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 1,25-dihydroxy-16-ene-23-yne-vitamin D3 [1,25(OH)2-16-ene-23-yne-D3] is a vitamin D analog that is very potent in inhibiting proliferation and inducing differentiation of myeloid leukemic cells in vitro. Also, 1,25(OH)2-16-ene-23-yne-D3 is 300 times less active in mediating intestinal calcium absorption and bone calcium mobilization as compared to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the physiologically active metabolite. Furthermore, 1,25(OH)2-16-ene-23-yne-D3 is 10-25 times less potent than 1,25(OH)2D3 in causing hypercalcemia in BALB/c mice injected intraperitoneally (i.p.) every other day (q.o.d.) for 6 weeks. We explored the therapeutic potential of 1,25(OH)2-16-ene-23-yne-D3 by developing and using the following three leukemia models. (i) Injection of 2.5 x 10(5) myeloid leukemic cells (WEHI 3BD+) into syngeneic BALB/c mice resulted in leukemic death of all diluent-injected mice by day 26. Mice who received the same number of leukemic cells and also received 1,25(OH)2D3 (0.1 micrograms q.o.d., i.p.) had nearly an identical survival curve. Those who received the leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (1.6 micrograms q.o.d., i.p.) had a significantly (P = 0.003) longer survival, with the last mouse dying of leukemia on day 50. (ii) Injection of 50% fewer leukemic cells (1 x 10(5) cells) into syngeneic BALB/c mice resulted in 86% dead of leukemia at 51 days. Experimental mice who received the same number of leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (0.8 microgram q.o.d.) had a significantly (P = 0.0006) longer survival than controls; only 53% of the mice were dead by day 100. (iii) After injection of 1.5 x 10(4) leukemic cells, 13% of syngeneic BALB/c mice were free of disease at day 180. In contrast, 43% of mice who received leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (1.6 micrograms q.o.d.) were still free of disease at day 180. In summary, 1,25(OH)2-16-ene-23-yne-D3 is a vitamin D analog that significantly increased survival of mice who had myeloid leukemia.
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PMID:1,25-Dihydroxy-16-ene-23-yne-vitamin D3 prolongs survival time of leukemic mice. 233 31

Three cases of pulmonary atypical mycobacteriosis (AM) were reported. Two cases were associated with lung cancer in which the diagnosis of malignancy was difficult and delayed by the coexistence of AM. The third was a case of adult T-cell leukemia (ATL) which manifested during the course of AM. In case 1 (73 years, male) and case 2 (86 years, male), chest roentgenogram abnormalities as well as clinical symptoms were considered to be caused by mycobacteriosis because of positive smear of acid-fast bacilli in sputa on admission. Therefore it took four months and three months respectively for final diagnosis of lung cancer. The autopsy of case 1 revealed a poorly differentiated adenocarcinoma with coexisting foci of squamous cell carcinoma in right lower lung, and granulomatous inflammations with caseating necroses in right mid and lower lungs. M. avium complex was cultured from sputum on admission, and also a high titer of HTLV-I antibody was demonstrated. In case 2 malignant cells were detected in sputa (class V), however his general condition did not allow an aggressive anticancer chemotherapy and he died of malignancy with complication of thromboangiitis obliterans on right lower leg. Case 3 was a 76-year-old male who had been diagnosed as lung AM for more than two years. His chest radiography showed bilateral infiltrative shadows with frequent positive cultures of M. avium complex (more than 100 colonies) from sputum. A generalized lymphadenopathy including right hilar lymph node on chest X-ray film was followed by the presence of atypical lymphocytes in peripheral blood and the elevation of HTLV-I antibody in serum. Four months later he died with hypercalcemia and renal failure in spite of chemotherapy (CPM + VCR + ADR + PLS). The above cases suggest that AM as well as tuberculosis should be considered when pulmonary infiltrates were observed in malignant patients, especially in patients with retrovirus infections.
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PMID:[Three cases of pulmonary atypical mycobacteriosis associated with lung cancer and adult T-cell leukemia]. 237 33

Adult T cell leukemia (ATL) is associated with human T cell leukemia virus type 1 (HTLV-1) infection, and almost all ATL patients have the complication of hypercalcemia. To understand the mechanism of the high incidence of hypercalcemia in ATL, we studied the expression of a parathyroid hormone-related protein (PTHrP) gene that has been proposed as a causative factor of hypercalcemia in some solid tumors. The polymerase chain reaction coupled with reverse transcription of mRNA was applied to RNA from peripheral blood mononuclear cells. Cells from all 13 ATL patients examined showed abundant expression of the PTHrP gene, while cells from uninfected normal subjects did not. Significant expression of PTHrP gene was also detected in HTLV-1 carriers without any symptoms and in patients with HTLV-1-associated myelopathy or tropical spastic paraparesis. PTHrP mRNA levels correlated with the number of infected cells that were estimated by the integrated HTLV-1 DNA. These results suggest that HTLV-1-infected cells are expressing the PTHrP gene. This concept was further supported by the finding that the HTLV-1 trans-activator, the tax gene product, caused trans-activation of the PTHrP gene promoter linked to the CAT gene. These observations might explain the general expression of the PTHrP gene in ATL patients and the high incidence of hypercalcemia in ATL.
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PMID:Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene. 238 34

The active metabolite of vitamin D known as 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is a major physiologic regulator of mineral metabolism in man. The compound is also a potent inducer of differentiation of a human promyelocytic leukemia cell line known as HL-60. The induction of differentiation of myeloid leukemia cells to functional end cells offers an appealing therapeutic prospect. We investigated the ability of 1,25(OH)2D3 both to induce in vitro the differentiation of blast cells taken from patients with acute myelogenous leukemia and to improve hematopoiesis in vivo in patients with the myelodysplastic syndromes (preleukemia). We found that high concentrations (10-6 M) of 1,25(OH)2D3 significantly induced the in vitro differentiation of blast cells as measured by morphology, phagocytosis, and superoxide production. A concentration of 10-9 M 1,25(OH)2D3 had no effect on blast cell differentiation. We gave 2 microgram/day of 1,25(OH)2D3 to 18 patients with myelodysplastic syndrome (preleukemia) in an attempt to improve their hematopoiesis. During therapy, their peak peripheral blood granulocyte, platelet, and macrophage concentrations were slightly elevated as compared to their baseline, starting levels. Eight patients had a partial or minor peripheral blood response to the compound during the administration of 1,25(OH)2D3. However, no patient showed significant improvement of peripheral blood cell or marrow blast cell counts by the end of the study (greater than or equal to 12 weeks) as compared to their starting levels. Seven of the patients developed leukemia before or by 12 weeks of treatment. Nine of the 18 patients developed hypercalcemia. Taken together, the study shows that high concentrations (10-6M) of 1,25(OH)2D3 can induce differentiation of leukemia blast cells in vitro, but the administration of 1,25(OH)2D3 to patients with the myelodysplastic syndromes (preleukemia) does not have an enduring therapeutic effect. Hypercalcemia prevented administering greater amounts of 1,25(OH)2D3. In the future, the use of new vitamin D analogs that induce hematopoietic cell differentiation without inducing hypercalcemia might allow the achievement of higher blood levels of the inducing compound and might be medically useful for selected preleukemic and leukemic patients.
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PMID:1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells. 241 38

Concentrations of 25-hydroxyvitamin D (25-OH-D), 24,25-dihydroxyvitamin D [24,25(OH)2D], and 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] in bone marrow and serum of patients with leukemia and normal subjects were assayed. There were highly significant correlations between the bone marrow and serum concentrations of the respective vitamin D metabolites. Especially, the concentrations of 25-OH-D and 1,25(OH)2D in the bone marrow gave very similar values to those in serum. This is a big advantage in controlling the bone marrow levels of vitamin D metabolites in patients with leukemia, because doctors can calculate the bone marrow levels from the serum levels of the respective vitamin D metabolites without bone marrow aspiration. When 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3) was administered orally to eight patients with leukemia, clinical conditions were improved in seven patients: four complete remissions (CR), one partial response (PR), and two minor responses (MR) without severe hypercalcemia. The results suggest that the therapy with 1 alpha-OH-D3 is fairly effective for curing human leukemia although it is not dramatic.
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PMID:Bone marrow and serum concentrations of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1 alpha,25-dihydroxyvitamin D in patients with leukemia and normal subjects. 258 43

Adult T-cell leukemia-lymphoma, an aggressive T-cell leukemia, is characterized by the presence in the peripheral blood of malignant T cells that have highly indented or lobulated nuclei. Phenotypically the cells are usually helper T cells, but functionally they behave as suppressor cells. Patients have skin and lung involvement, hepatosplenomegaly, moderate lymphadenopathy sparing the mediastinum, and various metabolic abnormalities such as hypercalcemia. The clinical course may be chronic or acute, usually followed by a rapidly progressive terminal course. Adult T-cell leukemia-lymphoma is now known to be caused by human T-cell lymphotropic virus type I, which has been identified in the cells of patients with the disease.
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PMID:Adult T-cell leukemia-lymphoma. 266 14

Induction of terminal differentiation of leukemic and preleukemic cells is a therapeutic approach to leukemia and preleukemia. The 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D3, can induce differentiation and inhibit proliferation of leukemia cells, but concentrations required to achieve these effects cause life-threatening hypercalcemia. Seven new analogs of 1,25(OH)2D3 were discovered to be either equivalent or more potent than 1,25(OH)2D3 as assessed by: (a) inhibition of clonal proliferation of HL-60, EM-2, U937, and patients' myeloid leukemic cells: and (b) induction of differentiation of HL-60 promyelocytes. Furthermore, these analogs stimulated clonal growth of normal human myeloid stem cells. The most potent analog, 1,25-dihydroxy-16ene-23yne-vitamin D3, was about fourfold more potent than 1,25(OH)2D3. This analog decreased clonal growth and expression of c-myc oncogene in HL-60 cells by 50% within ten hours of exposure. Effects on calcium metabolism of these novel analogs in vivo was assessed by intestinal calcium absorption (ICA) and bone calcium mobilization (BCM). Each of the analogs mediated markedly less (10 to 200-fold) ICA and BCM as compared with 1,25(OH)2D3. To gain insight into the possible mechanism of action of these new analogs, receptor binding studies were done with 1,25(OH)2-16ene-23yne-D3 and showed that it competed only about 60% as effectively as 1,25(OH)2D3 for 1,25(OH)2D3 receptors present in HL-60 cells and 98% as effective as 1,25(OH)2D3 for receptors present in chick intestinal cells. In summary, we have discovered seven novel vitamin D analogs that are more potent than the physiologic 1,25(OH)2D3 as measured by a variety of hematopoietic assays. In contrast, these compounds appear to have the potential to be markedly less toxic (induction of hypercalcemia). These novel vitamin D compounds may be superior to 1,25(OH)2D3 in a number of clinical situations including leukemia/preleukemia; they will provide a tool to dissect the mechanism of action of vitamin D seco-steroids in promoting cellular differentiation.
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PMID:Novel vitamin D analogs that modulate leukemic cell growth and differentiation with little effect on either intestinal calcium absorption or bone mobilization. 266 45

The effect of hypercalcemia on T wave morphology, polarity, and amplitude was studied in 14 patients with a primary diagnosis of malignant lymphoma (8 patients), adult T-cell leukemia (5 patients), and Hodgkin's disease (1 patient). Hypercalcemia was severe to extreme in 11 (14.9-22.8 mg/dl), moderate in 1 (13.4 mg/dl), and mild in 2 (11.8 and 12.2 mg/dl) patients. Ten of the 11 patients (91%) with severe hypercalcemia showed inverted, biphasic, and notched T waves, mainly in the chest leads. Notched T waves were observed in all 10 of these patients in anterior to lateral, mid to lateral, or lateral chest leads. Biphasic and/or inverted T waves in anterior or anterior to midchest leads were present in 4 of these 10 patients who had extreme hypercalcemia (greater than 16 mg/dl). Changes in T wave morphology were not observed in moderate or mild hypercalcemia. T wave amplitude showed significant inverse correlation with serum calcium (T mV vs Ca, r = -0.60, p less than 0.001; T/R ratio vs Ca, r = -0.68, p less than 0.001; n = 35). Decrease in T wave amplitude was marked in severe hypercalcemia (p less than 0.0001) and moderate hypercalcemia, but there was no change in mild hypercalcemia. Changes in T wave morphology, polarity, and amplitude either appeared with development of hypercalcemia or disappeared with normalization of serum calcium level. It was concluded that in addition to shortening the QT interval, severe to extreme hypercalcemia can cause development of inverted, biphasic, or notched T wave with a marked decrease in amplitude of T waves.
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PMID:Changes in T wave morphology during hypercalcemia and its relation to the severity of hypercalcemia. 270 29

Three examples of malignant neoplasms primary to the oral cavity and associated with paraneoplastic syndromes are presented. The first case is a squamous cell carcinoma of the maxilla associated with leukocytosis. The second case is a mandibular squamous cell carcinoma associated with hypercalcemia in the absence of bony metastases. The third case is a squamous cancer of the tongue that metastasized to the lumbar vertebrae and right second rib and was associated with both hypercalcemia and leukocytosis. There was no evidence of acute infection or leukemia that could be expected to account for leukocytosis. Hypercalcemia in the second case was defined as humoral hypercalcemia of malignancy by biochemical and clinical evaluations. To our knowledge, this is the first definitive report of a carcinoma primary to the oral cavity associated with humoral hypercalcemia of malignancy. In each case, the severity of hypercalcemia, leukocytosis, or both very closely correlated with tumor growth. Surgical excision of the tumors or regression of tumor mass due to aggressive anticancer drug administration resulted in decreases in leukocyte number, serum calcium level, or both. In contrast, recurrence or regrowth of tumors induced further development of hypercalcemia, leukocytosis, or both. It is therefore likely that humoral factors released by these oral carcinomas are responsible for the hypercalcemia, leukocytosis, or both.
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PMID:Three cases of oral squamous cancer associated with leukocytosis, hypercalcemia, or both. 281 15

Renal failure in patients with lymphoma or leukemia may be brought about by different causes, including ureteral obstruction, hypercalcemia, hyperuricemia, amyloidosis, immunologically mediated nephrosis and paraproteinemic nephropathy. Lymphomatous or leukemic infiltration of the kidneys is a frequent finding at autopsy but is rarely seen as a cause of renal failure. In this report three patients with lymphomatous infiltration of the kidneys causing renal failure are described. Clinical and laboratory criteria for establishment of diagnosis in such cases are suggested. Using these diagnostic criteria, a renal biopsy may not be necessary.
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PMID:[Renal insufficiency due to lymphomatous infiltration of the kidney: report of 3 cases and review of the literature]. 281 88


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