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)

The potential role of tumor necrosis factor alpha (TNF alpha), interferon alpha (IFN alpha) and interferon gamma (IFN gamma) in the therapy of non-lymphoid leukemia was studied in ten non-lymphoid leukemia cell lines. All three cytokines tested inhibited the growth of the cell lines. However, a high degree of variability in susceptibility to cytotoxic/cytostatic effect of the cytokines was found among individual cell lines. Some cell lines were sensitive to the antiproliferative action of only one of the cytokines tested, but were resistant to the others. Combinations of two cytokines had additive or synergistic effects and inhibited cell growth to a greater extent than did the individual cytokines alone. In addition to the growth-inhibitory effect, the cytokines induced an apparent cell differentiation. The differentiation of the two most sensitive cell lines, EoL-1 and PL-21, was confirmed using the nitroblue tetrazolium reduction test, by changes in cell morphology, immunophenotype marker profiles and by changes in c-myb expression. Furthermore, we showed that even in the cell lines relatively resistant to the antiproliferative effect of cytokines, such as cell line KCL-22, the inhibition of cell growth could be markedly increased with the DNA-topoisomerase-II-targeted drug, doxorubicin. Our data thus suggest that TNF alpha, IFN alpha and IFN gamma together have a potential role in the immunotherapy of non-lymphoid leukemia in terms of their antiproliferative action, and their ability to induce differentiation and to modulate drug sensitivity.
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PMID:Effects of tumor necrosis factor alpha, interferon alpha and interferon gamma on non-lymphoid leukemia cell lines: growth inhibition, differentiation induction and drug sensitivity modulation. 151 60

Treatment-related myelodysplasia (t-MDS) occurs less frequently with the nucleoside analogs than with DNA-damaging agents such as alkylators or topoisomerase II inhibitors. In a chemoimmunotherapy trial conducted between 1997 and 2003 in patients with stage IV indolent lymphoma, 202 patients were treated and 8 have developed MDS between 1 and 5 years after therapy, including 4 who received only fludarabine, mitoxantrone, and dexamethasone (FND) for 6 to 8 courses, with or without rituximab, followed by interferon alpha (IFN-alpha). Complex cytogenetic abnormalities were present in all patients. Abnormalities of chromosome 7 were present in 6 of the 8 patients, 3 of whom received only FND +/- rituximab and IFN-alpha. The abnormalities of chromosome 7 were monosomy 7 in 4 patients (1 of which had add 7p in the remaining chromosome); 1 del 7q; and 1 der 7. MDS with features classically associated with DNA-damaging agents can occur following therapy with FND, with or without rituximab, and IFN-alpha.
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PMID:Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. 1574 Dec 24

Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication.IMPORTANCE Ebola virus and other emerging RNA viruses are significant but unpredictable public health threats. Therapeutic approaches with broad-spectrum activity could provide an attractive response to such infections. We describe a novel assay that can identify small molecules that overcome Ebola virus-encoded innate immune evasion mechanisms. This assay identified as hits cancer chemotherapeutic drugs, including doxorubicin. Follow-up studies provide new insight into how doxorubicin induces interferon (IFN) responses, revealing activation of both the DNA damage response kinase ATM and the DNA sensor cGAS and its partner signaling protein STING. The studies further demonstrate that the ATM and cGAS-STING pathways of IFN induction are a point of vulnerability not only for Ebola virus but for other RNA viruses as well, because viral innate immune antagonists consistently fail to block these signals. These studies thereby define a novel avenue for therapeutic intervention against emerging RNA viruses.
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PMID:Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion. 2837 30