoming recognized as a determinant of malignant hypercalcemia. However, its importance as compared to increased bone resorption has not yet been widely investigated. We determined Ca fluxes of bone resorption and tubular reabsorption in 141 rehydrated patients with hypercalcemia of malignant or benign origin, before any specific treatment. Bone resorption (BRI) was evaluated by fasting urinary Ca excretion and Ca tubular reabsorption using an index (TRCaI) calculated from a nomogram relating fasting urinary Ca excretion and calcemia. The relationship between alterations in TRCaI and in the tubular capacity to reabsorb inorganic phosphate (Pi), as judged by TmPi/GFR, was also examined for each cause of hypercalcemia. Among 101 cases with malignancy, 67% had overt bone metastases, but all displayed increased BRI. Calcemia was highest in breast cancer and lowest in prostate carcinoma. BRI was markedly increased in breast cancer, lymphoma, and multiple myeloma, whereas it was slightly elevated in lung squamous cell, renal, and liver carcinomas. TRCaI was increased in 49% of malignant hypercalcemia, particularly in epidermoid (above the upper normal limit in 71% of the cases), renal, and liver carcinomas. It was elevated in 54% of breast cancer and normal in multiple myeloma and prostate cancer. In nonmalignant hypercalcemia, BRI was markedly increased in vitamin D intoxication, sarcoidosis, and immobilization. In primary hyperparathyroidism (PHP), BRI was moderately increased. TRCaI was abnormally elevated in PHP, but normal in vitamin D intoxication, sarcoidosis, and immobilization. In malignant hypercalcemia, TmPi/GFR was low in 77% of patients and in all types of tumors, except in prostate carcinoma. The index ratio [TRCaI/(TmPi/GFR)] gave a better discrimination of PHP from other causes of nonmalignant hypercalcemia than the use of either TRCaI or TmPi/GFR taken alone. Thus, in malignant hypercalcemia, increased bone resorption is associated with an elevation in tubular Ca reabsorption in half the patients surveyed, whereas low tubular Pi reabsorption is observed in more than 75%. Increased TRCaI is restricted to some types of tumor, whereas decreased TmPi/GFR is observed in all types except prostate carcinoma. In nonmalignant hypercalcemia, a significant increase in mean TRCaI was only observed in PHP, of which individual cases can be fully discriminated from other conditions by using a new index taking into account alteration in the renal transport capacity of both Ca and Pi.
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PMID:Evaluation of bone resorption and renal tubular reabsorption of calcium and phosphate in malignant and nonmalignant hypercalcemia. 205 36

In the course of a phase II study 15 patients (nine women and six men; mean age 58 [45-69] years) received 300 mg clodronate daily during a total of 16 episodes of tumour-induced hypercalcaemia. Four women had breast cancer, four patients had plasmocytoma and four had bronchial carcinoma. One woman each had leiomyosarcoma or squamous cell carcinoma of the uterus or pancreatic carcinoma, respectively. No other calcium-lowering treatment, such as forced diuresis, glucocorticoids, calcitonin or mithramycin, was employed. As early as two days after onset of treatment the serum calcium concentration fell significantly from 3.63 +/- 0.42 to 2.80 +/- 0.40 mmol/l. After a mean interval of 4.3 days the hypercalcaemia had been eliminated during 15 of the 16 episodes. The treatment was not adequate in one patient with paraneoplastic hypercalcaemia. The results indicate that this medication is to be recommended as a standard treatment of tumour-induced hypercalcaemia; side effects are minimal.
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PMID:[Monotherapy with clodronate for tumor-induced hypercalcemia]. 213 27

Hypercalcemia is a common metabolic problem in patients with metastatic breast cancer. Osteolytic bone destruction with release of calcium into circulation and humoral factors can lead to hypercalcemia. Clinical manifestations may be so mild as to be overlooked or include severe nervous system, gastrointestinal and renovascular complications. Treatment with saline infusions to replenish intravascular volume and restore renal function provides the basis for other therapeutic interventions. A variety of pharmacologic approaches include intravenous fluids, diuretics, steroids, calcitonin, bisphosphonates, and plicamycin. Investigation of new agents, particularly bisphosphonates and gallium, continues. The optimal treatment of hypercalcemia in breast cancer patients has not been defined, though control of metastatic disease obviously is of utmost importance.
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PMID:Management of hypercalcemia in breast cancer. 214 69


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