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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor alpha (TNF) exhibits cytotoxic activity on some solid tumors and has been reported to be synergistic with topoisomerase-II-targeted antineoplastic agents. A wide range of TNF concentrations (from 10 to 10,000 U/ml) was tested in 9 human lung cancer cell lines (5 small-cell and 4 non-small-cell carcinomas) using a semi-automated MTT assay. TNF was not cytotoxic in 8 cell lines, while an adenocarcinoma cell line was marginally sensitive to the cytokine. Using 125I-TNF we were able to show the presence of specific binding sites for TNF in 4/9 human lung cancer cell lines. Scatchard analysis of the marginally sensitive cell line showed high-affinity, saturable binding. With 5 cell lines we also tested whether TNF affected the cytotoxicity of doxorubicin and etoposide, 2 topoisomerase II-targeted drugs which are widely used in the therapy of lung cancer. No significant increase in cytotoxicity was seen when TNF was added to the 2 anti-neoplastic agents. In contrast to certain other human and mouse lines, human lung cancer cell lines appear to be resistant to TNF, despite the presence of the receptor in some of them; moreover, no synergistic effect of TNF and 2 topoisomerase-II-targeted drugs was evident in these human cell lines.
...
PMID:Effects of tumor necrosis factor, alone or in combination with topoisomerase-II-targeted drugs, on human lung cancer cell lines. 216 14

TNF is a pleiotropic cytokine that mediates diverse cellular responses, including cytotoxicity, cytostasis, proliferation, differentiation, and the expression of specific genes. Many of these processes require the activity of DNA topoisomerases I and II. We have investigated the interactions of TNF with inhibitors of both topoisomerases in 16-h assays using the murine L929 and human ME-180 cell lines, which undergo a cytotoxic TNF response. Camptothecin, a specific inhibitor of topoisomerase I, enhanced TNF cytotoxicity 150-fold against both cell lines. The topoisomerase II inhibitors VM-26 and VP-16, which stabilize covalent DNA-topoisomerase intermediates, greatly enhance TNF cytotoxicity against both cell lines. The most effective, VM-26, can lower the TNF LD50 to femtomolar levels. In contrast, the topoisomerase II inhibitors novobiocin and coumermycin, which bind to the enzyme ATPase site, protect L929 cells from TNF cytotoxicity but enhance TNF cytotoxicity in ME-180 cells. The large changes in TNF sensitivity induced by drug concentrations that by themselves show no effect, and the opposing synergistic effects of inhibitors with different inhibitory mechanisms (in L929 cells), suggest the active involvement of topoisomerases in TNF-mediated cytotoxicity. The correlation of cytotoxic synergy with the stabilization of DNA strand breaks indicates that DNA damage may play a significant role in TNF-mediated cytotoxicity.
...
PMID:Synergistic interactions between tumor necrosis factor and inhibitors of DNA topoisomerase I and II. 217 May 26

Murine bone marrow-derived hemopoietic cells, dependent on interleukin (IL)-3 for their growth in culture, undergo programmed cell death, or apoptosis, upon cytokine withdrawal. The topoisomerase II inhibitor etoposide causes a more rapid onset of apoptosis in the IL-3-dependent cell line BAF3, deprived of IL-3. This acceleration of apoptosis by etoposide is prevented by inhibitors of RNA and protein synthesis and by the nucleases inhibitor aurintricarboxylic acid. The presence of IL-3 or overexpression of the oncogene bcl-2 caused a marked delay in the induction of apoptosis by etoposide, acting in a cooperative manner. The time at which the apoptotic program is irreversible is close to the induction of endonuclease activity as indicated by the effect of the delayed addition of either IL-3 or aurintricarboxylic acid on the onset of apoptosis, suggesting the importance of endonuclease activation in the development of apoptosis in hemopoietic cells.
...
PMID:Interleukin-3 and Bcl-2 cooperatively inhibit etoposide-induced apoptosis in a murine pre-B cell line. 751 Feb 34

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 cytotoxic quinolone CP-115,953 specifically exerts its inhibitory effect upon eukaryotic topoisomerase II. CP-115,953 stimulates DNA cleavage mediated by topoisomerase II with a potency approximately 600 times greater than that of ciprofloxacin, a quinolone antibacterial agent that currently is in clinical use. Because ciprofloxacin has been reported to strongly enhance interleukin-2 production, we considered it important to study the effect of CP-115,953 on interleukin-2 and gamma interferon (IFN-gamma) mRNA and protein expression in mitogen-stimulated human peripheral blood lymphocytes. For comparison, novobiocin and the antineoplastic drug etoposide were also included in the study. CP-115,953 (25 microM) enhanced interleukin-2 mRNA levels up to 8-fold and IFN-gamma mRNA concentrations up to 6.5-fold. In contrast, ciprofloxacin (282 microM) induced mRNAs for interleukin-2 and IFN-gamma up to 20-fold and 7.8-fold, respectively. However, CP-115,953 showed more prolonged kinetics of IFN-gamma mRNA production than ciprofloxacin. At high concentrations (> or = 141 microM), ciprofloxacin was a greater inducer of interleukin-2 production and exhibited a higher level of stimulatory action than CP-115,953 on IFN-gamma synthesis. At low concentrations, however, CP-115,953 (< or = 25 microM) was more potent than ciprofloxacin in inducing interleukin-2 and IFN-gamma synthesis. Etoposide or novobiocin did not influence cytokine mRNA expression. Thus, among the topoisomerase II inhibitors tested, fluoroquinolones are unique in stimulating cytokine synthesis in lymphocyte cultures.
...
PMID:CP-115,953 stimulates cytokine production by lymphocytes. 772 18

Tumor necrosis factor (TNF) is a pleiotropic cytokine that mediates different cellular responses including cytotoxicity, cytostasis, proliferation, differentiation and expression of specific genes. Recent studies have demonstrated that chemotherapeutic drugs that inhibit the nuclear enzyme DNA topoisomerase II synergize with TNF in tumor cell killing in vitro and in vivo. We now report that a combination of TNF and the topoisomerase II inhibitor Mitoxantrone produced dose-dependent synergistic cytotoxicity against the human ovarian cancer cell line A2774 in a clonogenic assay (1 hr treatment). This result was obtained with simultaneous administration of the drug and the cytokine under test, and is independent of modification of Mitoxantrone uptake. This combination is responsible for an evident augmentation of "cleavable complex" formation. From isolated nuclei, we have isolated also the topoisomerase II activity; we observed an increment when the cells were previously treated with TNF, 2.5 min before nuclear extraction. After 10-30 min of treatment with TNF, the topoisomerase II activity returned to normal values. If TNF is not given with but 30 min before Mitoxantrone, no potentiation of cytotoxicity or break induction is observed. These results suggest that specific timing of the association may be needed also when attempting to translate it to animals and humans.
...
PMID:Potentiation of TNF-mediated cell killing by mitoxantrone. Relationship to DNA single-strand break formation. 821 70

Topotecan (TPT), a known inhibitor of topoisomerase I, has previously been shown to inhibit the replication of several viruses. The mechanism of inhibition was proposed to be the inhibition of topoisomerase I. We report that TPT decreased replication of human immunodeficiency virus type 1 (HIV-1) in CPT-K5, a cell line with a topoisomerase I mutation. TPT inhibited production of HIV-1 RNA and p24 in CPT-K5 and wild-type cells equally effectively. The antiviral effects of TPT were observed not only in the topoisomerase-mutated CPT-K5 line but also in peripheral blood mononuclear cells (PBMC) acutely infected with clinical isolates and in OM10.1 cells latently infected with HIV and activated by tumor necrosis factor alpha. Little toxicity from TPT was noted in HIV-1-infected PBMC and in CPT-K5 and OM10.1 cells as measured by cell growth and proliferation assays. These observations suggest that TPT targets factors in virus replication other than cellular topoisomerase I and inhibits cytokine-mediated activation in latently infected cells by means other than cytotoxicity. These results suggest a potential for TPT and for other camptothecins in anti-HIV therapy alone and in combination with other antiretroviral drugs.
...
PMID:Topotecan inhibits human immunodeficiency virus type 1 infection through a topoisomerase-independent mechanism in a cell line with altered topoisomerase I. 914 55

Between 1992 and 1995, we have had five virostatics available: zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) (as retrotranscriptase nucleosidic antagonists, RTNA), acriflavine (ACF), and hydroxy-methyl-ellipticine (HEL), as respectively a DNA synthesis and structure antagonist, and a topoisomerase II inhibitor. Between 1995 and now, we have had ten virostatics the same, plus lamivudine (3TC), stavudine (d4T) as RTNA, and indinavir (IDV), ritonavir (RTV) and saquinavir (SQV) as protease inhibitors. We first conducted a phase I-like study concerning the ratios of the drug numbers in combinations over the numbers available. The optimal model for the study was that of four virostatics selected out of the ten. The four virostatic combinations were applied in short (3 week) sequences, differing each others by drug rotation. The patients were, before treatment, nine at the phase of AIDS, one at the A3 stage. They presented a very rapid decrease of viral load (VL) which became undetectable at PCR, being first below 200 RNA copies/mL, then below 20. We call this condition 'minimum residual disease' as HIV1 persistence is revealed by virus rebounds, reversible, and probably induced by cofactors. The frequency of the latter selection is due to the very frequent (each 3 weeks) VL evaluations. The last part of the VL exponential curve which the minimum residual disease represents, is almost horizontal and quasi insensitive to the powerful virostatic model described above, though no resistance has appeared at the combination or sequence levels. Thus we propose to add phases of: a) reinforcements by virostatics, adding two more ones to the four of the model; and b) treatment complement by active immunotherapy phases: the most adapted immunomodulator is the combination of the peptidic cytokine, tuftsine, and of its antipeptidase, bestatine If they are not available, another interleukine, able to help restoring the AIDS disturbed immunologic system, interleukin 2, could be tried, as it has induced beneficial effects at very small doses by subcutaneous injections.
...
PMID:Combinations of four virostatics applied in rotational sequences induce an exponential VL regression curve, the first part of which is rapidly decreasing to a PCR-undetectable level, while the last part is insensitive to the model. Indications for virostatic and immunotherapeutic reinforcements? 1033 59

We have compared the induction of apoptosis and cytokine release by UVB and gamma-radiation in primary (untransformed) and in two immortalized human epithelial/keratinocyte cell lines, HaCaT and KB (KB is now known to be a subline of the ubiquitous keratin-forming tumour cell line HeLa and we therefore designate it HeLa-KB). In both the primary and the immortalized cell lines apoptosis and release of the inflammatory cytokine interleukin-6 are induced rapidly following UVB irradiation. In contrast, only the immortalized cells undergo apoptosis and release interleukin-6 after gamma-irradiation and here the onset of apoptosis and cytokine release are delayed. The same distinction between primary and immortalized cells was observed when double-strand breaks were induced with the anticancer drug mitoxantrone, which stabilizes topoisomerase II-cleavable complexes. We suggest that immortalization may sensitize keratinocytes to the apoptogenic effect of ionizing radiation or mitoxantrone by deregulating normal cell cycle checkpoints. In both human keratinocytes and fibroblasts, cell killing, as assayed by loss of colony-forming ability, is not coupled to apoptosis. Immortalization increases resistance to gamma-radiation killing but sensitizes to apoptosis. In contrast, although immortalization also sensitizes to UVB-induced apoptosis, it does not affect UVB-induced cell killing. Apoptosis unambiguously indicates death at the single cell level but clonal cell survival integrates all the cellular and genetic processes which prevent or permit a scorable clone to develop.
...
PMID:Apoptosis and cytokine release induced by ionizing or ultraviolet B radiation in primary and immortalized human keratinocytes. 1083 95

KILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta-Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA. Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53.
...
PMID:p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. 1113 40


1 2 3 4 Next >>

---