Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemoprevention studies utilizing calcium have now progressed from basic measurements to clinical trials. Calcium's effects on epithelial cells have demonstrated decreased proliferation and induced cell differentiation with increasing levels of calcium in vitro, similar in vivo effects in rodent and human colon, and decreased carcinogen-induced colonic tumor formation in rodents. Current studies are attempting to inhibit colonic adenoma formation in human subjects. Most but not all epidemiologic studies also link increased dietary calcium with a decreased risk of colon cancer. In animal models, supplemental dietary calcium has decreased mammary epithelial cell hyperplasia and hyperproliferation and colonic cell hyperproliferation when the latter was induced by bile acids, fatty acids, and partial resection of the small intestine. Supplemental dietary calcium also decreased carcinogen-induced colonic tumors in several rodent models. In normal mice, and in mice carrying a targeted apc gene mutation, we recently increased colonic polypoid hyperplasias by a Western-style diet containing low calcium and vitamin D. In human subjects at increased risk for colon cancer, oral calcium supplementation significantly reduced colonic epithelial cell proliferation in most of the studies, including four randomized clinical trials. These studies have now progressed to short-term human clinical trials, including trials that measure the regrowth of transformed adenoma cells. Short-term adenoma-regrowth clinical trials, however, are limited in their ability to measure whether chemopreventive agents inhibit early genotoxic events, abnormal cellular metabolic activities involved in tumor promotion over many years, or the progression of adenoma cells to carcinoma.
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PMID:Calcium and the prevention of colon cancer. 853 12

There is increasing evidence that growth and differentiation of prostatic carcinoma cells may be modulated not only by androgens and growth factors but also by vitamin D, retinoids, and phenylacetate (PA). The latter agonists may have a role in the prevention and therapy of prostate cancer but their exact therapeutic potential remains unclear. Since both retinoids and vitamin D act via nuclear receptors, the same way androgens do, we studied the interactions of these compounds with androgen-induced proliferation and differentiation using LNCaP cells as a model of androgen-responsive tumor cells. PA was included because of its suspected different mode of action [H3]-thymidine incorporation was used as a measure of proliferative activity, secretion of prostate-specific antigen (PSA) as a measure of differentiated function. The present data show that 1alpha,25-dihydroxycholecalciferol (VD3), all-trans retinoic acid (atRA), 9-cis retinoic acid (9cRA), and PA stimulated LNCaP cell-differentiated function in the presence or absence of androgens. The effects on cell growth were more complicated. In the absence of androgens growth stimulatory effects were observed for the retinoids and under some conditions for VD3. These effects were limited, however, and tended to be more pronounced at low cell densities. In the presence of androgens nearly exclusively growth inhibitory effects were observed. On a molar basis VD3 was the most effective antiproliferative agonist (ED50 = 10(-9) M). It completely neutralized the stimulatory effects of androgens. Growth inhibition was not due to a decrease in the concentration of androgen receptor: whereas atRA, 9cRA, and PA did not alter androgen receptor levels, VD3 provoked a twofold increase. Neither in the presence nor in the absence of androgens did we observe any cooperativity in the growth stimulatory or inhibitory effects of VD3, atRA, or 9cRA. To test whether treatment with any of the studied agonists resulted in a phenotypic reversion and sustained growth arrest, LNCaP cells were pretreated with VD3, atRA, 9cRA, or PA for 6-12 days and reseeded at equal densities as untreated cells. In all cases tested [3H]-thymidine incorporation was restored within 6 days suggesting that none of these compounds caused irreversible growth inhibition.
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PMID:Control of LNCaP proliferation and differentiation: actions and interactions of androgens, 1alpha,25-dihydroxycholecalciferol, all-trans retinoic acid, 9-cis retinoic acid, and phenylacetate. 862 21

A 62-year-old male was admitted because of numbness and twitching of both hands. Hypocalcemia with positive Trousseau's sign was noted. Chest X-ray and computed tomography (CT) showed an anterior mediastinal mass. Skull X-ray and whole body bone scan could not rule out bony metastasis to the left parietal bone, causing an anterior mediastinal tumor with bony metastasis to be suspected initially. Median sternotomy and extended thymectomy were done, and Stage II thymoma with negative calcitonin staining was noted. However, hypocalcemia persisted after thymectomy and the results of pre-operative and post-operative intact-parathyroid hormone (intact-PTH) were less than the detection limit (<13.3 pg/ml). Tumor markers and gallium tumor scan were all negative. Brain CT disclosed calcification over the bilateral basal ganglia and bilateral dentate nuclei of the cerebellum; the supposed metastatic osteolytic lesions of parietal bone were considered to result from pacchionion arachnoid granulation tissues. The coexistence of late-onset idiopathic hypoparathyroidism and thymoma has not been reported before. Long-term replacement therapy with vitamin D and calcium was necessary for this case.
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PMID:Late-onset idiopathic hypoparathyroidism with thymoma: a case report. 863 30

Epidemiological data suggest the protective role of vitamin D against the development of colorectal carcinoma in man. This could be due to the anti-mitogenic effect of the steroid hormone on human colon carcinoma cells which is mediated by a specific nuclear vitamin D receptor (VDR). Western blot analysis showed that VDR expression increases during the transition from normal mucosa to polyps and later to pT3 tumors. In later stages, however, VDR is dramatically reduced. Cytokeratin 20, which was monitored as a differentiation marker, decreases in parallel with advancing proliferation and disappears from "normal" mucosa adjacent to later stage carcinoma. Interestingly, VDR density was conspicuously higher in all tumors tested when compared to adjacent "normal" tissue. This suggest that, up to a certain degree of dedifferentiation, malignant colonocytes can upregulate the VDR, probably as a counteractive measure in response to tumor cell growth, but that this ability is finally lost in highly undifferentiated carcinoma cells.
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PMID:Vitamin D receptor and cytokeratin expression may be progression indicators in human colon cancer. 869 65

The 65-kDa oncofetal protein (p65), a potential tumor marker discovered and characterized in our laboratory, is highly conserved in different species. Its amino acid composition, peptide map, and N-terminal and internal peptide sequences are very similar if not identical in humans and rodents. We have now identified the p65 gene as a novel member of the superfamily of genes that encode nuclear receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid, and thyroid hormones. these receptors are composed of several domains important in hormone binding, DNA binding, dimerization, and transcription activation. The human p65 cDNA was partially cloned, revealing at its C-terminal end regulatory elements typical of this superfamily of genes. The DNA-binding domain coincides with the cysteine-rich region encompassing the two conserved zinc fingers. In addition, the domain homologous to the receptor dimerization site was found close to the C-terminal end. The p65 protein is highly homologous to estrogen receptor in its DNA-binding domain but not in other regions of the sequence, indicating that p65 is a new receptor with an as yet unknown ligand. In addition, we have identified in the cloned p65 cDNA fragment sequences encoding two peptides, obtained by CNBr cleavage, whose amino acid sequences were previously established.
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PMID:The oncofetal protein p65: a new member of the steroid/thyroid receptor superfamily. 870 45

Renal cell carcinoma is a chemotherapy-resistant tumor which is relatively responsive to immunotherapy. Immunotherapeutic regimes employ interferons or interleukin 2 with or without lymphokine-activated killer cells. Secondary cytokines, induced by interleukin 2 or interferon, may have an important impact on their anti-neoplastic activity. Notable among them is tumor necrosis factor (TNF alpha). We assessed the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the susceptibility of the human renal cell carcinoma cell line SK-RC-29 to the cytotoxic and cytostatic actions of TNF alpha, interferon alpha and lymphokine-activated killer cells. Using uptake of the vital dye neutral red as an indicator of viable cell number, we found that addition of 1,25(OH)2D3 (100 nM) to TNF alpha (30 ng/ml)-treated cultures resulted in a 2.6 +/- 0.2-fold (mean +/- S.E.) increase in the cytotoxic effect of the cytokine. The potentiating effect of 1,25(OH)2D3 was dose-dependent, and significant at concentrations equal to or higher than 10 nM. Another dihydroxylated vitamin D metabolite, 24,25(OH)2D3, had no effect on TNF alpha action. The cytotoxic effect of TNF alpha increased whereas the potentiation by 1,25(OH)2D3 decreased with cell density in culture. 1,25(OH)2D3, in contrast to its potentiating effect on TNF alpha action, did not modulate the cytostatic effect of interferon alpha or the susceptibility of SK-RC-29 to killing by lymphokine-activated killer cells. The findings reported here may explain some of the in vivo anti-tumor activity of 1,25(OH)2D3 and provide a rationale for the employment of active vitamin D analogs during immune anti-cancer therapy.
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PMID:1,25-dihydroxyvitamin D3 increases the sensitivity of human renal carcinoma cells to tumor necrosis factor alpha but not to interferon alpha or lymphokine-activated killer cells. 870 45

The incidence of hypercalcaemia and its association with humoral mechanisms involving parathyroid hormone-related protein (PTHrP), parathyroid hormone (PTH), or 1.25(OH)2 vitamin D were assessed in a prospective study of patients admitted to a clinical haematology unit. Hypercalcaemia was detected in 18/165 patients, and was due to primary hyperparathyroidism in 3/17 patients in whom results of humoral mediator assessments were obtained. In the other patients, hypercalcaemia was associated in nine instances with myeloma, in five with B-cell non-Hodgkin's lymphoma (NHL), and in one with myeloid neoplasia. No evidence was obtained of a humoral mechanism involving 1.25(OH)2 vitamin D, but elevated circulating levels of PTHrP, comparable with those in humoral hypercalcaemia of malignancy, were present in 2/4 patients with NHL, and in 3/9 with myeloma. The relationship between presence or absence of elevated circulating PTHrP, and presence or absence of hypercalcaemia during the course of treatment, indicated PTHrP was involved in the production of hypercalcaemia. Such an association raises the possibility that PTHrP released by neoplastic cells in these disorders acts in a paracrine manner to produce local bone resorption, and when produced in greater amounts causes elevated circulating levels which make an additional humorally-mediated contribution to the development of hypercalcaemia.
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PMID:Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy. 913 72

The effects of tumor-conditioned media (TCM) derived from cultured cells from an oncogenic hypophosphatemic osteomalacia (OHO) tumor on transformed human kidney cells were investigated. Dose-dependent cell detachment and aggregation occurred in kidney cells cultured in serum-free medium supplemented with TCM, but not in skin fibroblast controls, or in kidney cells cultured in the presence of serum. Kidney cells exposed to TCM in the presence of serum (0.5%) had reduced Na(+)-dependent phosphate cotransport (36%, p < 0.04) and increased 1alpha-hydroxylase activity (48%, p < 0.05). In contrast, TCM had no significant effect on Na(+)-dependent alpha-methyl-glucose transport. To investigate these effects further, serum from an OHO patient, before and after tumor resection, was used to raise polyclonal antiserum to tumor-derived products (preoperative and postoperative antiserum, respectively). Changes in Na(+)-dependent phosphate cotransport and vitamin D metabolism induced by TCM were prevented by the addition of preoperative but not postoperative antisera. Furthermore, Western analysis revealed the presence of two proteins (56-58 kDa) in TCM media screened with preoperative antisera. These proteins were not detected by postoperative antisera and were absent in skin fibroblast control media. Direct inhibition of Na(+)-dependent phosphate cotransport by phosphonoformic acid did not affect 1,25-dihydroxy vitamin D(3) synthesis. These studies provide support for a circulating component affecting phosphate handling and vitamin D metabolism in OHO.
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PMID:Candidate 56 and 58 kDa protein(s) responsible for mediating the renal defects in oncogenic hypophosphatemic osteomalacia. 883 10

In addition to a role in calcium and phosphate homeostasis other vitamin D receptor (VDR) mediated effects have been discovered during the past few years for the biologically active metabolite of vitamin D, 1,25(OH)2D3. An antiproliferative, differentiation-inducing effect on non-malignant and neoplastic cells of different origin has now been described. We examined the influence of 1,25(OH)2D3 on human squamous cell carcinomas of the head and neck (SCCHN). A differentiated (JP-PA) and undifferentiated (LF-FR) SCCHN line was studied with respect to proliferative capacity (using [3H]-thymidine uptake and cell number) and cell cycle distribution as determined by flow cytometry (FACS). Both cell lines were positive for VDR, which was found to be increased after the addition of 10(-7) M 1,25(OH)2D3, as shown by FACS analyses. The administration of 1,25(OH)2D3 at a concentration between 10(-7) M and 10(-10) M caused a dose-dependent moderate growth inhibition, as reflected by down-regulation of DNA synthesis (reduced [3H]-thymidine uptake) and a decrease in cell numbers. The JP-PA cell line showed a significant growth reduction for both concentrations tested, whereas for LF-FR a significant inhibition was detected only for 10(-7) M. The addition of 10(-7) M 1,25(OH)2D3 caused a blockade in the transition of cells from G1 to S phase in both cell lines, with a significant accumulation of cells in the G0/G1 phase. Our results demonstrate a receptor-mediated, dose-dependent inhibition of neoplastic growth by 1,25(OH)2D3 in human SCCHN lines.
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PMID:Antiproliferative effects of the biologically active metabolite of vitamin D3 (1,25 [OH]2 D3) on head and neck squamous cell carcinoma cell lines. 885 58

Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl- 5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z ),7(E) ,10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2(D)3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2(D)3 or EB1089 (1 x 10(-8) M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10(-8) M 1,25(OH)2(D)3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. Taken together our findings indicate that vitamin D derivatives may play a role in regulating the expression of genes and protein products implicated in apoptosis.
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PMID:Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. 890 23


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