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

Human endothelial cells were transiently transfected with E-Selectin which enabled us to study tumor cell/endothelial interactions following engagement of E-Selectin without the added complications of metabolic stimulation, morphological changes, and/or up regulation of other adhesion molecules due to cytokine induction. Similar results were received from in vitro binding studies and FACS analyses on both Tumor Necrosis Factor-alpha activated and E-Selectin transfected endothelial cells. These data suggest that this methodology is appropriate for dissecting the individual activities of E-selectin while minimizing the participation of other adhesion molecules, thereby allowing us to develop a better understanding of the role of E-Selectin and endothelia in metastatic disease.
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PMID:Cancer cell binding to E-selectin transfected human endothelia. 128 Apr 20

Cell adhesion molecules are pivotal to the development and maintenance of tissue structure in metazoan organisms. In mammals, several families of proteins are involved in cell-cell and cell-matrix adhesion. The cadherins are homophilic, primary CAMs, involved in the establishment of boundaries between cell collectives early in embryogenesis. The Ig gene superfamily have diversified widely, with homophilic and heterophilic CAMs and antigen recognition molecules amongst the members. The Integrin family play an important role in binding to extracellular matrix, as well as counter-receptors on the surface of other cells. The Selectin family and HCAM are carbohydrate-binding proteins, and play a prominent role in the circulation of lymphocytes and neoplastic cells. CAMs are fundamental to development of tissue structure in metazoan organisms. Cellular differentiation dictates adherence to a specific microenvironment, through the pattern of surface CAM expression. Conversely, CAM binding can affect gene expression within the cell itself. Cell differentiation and cell adhesion are interdependent processes. In the adult, CAM are crucial to tissue maintenance. Cells frequently change their adhesive properties in response to physiological or pathological processes. The integrity of the vascular system is maintained by circulating platelets which are capable of rapid upregulation of cell adhesion and profound changes in metabolism, on contact with subendothelial matrix. Both endothelial cells and neutrophils undergo changes in CAM expression in response to inflammatory mediators, permitting rapid and appropriate recruitment of phagocytes to damaged tissue. Tissue repair is dependent on phenotypic changes in normally static cells, allowing increased motility and replication. The immune system requires constitutive cells to undergo multiple complex adhesion and detachment events over short periods of time, and is capable of discriminating normal self from aberrant-self or non-self, through antigen specific recognition and adhesion molecules. The pathophysiology of processes such as infection and neoplasia are profoundly affected by cellular CAM expression. CAMs and related molecules are fundamental to the development, maintenance and surveillance of tissue structure.
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PMID:Cell adhesion molecules: a unifying approach to topographic biology. 142 Jul 29

Synchronization of mammalian cells is essential for investigations involving cell proliferation. A simple method for obtaining synchrony in all types of cells, through several cycles and with minimal overall metabolic perturbations, has not yet been available. We describe a procedure for synchronizing normal as well as tumor cells reversibly in the G1 phase of the cell cycle using Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. This method of synchronization was successful with all cell lines tested, including normal and tumor cells of mouse, hamster, and human origins. For example, when MCF-7 human breast cancer cells were synchronized with Lovastatin and released by the addition of mevalonic acid (the product of the reaction catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase), 3 phases of accelerated thymidine incorporation into DNA corresponding to 3 S phases of the cell cycle occurred during a 90-h period of cell replication. Thymidine incorporation was decreased to less than or equal to 4% during the initial lag of 18 h before the first S phase, and maximum incorporation was then achieved after only 6 h. The antibody Ki-67, which detects a nuclear antigen associated with proliferation, was present in cells arrested with Lovastatin. This fact, together with the lack of thymidine incorporation during the initial lag time, indicates that the cells were arrested in the G1 and not in the G0 phase of the cell cycle. Furthermore, in synchronized tumor-derived human breast epithelial cells, histone H4 RNA was low after Lovastatin release and increased with the onset of DNA synthesis. Concomitant synthesis of DNA and histone H4 RNA expression could be observed for 2 cycles. Minimal perturbations of general metabolic functions occurred since the rate of RNA, protein, and initial DNA synthesis were unaffected by Lovastatin, as evidenced by [3H]uridine, [3H]leucine, and initial [3H]thymidine incorporation. Finally, while the Lovastatin-induced synchronization was overcome by mevalonic acid, addition of squalene or cholesterol-ethanol had no such effect. Thus, Lovastatin appears to prevent formation of an early intermediate in the cholesterol pathway that is essential for progression of cells through early G1 phase.
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PMID:Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. 171 13

Studies were conducted to explore the effects of mevinolin, a competitive inhibitor of HMG CoA reductase, on the growth and morphology of normal and transformed murine fibroblasts. Mevinolin is known to block DNA synthesis and cell growth in a number of kinds of non-transformed cells. Eight cell lines were studied, including two normal fibroblast cell lines (C3H 10T 1/2 and NIH 3T3) and derivatives of these cell lines transformed by chemical carcinogens, X-irradiation or the H-ras oncogene. All of the eight cell lines displayed appreciable growth inhibition by 5 microM mevinolin and marked inhibition by 30 microM mevinolin. Mevinolin also induced a marked rounding in the morphology of all of the cell lines. These effects of mevinolin on cell growth and morphology were blocked or reversed by the addition of mevalonic acid. Thus, both normal and transformed cells require mevalonate, or an as yet unidentified metabolite of mevalonate for their growth, even though some transformed cells have become relatively autonomous of other growth factors. Whereas mevinolin acted primarily as a cytostatic agent for most of the cell lines studied, with the transformed cell line MCA/10T 1/2, which ordinarily grows to a very high cell density, prolonged exposure to mevinolin caused marked cytotoxicity. Thus mevinolin might be useful as an anti-tumor agent for specific tumors.
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PMID:Effects of mevinolin and mevalonate on cell growth in several transformed cell lines. 363 76

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, an essential precursor for isoprenoid compounds in mammalian cells. Recent studies have shown that mevinolin, a competitive inhibitor of the reductase, inhibits cell proliferation and induces differentiation in cultured C1300 (Neuro-2A) murine neuroblastoma cells. We now report that mevinolin can inhibit neuroblastoma growth in vivo. The specific activity of HMG-CoA reductase in subcutaneous neuroblastomas increased more than 20-fold between the fifth and eighth days after tumor inoculation, and remained elevated for the remainder of the tumor lifetime in mice. The increase in reductase activity was correlated with a marked increase in tumor DNA content and exponential increase in tumor weight. Using an in vitro assay to monitor the ability of mouse serum to suppress sterol synthesis, we determined that mevinolin was inactivated or cleared from the circulation within 3-6 h after a single subcutaneous injection. However, by using subcutaneous osmotic pumps to deliver a constant infusion of mevinolin, we were able to maintain adequate blood levels of the drug for 7 d. Mevinolin (5 mg/kg per h) suppressed tumor growth (wet weight) significantly when treatment was carried out between day 1 and day 8 or between day 5 and day 12 after tumor inoculation. Histopathological examination of tumors from mevinolin-treated mice revealed few or no mitotic figures and marked cellular degeneration. Measurements of incorporation of (3H)acetate into neuroblastoma sterols and ubiquinones 24 h after implantation of osmotic pumps showed that mevinolin produced a marked inhibition of isoprenoid synthesis in the tumors in vivo. The data suggest that, in addition to their demonstrated utility as cholesterol-lowering drugs, competitive inhibitors of HMG-CoA reductase may have considerable potential as novel antineoplastic agents.
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PMID:Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. 385 Sep 4

We assessed the antiproliferative effect of tumor necrosis factor alpha (TNF-alpha) and lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, alone and in combination, on two murine tumor cell lines. Recombinant TNF-alpha inhibited proliferation of murine MmB16 melanoma cells in a concentration-dependent fashion but stimulated growth of murine L1210 leukemia cells at 0.1 ng/ml concentration. Lovastatin inhibited proliferation both of murine MmB16 melanoma cells and of murine L1210 leukemia cells in a concentration-dependent fashion. In combination with tumor necrosis factor alpha lovastatin inhibited synergistically growth of both cell lines as assessed by isobologram analysis. Our data show that lovastatin, a cholesterol synthesis inhibitor, introduced to the clinic to treat hypercholesterolemia, used either as a single or in combination with TNF-alpha inhibits growth of MmB16 melanoma and L1210 leukemia cells.
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PMID:Synergistic antiproliferative activity of tumor necrosis factor alpha (TNF-alpha) and lovastatin. 748 65

Lovastatin, the drug introduced recently to treat hypercholesterolemia and displaying antiproliferative activity against tumor cells in vitro, was used for the local therapy of MmB16 melanoma in mice. Female B6D2F1 mice were injected with 1 x 10(6) of MmB16 melanoma cells into the right hind limb. On the 7th day after the injection of tumor cells mice were divided into four groups and were injected with: (a) saline solution (control group), (b) TNF-alpha alone, (c) lovastatin alone, and (d) a combination of TNF-alpha and lovastatin. Statistically significant inhibition of tumor growth was observed in mice treated with both TNF (5 micrograms/day) and lovastatin (200 micrograms/day). We also observed the prolongation of survival of tumor-bearing mice after combined therapy with both TNF-alpha (5 micrograms/day) and lovastatin (1 mg/day) in comparison to all other groups. Our data suggest that lovastatin may synergistically potentiate the antitumor activity of TNF-alpha.
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PMID:Synergistic antitumor activity of tumor necrosis factor-alpha and lovastatin against MmB16 melanoma in mice. 761 79

The ras oncogene family has been implicated in tumor resistance to ionizing radiotherapy. Using the gene-transfer model, we show here that ras expression may also affect cell responses to chemical inducers of oxidative stress. Studies involving human osteosarcoma subclones, which vary in their levels of EJras expression, revealed a tight correlation between the amounts of ras-encoded mRNA and p21 produced, and the degree of resistance to doxorubicin or hydrogen peroxide. Differences in response could not be explained by increased activity of anti-oxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione S-transferase or glutathione peroxidase. Moreover, there were no significant differences in glutathione levels. Although the resistant cells had elevated levels of gamma-glutamyl-transferase mRNA indicative of an increased rate of glutathione turnover, this elevation was not specific for ras-transfected cell lines. Lovastatin, an inhibitor of protein isoprenylation critical for p21ras membrane association and function, restored the sensitivity of ras-transformed cells to doxorubicin and hydrogen peroxide. The data indicate that pharmacological agents affecting ras expression may enhance responses of some human tumors to free-radical-mediated chemotherapies.
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PMID:Tumor resistance to oxidative stress: association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21ras isoprenylation. 782 24

Lovastatin (LST) is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme that regulates the biosynthesis of cholesterol. This drug is used clinically to treat patients with hypercholesterolemia. Numerous studies have also suggested an important, if not essential, role of the cholesterol biosynthetic pathway to cell growth and proliferation. In fact, recent studies demonstrating the inhibitory effects of LST on various tumor cells have drawn much attention. We now describe a novel action of LST that inhibited experimental lung metastasis of the highly metastatic B16F10 mouse melanoma in nude mice. Further, when used in in vitro studies, LST pretreatment of B16F10 cells resulted in inhibition of attachment, motility, and invasion, which are key steps in the dynamic sequence of events that comprise the metastatic cascade. Our studies also suggested that the antimetastatic effect of LST on B16F10 cells is probably not mediated by a growth inhibitory action. We submit that these observations identify an antimetastatic agent with potentially useful clinical application.
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PMID:Metastasis of B16F10 mouse melanoma inhibited by lovastatin, an inhibitor of cholesterol biosynthesis. 786 Feb 24

Anutritive isoprenoid constituents of fruits, vegetables, cereal grains and essential oils exhibit a spectrum of anticarcinogenic activities. The induction of hepatic Phase II detoxifying activities by dietary isoprenoids appears to underlie their blocking action. The second anticarcinogenic action of the dietary isoprenoids, suppression of the growth of chemically initiated and transplanted tumors is, we suggest, secondary to the inhibition of mevalonate pathway activities. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity, depletes cells of the intermediate products of the pathway that are required for the posttranslational modification of proteins, a process giving the proteins lipophilic anchors that bind to membranes. As a consequence, nuclear lamins and ras oncoproteins remain in nascent states, and cells do not proliferate. gamma-Tocotrienol, perillyl alcohol, geraniol and d-limonene suppress hepatic HMG-CoA reductase activity, a rate-limiting step in cholesterol synthesis, and modestly lower serum-cholesterol levels of animals. These isoprenoids also suppress tumor growth. The HMG-CoA reductase of neoplastic tissues differs from that of sterologenic tissues in being markedly resistant to sterol feedback inhibition. Our review suggests that the mevalonate pathway of tumor tissues is uniquely sensitive to the inhibitory actions of the dietary isoprenoids.
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PMID:The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. 816 51


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