Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine stimulation of human umbilical vein endothelial cells (HUVE) induces surface expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin). We previously found that induction of adhesion molecule expression in HUVE is regulated, at least in part, by protein kinase C (PKC) activation, although this is not associated with the expected translocation of PKC from the cytosolic to the particulate fraction. We therefore investigated potential nuclear targets for PKC. Topoisomerase II is localized to the nuclear matrix and has been shown to be phosphorylated, both in vitro and in vivo, by PKC. In HUVE, the topoisomerase II selective inhibitors novobiocin, nalidixic acid, and etoposide prevented cytokine-induced VCAM-1 surface expression, but not E-selectin or ICAM-1 surface expression. Similarly, novobiocin and nalidixic acid reduced the accumulation of VCAM-1 mRNA in response to tumor necrosis factor-alpha treatment of HUVE. The inhibitory effect of the topoisomerase II inhibitors on VCAM-1 expression was not due to non-specific toxicity, as protein synthesis, measured by trichloroacetic acid precipitation of 35S-methionine labeled proteins, and transcription, determined by beta-actin mRNA levels, were not decreased. In contrast to the observed reduction of VCAM-1 mRNA accumulation and surface protein expression, inhibition of topoisomerase II activity enhanced E-selectin mRNA accumulation and surface protein expression in response to tumor necrosis factor-alpha stimulation of HUVE. This work demonstrates that topoisomerase II activity may differentially regulate the expression of adhesion molecules on HUVE.
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PMID:Inhibitors of topoisomerase II prevent cytokine-induced expression of vascular cell adhesion molecule-1, while augmenting the expression of endothelial leukocyte adhesion molecule-1 on human umbilical vein endothelial cells. 752 51

Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.
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PMID:A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis. 1115 22