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)

N-nitrosomethylurea (NMU) given intravenously to rats at age 50 days induced mammary carcinomas in 89% of BUF/N, 73% of Sprague-Dawley, and 89% of F344 females. Latent periods were, respectively, 77, 86, and 94 days. Mortality was negligible. Biologic properties of NMU-induced tumors were tested in the BUF/N inbred strain. Before treatment, it reduced the number of tumors per rat but not the incidence; and after the tumor was established, castration arrested tumor growth or caused a temporary regression of the tumor. Metastases to bone marrow and spleen were constant, but they were rare to the liver and lungs. After the primary tumor was removed, metastases continued to grow but at a slower rate than the growth of the primary tumor. Almost all tumors were transplantable intraperitoneally and/or subcutaneously in the inguinal area of intact as well as ovariectomized and adrenalectomized rats. Transplanted tumors were able to metastasize as were primary tumors. Doubling times of NMU-induced primary and transplanted carcinomas were similar to 7 days. Cachexia ensued at the 5th week from the onset of the first tumor. When the tumor was larger than 15 g, hypercalcemia was usually observed. The treatment described appears to be the simplest method for inducing in rats a most nearly complete model for human mammary carcinomas.
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PMID:N-nitrosomethylurea as mammary gland carcinogen in rats. 111 23

Stimulation of tumor growth and induced hypercalcemia both may occur during the initiation of estrogen therapy in breast cancer. This study was conducted to determine whether cyclophosphamide (CTX) as an adjuvant to estrogen therapy might (1) prevent induced hypercalcemia or (2) achieve a higher tumoricidal effect during the phase of tumor stimulation. Fifty postmenopausal women with inoperable or recurrent disseminated breast carcinoma were divided into two random groups. Results could be evaluated in 44 patients; 21 received diethylstilbestrol (DES), and 23 received DES plus a 4-week course of cyclophosphamide (DES + CTX). The response rate was 5/21 (24%) in the DES group and 8/23 (35%) in the DES + CTX group (p greater than 0.05). The median duration of response for both groups was 9 months. The survival rate at 24 months was 52% in the DES group and 25% in the DES + CTX group (p = 0.05). Induced hypercalcemia occurred in 3 patients treated with DES + CTX. Short-term cyclophosphamide adjuvant to estrogen therapy did not prevent induced hypercalcemia nor prolong the duration of response or survival.
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PMID:The effect of short-term cyclophosphamide on estrogen therapy in metastatic breast cancer. 123 33

We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated vipoma. Marked tumor-associated hypercalcemia could be treated successfully with somatostatin analogues prior to surgical therapy of the pancreatic tumor. Sixteen months after extirpation of the primary tumor recurrent tumor growth was diagnosed; at this time the patient was clinically asymptomatic and had no abnormal laboratory test results. Liver metastases and local metastases were identified using somatostatin receptor scintigraphy. We report and discuss the use of somatostatin in the treatment of tumor-associated symptoms in endocrine tumors and the possibility of identifying endocrine tumors by means of somatostatin receptor scintigraphy.
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PMID:[Somatostatin in preoperative therapy and postoperative diagnosis of a patient with Verner Morrison syndrome]. 128 41

1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] was administered to female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. 1 alpha(OH)D3 suppressed the growth of the rat mammary tumors dose-dependently, and in the high dose groups treated with 0.5-1.0 micrograms/kg of 1 alpha(OH)D3, significant inhibition of tumor growth was observed. But daily oral administration of 1 alpha(OH)D3 for four consecutive weeks caused side effects such as hypercalcemia and weight loss. We compared 0.5 microgram/kg of 1 alpha(OH)D3 three times weekly with the same dose six times weekly to discover whether or not the side effects can be reduced by treatment schedule. Both groups showed a significant oncostatic effect, compared with the control group, while the side effects were relieved in the three times weekly group. Regarding estrogen receptors (ER) in the tumors, there was no significant difference among the groups. These results suggested that the antitumor effect of 1 alpha(OH)D3 on DMBA-induced mammary tumors was not related to ER status. Combined use of 1 alpha(OH)D3 with 5-fluorouracil (5-FU) or medroxyprogesterone acetate (MPA) was also examined. No significant augmentation of the antitumor effect was seen in the two combinations, although the combined therapy with MPA showed a significant inhibition of weight loss in the rats.
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PMID:1 alpha-hydroxyvitamin D3, hypercalcemia, and growth suppression of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors. 139 78

The calcium channel antagonists (CCAs) amlodipine, diltiazem, and verapamil inhibited HT-39 human breast cancer cell proliferation in a concentration-dependent manner. The apparent 50% inhibitory dose values were 1.5 microM for the dihydropyridine amlodipine, 5 microM for the benzothiazapine diltiazem, and 10 microM for the phenylalkylamine verapamil. Amlodipine treatment caused a rapid concentration-dependent decrease of intracellular calcium concentration in the HT-39 cell line. Addition of 1 microM amlodipine had no effect on intracellular calcium levels, 3 microM amlodipine lowered intracellular calcium levels in the HT-39 cells by 13.7%, and 10 microM amlodipine lowered intracellular calcium levels by 33.2%. Also, lowering medium calcium levels from 2.0 mM to 0.5 microM resulted in a rapid 41.3% decrease in intracellular calcium and a concomitant 60% inhibition of HT-39 cell DNA synthesis. When HT-39 cells were transplanted into athymic mice, marked hypercalcemia developed. Serum calcium levels from control mice were 8.3 +/- 0.6 mg/dl (mean +/- SE; n = 4); those from tumor-bearing mice were 11.3 +/- 0.08 mg/dl (mean +/- SE; n = 17). Blood calcium levels correlated directly with tumor size (r = 0.91, P less than 0.01). We examined the capacity of three CCAs to specifically inhibit HT-39 tumor growth in vivo. One week after inoculation of HT-39 cells, mice were acclimated to vehicle or 0.1 mg/day amlodipine, 1.0 mg/day diltiazem, or 1.0 mg/day verpamil, in their drinking water, for 7 days. Oral administration of the dihydropyridine amlodipine (0.35 mg/day) for 10 days inhibited HT-39 breast tumor growth by 83.5 +/- 20.1% (mean +/- SE). Oral administration of diltiazem (3.5 mg/day) inhibited HT-39 breast tumor growth rate by 46.5 +/- 6.6% over a 2-week measurement period, and verapamil (3.5 mg/day) inhibited tumor growth rate by 68.2 +/- 9.7% (mean +/- SE). The CCAs had no effect on mouse body weight or gross organ morphology at the concentrations used. Lack of depolarization-induced calcium fluxes in the HT-39 cell line suggests that these cells do not express voltage-operated calcium channels. Thus, our study correlates an effect of amlodipine to lower intracellular calcium levels, by a mechanism not known at present, with its effect to inhibit HT-39 cell proliferation. These findings are important since they demonstrate that amlodipine and other CCAs with known pharmacodynamics and side effects act to blunt breast tumor progression in vivo.
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PMID:Inhibition of cancer cell growth by calcium channel antagonists in the athymic mouse. 153 73

Transforming growth factor alpha (TGF-alpha) is a polypeptide regulator of cell growth produced by many malignant tumors. It stimulates osteoclastic resorption in bone organ culture and osteoclast-like cell formation in marrow culture. To determine whether tumor production of TGF-alpha can cause hypercalcemia in vivo, we used Chinese hamster ovarian (CHO) cells transfected with the human TGF-alpha gene (TCHO), which stably express and secrete TGF-alpha. We used nontransfected CHO cells as controls (CCHO). TCHO and CCHO were inoculated intramuscularly into one hindlimb of nude mice and grew as local solid tumors. After 4 weeks of TCHO tumor growth, plasma ionized calcium (Ca2+) increased to reach 1.48 +/- 0.03 mM (mean +/- SEM), whereas mice bearing similarly sized CCHO tumors and non-tumor-bearing mice (NTB) remained normocalcemic (normal range for Ca2+, 1.15-1.30 mM). Plasma TGF-alpha was undetectable by an ELIFA assay in all NTB mice, was markedly increased in all TCHO mice (5.75 +/- 0.78 ng/ml), and was slightly increased in CCHO mice (0.50 +/- 0.22 ng/ml). Quantitative bone histomorphometry showed a prominent increase in osteoclastic bone resorption in TCHO mice. These data suggest that TGF-alpha is a mediator of hypercalcemia and increased osteoclastic bone resorption in tumors that produce it in sufficient quantity.
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PMID:Expression of human transforming growth factor alpha by Chinese hamster ovarian tumors in nude mice causes hypercalcemia and increased osteoclastic bone resorption. 164 53

Recently, we have established a human squamous cell carcinoma of the maxilla (called MH-85) associated with hypercalcemia, leukocytosis, and cachexia in culture. MH-85 tumor cells caused the same paraneoplastic syndromes in tumor-bearing nude mice. We found that there was a sixfold increase in splenic size in MH-85 tumor-bearing mice. This increase paralleled tumor growth and was reversed by surgical removal of the tumor. Splenectomy in nude mice 1 wk before or 6 wk after tumor inoculation resulted in a decrease in tumor growth, and impairment of hypercalcemia, leukocytosis, and cachexia. In MH-85 tumor-bearing animals that had been pretreated by splenectomy, intravenous injection of fresh normal spleen cells caused an immediate reversal of leukocytosis, hypercalcemia, and cachexia. Since the presence of cachexia in both the patient and the mice carrying the tumor suggested tumor necrosis factor (TNF) may be overproduced, we injected polyclonal neutralizing antibodies raised against murine TNF into tumor-bearing mice. There was a rapid and reproducible decrease in blood ionized calcium, accompanied by suppression of osteoclast activity. No changes in blood ionized calcium were seen in mice injected with normal immune sera. In addition, there was an increase in body weight and decrease in white cell count. Plasma immunoreactive TNF was increased almost fourfold in tumor-bearing nude mice compared with control nude mice. Although TNF activity was undetectable in MH-85 culture supernatants, cells of the macrophage lineage, including spleen cells, released increased amounts of TNF when cultured with MH-85 tumor-conditioned media. These results suggest that splenic cytokines such as TNF may influence the development of the paraneoplastic syndromes of hypercalcemia, leukocytosis, and cachexia in these animals, as well as tumor growth. They also show that paraneoplastic syndromes may be due to factors produced by normal host cells stimulated by the presence of the tumor.
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PMID:Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice. 199 5

Increased levels of epidermal growth factor receptor (EGFR) have been shown on squamous cell carcinomas. Recently, we described a squamous cell carcinoma (MH-85) derived from the oral cavity which was associated with several paraneoplastic syndromes including hypercalcemia and cachexia. This tumor induced the same paraneoplastic syndromes in nude mice (BALB/c, nu/nu, male, 4-6 weeks old). Scatchard analysis revealed that there are two classes of EGFR in MH-85. The dissociation constant and number of binding sites for the high affinity receptors were 38 pM and 5 x 10(4)/cell, respectively, and 2.2 nM and 6 x 10(5) cell, respectively, for the low affinity receptors. Growth of MH-85 in culture was stimulated by epidermal growth factor (EGF) and inhibited by monoclonal antibody 108 to human EGFR, which recognizes the extracellular domain of the EGF receptor. Surgical removal of submandibular glands from male nude mice resulted in a dramatic decrease in plasma EGF levels and a significant reduction of tumor growth, hypercalcemia, and cachexia. When EGF (5 micrograms/mouse, every 2 days for 6 weeks, i.p.) was administered to these sialoadenectomized animals, tumor growth increased, with a parallel increase in hypercalcemia. When monoclonal antibody 108 (1 mg/mouse, i.p.) was given 1, 5, and 10 days after MH-85 tumor implantation, tumor formation was retarded, which resulted in delayed onset of hypercalcemia and cachexia. Moreover, when the antibody was injected 6 times in nude mice exhibiting large tumors and profound hypercalcemia and cachexia, there was a striking decrease in tumor growth, which was accompanied with a reversal of hypercalcemia and cachexia. These results indicate that growth of the human squamous cell carcinoma MH-85 is dependent on the EGFR pathway and that subsequent development of hypercalcemia and cachexia is dependent on tumor growth. They also suggest that agents which interfere with the EGFR pathway may have therapeutic potential as anticancer agents in some human tumors.
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PMID:Dependence of a human squamous carcinoma and associated paraneoplastic syndromes on the epidermal growth factor receptor pathway in nude mice. 201 5

It has long been known that complex interactions occur between tumors and normal host immune cells. The human melanoma cell line A375 has been used previously as an indicator cell for tumor cell cytotoxicity mediated by monocytes. During other studies on this tumor cell line, we noted that the conditioned media harvested from A375 cultures induced both the human monocytoid cell line U937 and human blood monocytes to release the cytokine tumor necrosis factor (TNF). We characterized this tumor factor which induced TNF release by monocytic cells. Purification was performed using ammonium sulfate precipitation, ion exchange (DEAE) chromatography, gel filtration, and reversed-phase high performance liquid chromatography. The factor copurified with granulocyte-macrophage colony-stimulating factor (GM-CSF). The purified material caused the release of TNF by U937 cells and stimulated formation of granulocyte-macrophage colonies in methyl cellulose. TNF release by U937 cells in response to A375-conditioned medium was inhibited by neutralizing antibodies to GM-CSF. The TNF-inducing activity in A375-conditioned medium was completely removed by an anti-GM-CSF affinity column. Western blotting using antibodies to GM-CSF confirmed a single Mr27,000 band in A375-conditioned medium. We found that recombinant human GM-CSF stimulated TNF production by the same cells as the tumor-conditioned medium. These data show that A375 human melanoma cells produce GM-CSF, which in turn causes TNF production by cells in the monocyte lineage. The combination of GM-CSF production by the tumor and TNF production by immune cells may influence not only tumor growth but also some of the paraneoplastic syndromes associated with malignancy such as hypercalcemia, cachexia and leukocytosis.
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PMID:Stimulation of tumor necrosis factor release from monocytic cells by the A375 human melanoma via granulocyte-macrophage colony-stimulating factor. 218 30

Male Copenhagen rats were inoculated with monodispersed R3327-MatLyLu prostate tumor cells via the tail vein under concomitant temporal occlusion of the inferior vena cava to develop an animal model for skeletal metastasis of prostate cancer. This procedure reproducibly resulted in metastatic tumor growth in the lumbar region of the vertebral column. Microscopically, tumor growth became visible in the fifth and sixth lumbar vertebrae within 4 days after inoculation. Clinical signs of nerve function disablement (hind leg paresis and paralysis) followed within 14 days of such a procedure. Cell culture technique confirmed the presence of a viable, proliferating tumor cell population within the spinal canal of the fifth and sixth lumbar vertebrae. Histologically, a clear response of osteoclastic and concomitant osteoblastic activities was observed in the lumbar spinal column. In the serum, a transient phase of hypercalcemia could be demonstrated. The development of skeletal metastases in these animals was not reflected by significant alteration in serum levels of acid phosphatase, prostatic-specific antigen, or osteocalcin. These observations support the concept of the vertebral venous plexus being involved in the dissemination of prostate tumor cells. The surgical procedures described permit experimental investigations of bone metastasis of prostatic cancer.
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PMID:Prostatic tumor (R3327) skeletal metastasis. 237 Nov 74


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