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)

The activities of 1,25-dihydroxyvitamin D3 and its synthetic analogs have been extensively studied in humans as well as in preclinical species, and recent data show potential therapeutic utility in cancer treatment. However, their chronic administration leads to changes in blood mineral ion concentrations, and at high doses can result in symptomatic hypercalcemia limiting therapeutic applicability. To overcome this issue, a therapeutic approach based on administration of intermittent, high doses of 1,25(OH)2D3 has been explored in prostate cancer patients. Despite these and other investigations, limited information is available on the effects of acute systemic administration of high doses of 1,25(OH)2D3 or its analogs. Here, we report a comparative analysis of the pro-calcemic effects of the novel 1,25(OH)2D3 analog BXL746 following acute or chronic administration in animals and humans. While chronic administration of BXL746 to rats, dogs and humans leads to similar modulation of calcemia in these species, single dose administration reveals >1000-fold higher sensitivity of dog compared to rat and human in induction of hypercalcemia and consequent systemic toxicity. Our data indicate that the rat is a more relevant species than the dog for the prediction of human results when acute administration of a 1,25(OH)2D3 analog is envisaged.
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PMID:Inter-species differences in sensitivity to the calcemic activity of the novel 1,25-dihydroxyvitamin D3 analog BXL746. 1885 4

Lately clinical evidence has suggested that the development of osteonecrosis of the jaws (ONJ) might be associated to assumption of high doses of nitrogen-bisphosphonate (N-BPs), quite common in the treatment of multiple myeloma and skeletal metastasis due to breast and prostate cancer. Bisphosphonates are used for the treatment of several pathologies such as osteoporosis, Paget's disease, multiple myeloma, malignant hypercalcemia, breast and prostate tumours, and other tumours associated with bone metastasis. Their use might improve patient's life standard, reducing pain and complications of the skeletal structure. In this report three clinical cases of ONJ of patients in treatment with BPs are presented, and the possible pathogenesis is analysed. Further-more, treatment guidelines for the management of patients in treatment with BPs who need restorative dental care and oral surgery are proposed.
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PMID:Clinical guidelines for prevention of osteonecrosis of the jaws in patients in treatment with bisphosphonates: literature review and report of three cases. 1892 78

Bisphosphonates are widely used in the treatment of nonmalignant bone disease like osteoporosis, Paget's disease and malignant disease like malignant hypercalcemia, osteolytic metastasis from breast and prostate cancer and multiple myeloma. Jaws osteonecrosis is described since 2003 and is more often associated with the intraveinous use than oral use. Higher risk of osteonecrosis is noted after 3 years of osteoporosis treatment. The precipitating event is often a tooth extraction or other invasive procedure. There is no effective treatment for this pathology. Careful oral examination is necessary before prescribing bisphosphonates and dental treatment must be achieved before the initiation of treatment.
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PMID:[Osteoporosis, bisphosphonates and jaws osteochemonecrosis]. 1894 74

Bone metastasis is very frequent in prostate cancer. Diagnosis is generally easy to make with scintigraphy and it can be confirmed by TDM and RMI. Before metastasis become symptomatic, treatment includes physical and nutritional advice with drugs to prevent bone events (pain, fracture, compression and hypercalcemia). Associated with a effective hormonal treatment, radiotherapy, surgery and analgesics are the principal treatments for symptomatic bone metastasis. Bisphosphonates play a very important role to prevent bone mass loss and to reduce bone complication events. Endothelin inhibitors belong to a new exciting concept to treat these bone metastases, data are needed in order to use them routinely.
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PMID:[Physiopathology, diagnosis and management of bone metastases from prostate cancer]. 1907 Aug 15

1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the most active form of vitamin D(3), and its analogues have therapeutic benefits for prostate cancer treatment. However, the development of hypercalcemia is an obstacle to clinical applications of 1alpha,25(OH)(2)D(3) for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1alpha,25(OH)(2)D(3) in LNCaP prostate cancer cells. We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1alpha,25(OH)(2)D(3)-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1alpha,25(OH)(2)D(3) does not induce acute Ca(2+) response, whereas menthol evokes an increase in [Ca(2+)](i), which suggests that cross-talks of menthol-induced Ca(2+) signaling with 1alpha,25(OH)(2)D(3)-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1alpha,25(OH)(2)D(3) and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1alpha,25(OH)(2)D(3)-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1alpha,25(OH)(2)D(3).
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PMID:Menthol Enhances an Antiproliferative Activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP Cells. 1930 66

Osteonecrosis means the process of bone death. Bisphosphonates (BPs) are becoming recognized increasingly as having a significant impact on dental treatments. BPs are the most widely used class of anti-resorptive drugs. They prevent bone resorption through osteoclast inhibition and are considered the standard of care for the management of metastatic bone disease. BPs are used for the treatment of skeletal disorders such as osteoporosis, hypercalcaemia of malignancy, osteolytic lesions arising from solid tumours and Paget's disease, breast cancer or prostate cancer. Jaw necrosis appears to be associated with the intravenous (i.v.) use of BPs. The aim of this review paper is to update the understanding of healthcare professionals to the osteonecrosis of jaws, mechanism of action and classification of BPs, management of the patients with BP-related osteonecrosis (BRON) of the jaws. An interdisciplinary approach has been emphasized to prevent and manage the condition. Finally, the role of dental practitioners including dental hygienists has been discussed to early diagnose the BRON and improve the quality of life of patients with the condition.
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PMID:Bisphosphonate-related jaw necrosis: a team approach management and prevention. 2052 42

Bone metastases frequently occur in patients with advanced solid tumors, particularly breast and prostate cancers, and nearly all patients with multiple myeloma have some degree of skeletal involvement. The strides made in treating these primary tumors have extended median survival times and thereby increased patient risk for skeletal-related events (SREs), including pathologic fractures, spinal cord compression, need for palliative radiation therapy or surgery to bone, and hypercalcemia. Bisphosphonates, inhibitors of osteoclastic bone resorption that were first established as treatment of osteoporosis, have been shown to prevent and/or delay SREs related to malignancy. The results of a large, randomized phase 3 study comparing zoledronic acid and pamidronate in breast cancer or multiple myeloma patients with osteolytic lesions showed that the incidence of SREs, time to first SRE, and risk of developing a SRE were similar between treatment groups. However, in patients with solid tumors (excluding breast or prostate cancer) metastatic to the bone, only zoledronic acid has demonstrated clinical efficacy. Although bone turnover marker levels, such as N-telopeptide of type I collagen, have been shown to correlate with clinical response, additional studies are needed to validate their ability to predict response to bisphosphonate therapy.
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PMID:Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases. 1992 Sep 19

The role of vitamin D3 in cancer prevention and its potential as an anticancer therapeutic agent have been researched and are well established. However, the clinical use of the natural vitamin D3 metabolite, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol] is limited by a possible cause of hypercalcemia and hypercalciuria. A new 24-chloro calcipotriene-based vitamin D3 analog (BGP-15) was synthesized and examined for antiproliferative activity in the androgen-dependent cell lines of prostate cancer (LNCaP) and breast cancer (MCF-7). The new analog led to significant decrease in cell viability in cultured LNCaP and MCF-7 cell lines compared with calcipotriene and 1,25(OH)2D3. We observed elevated vitamin D receptor protein levels in both LNCaP and MCF-7 cells, which were treated with 5 micromol/l of 1,25(OH)2D3, calcipotriene or BGP-15 for 20 h, indicating vitamin D receptor-binding ability. Treatments of LNCaP and MCF-7 cells with 5 micromol/l BGP-15 and calcipotriene for 20 h generated procaspase-3 cleavage and therefore, apoptosis. Interestingly, BGP-15, and to a lesser extent calcipotriene, but not 1,25(OH)2D3, activated caspase-3 in MCF-7 cells, a cell line that normally lacks this specific caspase (and procaspase). It is presumed that management of MCF-7 with BGP-15 modulates procaspase-3 expression and cleavage, and a subsequent activation of caspase-3. Similar treatments of LNCaP cells induced procaspase-9 cleavage and therefore caspase-9 activation, whereas similar treatments of MCF-7 cells failed to induce caspase-9 activation. Cytochrome c release was, however, detected in both cell lines, LNCaP and MCF-7. In-vivo results suggested that BGP-15 (similar to its parent drug) did not cause calcium-related toxic side effects after chronic treatment.
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PMID:Induction of apoptosis and inhibition of prostate and breast cancer growth by BGP-15, a new calcipotriene-derived vitamin D3 analog. 2033 94

The electrolyte imbalance in advanced cancer patients, including hyperkalemia, hypercalcemia and hyponatremia, can be induced by various factors. Hyperkalemia is occasionally induced by chemotherapy for very large malignant tumors, due to tumor lysis syndrome. Hypercalcemia and hyponatremia are often observed in patients with breast cancer, renal cancer, prostate cancer, and the like, as a paraneoplastic syndrome. Some part of hypercalcemia results from osteolysis, but the majority is induced by hormonal factors, such as parathyroid hormone-related protein. One of the paraneoplastic causes of hyponatremia is antidiuretic hormone-producing tumor. These disorders could be morbid or even motile, resulting from encephalopathy or arrhythmia in some cases. However, it should be kept in mind that they could be improved or cured by prompt treatment. Recently, after approval of the molecular targeted drugs for epidermal growth factor receptors, such as cetuximab and panitumumab, the incidence of hypomagnesia with use of these monoclonal antibodies, is relatively frequent. In addition, small molecular targeted drugs, such as m-TORinhibitors and ABL kinase inhibitors, also exert adverse reactions including hypomagnesia and hypophosphatemia. Careful monitoring of the serum concentration of magnesium and phosphate ions, to which little attention was paid previously, is a key issue in these cases.
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PMID:[Cancer and electrolytes imbalance]. 2056 1

High systemic exposures to calcitriol are necessary for optimal antitumor effects. Human prostate cancer PC3 cells are insensitive to calcitriol treatment. Therefore, we investigated whether the inhibition of 24-hydroxylase (CYP24A1), the major calcitriol inactivating enzyme, by ketoconazole (KTZ) or RC2204 modulates calcitriol serum pharmacokinetics and biologic effects. Dexamethasone (Dex) was added to minimize calcitriol-induced hypercalcemia and as a steroid replacement for the KTZ inhibition of steroid biosynthesis cytochrome P450 enzymes. KTZ effectively inhibited time-dependent calcitriol-inducible CYP24A1 protein expression and enzyme activity in PC3 cells and C3H/HeJ mouse kidney tissues. Systemic calcitriol exposure area under the curve was higher in mice treated with a combination of calcitriol and KTZ than with calcitriol alone. KTZ and Dex synergistically potentiated calcitriol-mediated antiproliferative effects in PC3 cells in vitro; this effect was associated with enhanced apoptosis. After treatment with calcitriol and KTZ/Dex, although caspase-9 and caspase-3 were not activated and cytochrome c was not released by mitochondria, caspase-8 was activated and the truncated Bid protein level was increased. Translocation of apoptosis-inducing factor to the nucleus was observed, indicating a role of the apoptosis-inducing factor-mediated and caspase-independent apoptotic pathways. Calcitriol and KTZ/Dex combination suppressed the clonogenic survival and enhanced the growth inhibition observed with calcitriol alone in PC3 human prostate cancer xenograft mouse model. Our results show that the administration of calcitriol in combination with CYP24A1 inhibitor enhances antiproliferative effects, increases systemic calcitriol exposure, and promotes the activation of caspase-independent apoptosis pathway.
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PMID:CYP24A1 inhibition enhances the antitumor activity of calcitriol. 2059 73


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