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

---

Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of tumor necrosis factor (TNF)-induced cytotoxicity has been investigated using two clonal variants of the ME-180 human cervical carcinoma cell line. The clonal lines were characterized with respect to their expression of TNF receptors, kinetics of cell death, and their ability to communicate intercellularly through gap junctions. The ME-180.4 and ME-180.8 clones were identified by their relative sensitivity to TNF induced lysis in a 24-h assay. The dose of TNF required to kill 50% of the target cells was 60 pM for the sensitive ME-180.4 and 2.5 nM for the ME-180.8. However, when assay times were extended, the dose response for both clones was the same, indicating that a difference in the kinetics of cell death and not absolute TNF sensitivity existed between the ME-180.4 and ME-180.8 clones. Both clones were gap junction deficient as judged by their inability to transfer Lucifer yellow or 6-carboxyfluorescein, a characteristic phenotype of cells sensitive to cytotoxicity by TNF. The level of surface receptor expressed on these clones was nearly identical with a Kd = 0.3 nM and 5,000 binding sites per cell. Measurement of the kinetics of cell death revealed that the time between the addition of TNF and the onset of observed cell death (induction phase) was much shorter for the ME-180.4 (32-55 h) than for the resistant ME-180.8 (55-80 h). Mitomycin C, a DNA alkylating agent, significantly reduced the length of the induction phase for both clones, although the kinetic difference between the clones remained unchanged. Two epipodophyllotoxins, VP-16 and VM-26, which specifically inhibit the rejoining activity of DNA topoisomerase II, showed a 10-100-fold synergistic effect when combined with TNF as shown by isobologram analysis. VM-26 when added to the resistant ME-180.8 clones decreased the length of induction phase and abolished the kinetic difference observed with the ME-180.4 clone. These results indicate that the variance in the TNF response of these two clones was closely associated with DNA topoisomerase II, and suggest that this enzyme may play an important role in TNF mediated cytotoxicity.
...
PMID:Cytotoxicity mediated by tumor necrosis factor in variant subclones of the ME-180 cervical carcinoma line: modulation by specific inhibitors of DNA topoisomerase II. 254 Nov 44

Recombinant human tumor necrosis factor (rTNF) is a macrophage secretory protein with antitumor activity. The murine bladder tumor cell line MBT-2 was used to evaluate the in vitro and in vivo antitumor effects of rTNF in combination with chemotherapeutic drugs targeted at DNA topoisomerase II. These drugs, such as adriamycin and etoposide (VP 16), are in widespread use in the treatment of human cancer. The rTNF significantly enhanced the cytotoxic efficacy of the topoisomerase-targeted drugs actinomycin D, adriamycin, etoposide (VP 16) and teniposide (VM 26) against MBT-2 cells in vitro. The rTNF alone had no effect upon the cells in the same assay. When examined in vivo using MBT-2 tumor-bearing C3H/HeJ mice, these same antitumor relationships were seen. The addition of rTNF to actinomycin D or VP 16 resulted in a significant reduction in tumor volume at 20 days compared to untreated animals. Actinomycin D, VP 16 or rTNF treatment alone had no significant effect on 20 day tumor volume. The data provide a reasonable basis for the addition of rTNF to experimental protocols for the treatment of human bladder cancer using topoisomerase-targeted drugs such as adriamycin both intravesically and systemically. These observations may also be relevant to other human cancers currently treated with these drugs.
...
PMID:Tumor necrosis factor enhances the in vitro and in vivo efficacy of chemotherapeutic drugs targeted at DNA topoisomerase II in the treatment of murine bladder cancer. 303 27

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.
...
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

The combination of cytokines and cytotoxic drugs offers a new approach to increase the therapeutic index in the treatment of neoplastic diseases. There is no consensus on optimal strategies for combining these agents so far. The molecular mechanisms underlying the interaction, however, should be defined in order to design clinical trials based on preclinical rationales. The broad spectrum of cytotoxic drugs whose activity can be enhanced by cytokines argues for multiple levels of drug interaction in vitro: alteration in the cellular drug uptake, modulation of drug target enzymes, and changes in metabolism or disposition of a drug. In vivo interaction between cytokines and cytotoxic agents involves an additional layer of complexity because of the effects of cytokines on the host immune system and on drug-metabolizing enzymes. A major mechanism involved in the synergistic interaction of interferon (IFN) and 5-fluorouracil (5-FU) seems to be the increase of active 5-FU metabolites by IFN. Moreover, IFN can reverse resistance against 5-FU by inhibiting the overexpression of thymidylate synthase. The absence of cytokinetic effects of IFN and FU argues against the recruitment of Gs cells into the cell cycle. Topoisomerase has emerged as a critical intracellular target of cytotoxic drugs. There is convincing evidence that the synergy between tumor necrosis factor (TNF) and topoisomerase-targeted intercalative (Adriamycin, doxorubicin hydrochloride; m-AMSA, amsacrine; mitoxantrone) and nonintercalative (VM-16, etoposide; VM-26, teniposide) drugs is related to a rapid increase in specific activity of topoisomerase I and II, resulting in enhanced DNA strand breaks and cleavage complex. Furthermore, sensitivity to topoisomerase II targeted drugs can be enhanced by granulocyte colony-stimulating factor (G-CSF) through elevated enzyme activity in tumor cell response to G-CSF. The synergistic interaction between cytokines and cytotoxic agents seems to be sequence dependent. It has recently been demonstrated that newly synthesized metal compounds and IFN are synergistic only after preincubation with cytokines. Cytokines can modulate expression of adhesion receptors on tumor cell lines, thereby influencing their metastatic potential. A considerable number of phase II trials with combination of cytokines and cytotoxic drugs based on these mechanisms have demonstrated promising response rates and tolerable toxicity. Phase III trials are currently in progress to identify enhanced activity combining cytokines and cytotoxic drugs in the treatment of malignancies.
...
PMID:Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. 759 4

It has been shown recently that apoptotic degradation of genomic DNA in mammalian cells starts by excision of large DNA fragments ranging in size from 50 kilobases to more than 300 kilobases. Although it was suggested that the above fragments could represent chromosomal DNA loops, the supposition was not supported by direct experimental evidence. In present work, we have studied the specificity of nucleolar and euchromatic gene long-range fragmentation in mouse and human cells triggered to undergo apoptosis either by tumor necrosis factor or by serum deprivation. Separation of the excised large DNA fragments by pulsed field gel electrophoresis followed by Southern analysis has demonstrated that in all cases studied the above fragmentation proceeds in a specific way. Furthermore, the patterns of DNA long-range fragmentation in the cells undergoing apoptosis were indistinguishable from the patterns of DNA cleavage into chromosomal loops by the high salt-insoluble topoisomerase II of the nuclear matrix. These results suggest the conclusion that apoptotic degradation of chromosomal DNA starts by excision of DNA loops and their oligomers.
...
PMID:Large-scale fragmentation of mammalian DNA in the course of apoptosis proceeds via excision of chromosomal DNA loops and their oligomers. 765 90

In preclinical studies, synergy was observed between tumor necrosis factor-alpha (TNF-alpha) and agents that interact with DNA topoisomerase II, such as actinomycin D (Act D). Based upon this, a Phase I study was conducted in pediatric patients utilizing an escalating dose of recombinant TNF (rTNF) in combination with a fixed dose of Act D. Act D (15 micrograms/kg/day) was administered daily by intravenous push immediately followed by intravenous rTNF daily for 5 consecutive days. Thirty-three patients with refractory malignancies were entered in the study, of whom 28 patients could be evaluated for toxicity. Malignancies included sarcomas (16), Wilms' tumor (6), leukemias (3), and others (3). The starting dose for rTNF was 40 micrograms/m2/day x 5 and was escalated in subsequent patient groups until nonhematopoietic, dose-limiting toxicity occurred. At 240 micrograms/m2/day of rTNF, three of six patients experienced grade 4 toxicity consisting of hypotension, hemorrhagic gastritis, and renal and liver biochemical abnormalities. Evidence of antitumor response was observed in two patients: one with metastatic Ewing's sarcoma and one with Wilms' tumor. We conclude that the maximum tolerated dose of rTNF when combined with Act D is between 200 and 220 micrograms/m2/day x 5 for pediatric patients.
...
PMID:Phase I study of tumor necrosis factor-alpha and actinomycin D in pediatric patients with cancer: a Children's Cancer Group study. 780 27

A number of chemotherapeutic agents which inhibit the DNA topoisomerases markedly potentiate cell death mediated by tumor necrosis factor, suggesting a role for these enzymes in the TNF cytotoxic mechanism. To investigate this possibility, topoisomerase I and II activities were assayed following TNF addition to murine L929 cells. Topoisomerase I and II activities increased within 15 min of TNF addition and returned to baseline levels within 1 and 2 hr, respectively. The increases in both topoisomerase activities were blocked by H-7 (but not H-8) and similar increases were seen following PMA addition. However, concentrations of H-7 which blocked the increased topoisomerase activities had no effect on TNF cytotoxicity nor on the enhancement of TNF cytotoxicity by topoisomerase inhibitors. Thus, in these cells topoisomerase activities are directly modified by TNF during the initial phases of a cytotoxic response. However, neither TNF cytotoxicity nor the enhancement of TNF cytotoxicity by topoisomerase inhibitors appears to require the TNF-mediated increases in topoisomerase activities.
...
PMID:Modulation of topoisomerase activities by tumor necrosis factor. 784 91

Human monocytic leukemia U937 cells underwent apoptosis when the cells were treated with a variety of antitumor drugs. We isolated and characterized a mutant, UK711, that was resistant to apoptosis induced by antitumor agents. When U937 cells were treated with etoposide (VP-16), an inhibitor of DNA topoisomerase II, apoptosis occurred in a large number of cells, and flow-cytometric analysis revealed that the majority of cells in S phase underwent apoptosis within 2 h of the end of treatment. Such treatment, however, induced apoptosis in only a few UK711 cells. The levels of protein-DNA covalent links and DNA double-strand breaks caused by VP-16 were similar in both cell lines, indicating that the initial DNA damage caused by VP-16 were comparable, whereas the following cellular responses that resulted in apoptosis differed between these cell lines. UK711 cells also showed resistance to apoptosis induced by such antitumor agents as 1-(beta-D-arabinofuranosyl) cytosine (Ara-C), adriamycin, mitomycin C, camptothecin, and by cytotoxic stimuli such as staurosporine, cycloheximide, and uv irradiation. UK711 cells, however, were sensitive to apoptosis induced by tumor necrosis factor (TNF), as were U937 cells. In accordance with resistance to apoptosis induced by antitumor agents, UK711 cells showed significant actual drug resistance to these antitumor agents. The present results indicate that UK711 cells acquired resistance to apoptosis induced by a variety of cytotoxic stimuli resulting in actual anticancer drug resistance. This cell line may be useful in studying the mechanism of apoptosis induced by cytotoxic agents.
...
PMID:Resistance to antitumor agent-induced apoptosis in a mutant of human myeloid leukemia U937 cells. 795 69

Some "multidrug-resistant" (MDR) cell lines are not associated with a defect in drug accumulation or with the overexpression of P-glycoprotein. These cell lines are defined as "atypical MDR" (at-MDR) and they often express altered or mutated topoisomerase II. We investigated the ability of tumor necrosis factor to reverse at-MDR (in the human ovarian cancer cell line A2780 DX3) on the basis of its efficacy in potentiating in vitro topoisomerase II-targeted drugs, and because there is convincing evidence that the synergy is due to an increased number of topoisomerase-associated strand-breaks as well as to an increased level of extractable topoisomerase.
...
PMID:Circumvention of atypical multidrug resistance with tumor necrosis factor. 814 94

In this study, we demonstrated that tumor necrosis factor (TNF), secreted endogenously by four human ovarian cancer cell lines (A2774, IGROV-1, OVCAR-8, SW626), is biologically active against L929 cells and its activity is specifically inhibited by anti-TNF antibodies. Its endogenous production is increased by treatment for 24 h with phorbol myristate acetate (PMA)/ Ionomycin (Iono). All cell lines express TNF high-affinity receptors and release only 60-kdalton soluble TNF receptor, both spontaneously and after stimulation with PMA/Iono. TNF endogenously secreted by human ovarian cancer cell lines is very efficient in potentiating the activity of DNA topoisomerase II inhibitors (doxorubicin, mitoxantrone, VP16). The activity of vinblastine and bleomycin is not potentiated and, more interestingly, cisplatin's activity is inhibited. In 24-h PMA/Iono-stimulated A2774 cells, mitoxantrone specifically generated more cleavable complexes than in unstimulated cells. This result could provide an important tool in the therapy of human ovarian cancer secreting TNF protein, previously considered as a negative prognostic factor.
...
PMID:Endogenous tumor necrosis factor enhances topoisomerase II inhibitors activity in human ovarian cancer cell lines. 885 79


<< Previous 1 2 3 4 Next >>

---