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)

Murine gamma-interferon (MuIFN-gamma) is a potent inhibitor of bone resorption induced by interleukin 1 and parathyroid hormone-related protein in vitro. To investigate whether MuIFN-gamma is also effective in vivo, the cytokine was injected s.c. into hypercalcemic, tumor (EC-GI)-bearing nude mice, in which parathyroid hormone-related protein and interleukin 1 alpha are synergistically responsible for causing humoral hypercalcemia. When MuIFN-gamma was injected s.c. at a dose of 1 to 20 x 10(4) units for 5 days consecutively, serum calcium concentrations in the tumor-bearing mice decreased in a dose-dependent manner. The minimal effective dose was 5 x 10(4) units/mouse. Unlike calcitonin, which decreased the serum calcium concentration for only 1 to 2 days despite continuous daily injections, MuIFN-gamma decreased it for more than 7 days even after the injections had been stopped. Human gamma-interferon was completely ineffective. The decrease in serum calcium concentration was accompanied by a decrease in urinary calcium excretion. Histological examination of the femur revealed a decreased number of osteoclasts in the MuIFN-gamma-treated mice. Furthermore, MuIFN-gamma, when injected into nude mice or normal mice at a dose of 15 x 10(4) units for 3 days, almost completely abolished the formation of multinucleated osteoclast-like cells in vitro. These findings suggest that MuIFN-gamma suppresses the formation and maturation of osteoclasts and inhibits osteoclastic bone resorption, resulting in the prolonged decrease of serum calcium concentration seen in hypercalcemic, tumor-bearing nude mice. Therefore, bone resorption inhibitors like MuIFN-gamma, which ameliorate humoral hypercalcemia without an escape phenomenon, are potentially useful for the treatment of malignancy-associated hypercalcemia.
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PMID:Prolonged decrease of serum calcium concentration by murine gamma-interferon in hypercalcemic, human tumor (EC-GI)-bearing nude mice. 172 16

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing a variety of host cellular genes including many of the cytokines responsible for immune regulation and osteoclast activation. This derangement in cytokine expression may contribute to the panoply of disease states associated with HTLV-I infection such as the adult T-cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We wished to determine if there was a correlation between the expression of an array of cytokines and the diverse clinical manifestations of ATL and HAM/TSP. Utilizing the techniques of specific mRNA amplification by the polymerase chain reaction (PCR) as well as Northern blotting, we analyzed the ex vivo mRNA expression of gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF-beta 1) in the peripheral blood of HAM/TSP and ATL patients as well as asymptomatic seropositive carriers. IFN-gamma, TNF-alpha, and IL-1 beta transcripts were up-regulated in patients with HAM/TSP and seropositive carriers when compared to their levels in ATL and normal controls. In contrast, the ATL patients constitutively expressed higher levels of TGF-beta 1 mRNA than HAM/TSP and seropositive carriers. In addition, TNF-alpha and IL-1 beta serum levels were elevated in HAM/TSP, but not in ATL patients nor seropositive carriers. However, the circulating leukemic cells from ATL patients secreted increased levels of TGF-beta 1 protein into the culture medium than T-cells derived from HAM/TSP patients. Collectively these results suggest that induction of IFN-gamma, TNF-alpha, and IL-1 beta in HAM/TSP may initiate an inflammatory cascade with subsequent events leading to immune mediated destruction of the central nervous system in these patients. Expression of osteoclast activators such as TNF-alpha and IL-1 beta is not associated with hypercalcemia in ATL. Finally, impaired cellular and humoral immune responses present in ATL, but not in HAM/TSP, may be related to elevated levels of TGF-beta 1 produced by the leukemic cells. These differences in retroviral-induced host cytokine expression in ATL and HAM/TSP suggest alternate roles in disease pathogenesis.
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PMID:Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. 175 74

Both human lymphoblastoid interferon (HLBI) and bestrabucil, the conjugate of chlorambucil and beta-estradiol, have antitumor activity against adult T-cell leukemia-lymphoma (ATLL). Because an in vitro study showed that these two agents combined had a synergistic antiproliferative effect on MOLT-4 and WI-38VA13 cell lines, the authors evaluated the clinical efficacy of this combination in a pilot study with a poor-risk group of ATLL patients. The patients were treated daily with 6 x 10(6) IU of HLBI subcutaneously and 100 mg of bestrabucil orally. In patients with lymphoma-type ATLL or hypercalcemia, prednisolone also was given daily. Of 12 patients suitable for evaluation, nine had partial responses, one had a minor response, and two had no response. All five patients with skin infiltration and both patients with hypercalcemia responded. A history of prior chemotherapy did not affect the response rate. The time to clinical response was 3 to 16 days (median, 11 days) after initiation of treatment. The response duration was 4 to 108+ weeks (median, 9 weeks), but all patients except one relapsed, even during continuing treatment. No serious side effects were observed. Although the response rate with this combination treatment was high, the response duration was short, and other treatments would have to be added to achieve control of this aggressive disease.
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PMID:A combination trial of human lymphoblastoid interferon and bestrabucil (KM2210) for adult T-cell leukemia-lymphoma. 185 69

Myeloma is a malignancy of plasma cells that are terminally differentiated B-lymphocytes. The clinical spectrum varies from the incidental discovery of a pathologically raised monoclonal immunoglobulin on routine electrophoresis in asymptomatic patients to widespread skeletal involvement with incapacitating bone pain. Symptoms may result from a solitary tumor mass, described as an extramedullary plasmacytoma, in virtually any part of the body. Metabolic abnormalities commonly include hypercalcemia, elevated plasma urate levels, or the development of amyloidosis, all of which may disturb renal function. High paraprotein levels cause hyperviscosity, resulting in generalized debility and varying degrees of disturbed mental function. The natural history is determined by the mass of the tumor coupled with its unique biologic features. Median survival of unselected patients, without effective treatment but once symptoms are evident, is approximately 7 months; this period can be significantly prolonged with appropriate therapy. As a first step, urgent medical management is often necessary, centering on rehydration, correction of hyperviscosity, and reversal of metabolic defects, each of which may improve renal function. Over the longer term, specific antitumor drugs have extended median survival to approximately 30 months, and most regimens include a combination of melphalan and prednisone, with or without other cytotoxic drugs. Alternative forms of treatment include sequential hemibody irradiation, recombinant alpha interferon, and in suitably selected patients, high-dose chemoradiotherapy followed by bone marrow transplantation. The latter approaches offer promising management options and are currently the subject of evaluation in controlled clinical trials.
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PMID:Myeloma. 218 18

A 59 years old woman, born in Fukuoka Prefecture, was admitted to our hospital in Aug, 1988 because of diarrhea, fever and skin eruption. Physical examination revealed systemic lymphadenopathy and hepatosplenomegaly. The white blood cell count was 11,200/microliters with 28% atypical lymphocytes with convoluted nuclei. Mild anemia, thrombocytopenia and hypercalcemia were also observed. Antibody against the adult T-cell leukemia (ATL) associated antigen in serum was positive. OKT 4/8 ratio was high. A diagnosis of ATL was made. Because of the complications of pneumonia and herpes simplex, systemic chemotherapy was not given, and interferon (IFN)-alpha-2b was intramuscularly injected daily from Oct, 1988, resulting in the disappearance of atypical lymphocytes and improvement of skin lesions. The effect of IFN therapy lasted for three months, followed by increase of atypical lymphocytes. Although the patient became refractory to systemic IFN therapy, local injection of IFN into a buccal tumor infiltrated with atypical lymphocytes resulted in its regression of size. In spite of continued administration of IFN, the patient died of pneumonia in Jan, 1989.
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PMID:[Successful treatment of adult T-cell leukemia with interferon-alpha-2b by systemic and local administration]. 224 35

Patients with adult T-cell lymphoma frequently have hypercalcemia. Bone biopsies from these patients show increased numbers of osteoclasts. We hypothesized that substances produced by the malignant T-cell caused these phenomena by increasing the formation and/or activity of osteoclasts. To test this hypothesis, we cultured U937 cells in conditioned media from a clonal T-cell line derived from a patient with adult T-cell lymphoma and hypercalcemia. This conditioned media produced maturational changes in the U937 cells as evidenced by decreased proliferation, increased adherence, increased expression of complement receptors, and formation of multinucleated giant cells. These changes were synergistically enhanced by the addition of 1 alpha, 25-dihydroxyvitamin D3 which is known to promote monocyte differentiation. We also tested interleukin 2 and gamma- and alpha-interferon to see if they were responsible for the maturational changes. Although some effects were seen, these lymphokines could not account for all the changes induced by the T-cell conditioned media. These findings support the above hypothesis and suggest that other unidentified factors may promote the differentiation of osteoclast precursors and be involved in the pathogenesis of the hypercalcemia.
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PMID:Lymphokine-induced monocytic differentiation as a possible mechanism for hypercalcemia associated with adult T-cell lymphoma. 258 Jun 22

Multiple myeloma accounts for approximately 10% of hematologic cancers; it is characterized by an uncontrolled malignant growth of plasma cells occurring usually in the bone marrow or sometimes in other body sites as well. Malignant myeloma cells produce monoclonal immunoglobulins appearing as monoclonal spikes in the serum and/or urine. Patients with multiple myeloma suffer from various clinical features including bone destruction, bone marrow suppression, impaired renal function, hypercalcemia, serious infection, and amyloidosis. The combination of melphalan and prednisolone has been used as a standard therapy for this disease for over 30 years. The median survival of patients with multiple myeloma is 2.5-3 years, and only 10% of them survive longer than 10 years. To improve the prognosis for multiple myeloma, some strategies have been attempted. In this article, we introduce combination chemotherapy, interferon therapy, and bone marrow transplantation as newer approaches to therapy for multiple myeloma based on the biological characteristics of intractable multiple myeloma. Future therapeutic approaches are also discussed.
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PMID:[Current and future approaches to therapy for multiple myeloma]. 782 84

The converging epidemics of tuberculosis and acquired immunodeficiency syndrome (AIDS) in the RSA and their expected catastrophic interaction afford an ideal opportunity for well-planned and essential research by clinicians, molecular biologists, epidemiologists and other health workers. The enigmatic relationship between tuberculosis, vitamin D and calcium is a field of study which should be considered urgently. An optimal vitamin D status not only assures sound calcium-phosphorus homeostasis, but is also essential for maximal immune competency. Hypovitaminosis D probably predisposes towards vulnerability to tuberculosis due to deficient monocyte-macrophage function. In contrast, hypervitaminosis D can correct this deficiency, but would do so at the cost of both B- and T-lymphocyte efficiency. One example of such a state is the endogenous over-production of activated vitamin D by gamma-interferon-activated monocytes, tissue macrophages and granulomatous tissue in tuberculosis. This would not only cause the coincidental hypercalcaemia, but may also complicate the effective co-ordination of monocyte-lymphocyte interaction and consequently compromise an appropriate immune response. It can reasonably be expected that the raised plasma interferon levels in the AIDS patient may trigger similar vitamin D-related pathophysiological processes. It is proposed that the ideal situation for enhanced vulnerability to tuberculosis in the AIDS patient will have been created if the known destructive effects of the human immunodeficiency virus on CD4-positive lymphocytes act synergistically with the vitamin D-mediated complications listed above.
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PMID:[The relationship between tuberculosis, vitamin D, potassium and AIDS. A message for South Africa?]. 804 2

Ca absorption is regulated by 1,25(OH)2D, and serum values vary inversely with Ca intake. In sarcoidosis, 1,25(OH)2D is produced by alveolar macrophages in response to gamma-interferon, and patients may develop hypercalcemia after prolonged exposure to sunlight and increased dermal production of vitamin D3. To determine if increased Ca intake suppresses serum 1,25(OH)2D in normocalcemic patients and to identify those at risk, 17 normal subjects and 11 patients were studied on a metabolic ward for two and one-half days while receiving first 400 and then 1,000 mg/d of Ca. On the low Ca intake, serum angiotensin-converting enzyme (ACE), an index of disease activity, was higher in only three of the patients than in the controls, mean serum 1,25(OH)2D was higher in the patients, and mean serum total Ca, serum Ca++, and urinary Ca were not different in the two groups. On the higher Ca intake, mean urinary Ca increased in both groups, but mean serum 1,25(OH)2D was suppressed only in the normal subjects. Thus, 1,25(OH)2D production is abnormally regulated, indicating that (a) normocalcemic patients with sarcoidosis are at risk for developing abnormal Ca metabolism, and (b) a better index of disease activity is provided by the oral Ca suppression test than by serum ACE.
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PMID:Increased calcium intake does not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic patients with sarcoidosis. 838 85

Metastatic lesions from renal cell carcinoma are commonly recognized in the lung and bone, however, thyroid metastasis has rarely been reported in the literature. We present herein a case of a man with lung and thyroid metastatic tumors from renal cell carcinoma. Although making a preoperative diagnosis of thyroid metastasis is difficult because there is no established diagnostic criteria, we were able to identify this thyroid lesion as a metastatic tumor from renal cell carcinoma by the pathological findings. Interestingly, hypercalcemia was recognized in this patient whose serum parathyroid hormone (PTH) level was not increased. Moreover, this patient also had early gastric cancer simultaneously, being a so-called 'double cancer'. After surgical resection of the right kidney and stomach, interferon was administered without any efficacy against the metastatic lesions of the lung and thyroid gland.
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PMID:A case of renal cell carcinoma with metastasis to the thyroid gland and concomitant early gastric cancer. 846 61


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