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)

Studies have suggested that recombinant tumor necrosis factor-alpha (TNF-alpha) may potentiate the killing of murine tumor cells by drugs targeted at DNA topoisomerase II. We have examined the combined cytotoxic effects of the topoisomerase-targeted drug etoposide and TNF in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines using clonogenic assays and a novel flow cytometry technique relying on differential uptake of fluorescein diacetate (FDA) and propidium iodide (PI) by viable and nonviable cells. Good correlation of IC50 determinations for etoposide were noted between clonogenic assays and the FDA/PI technique for both classic and variant SCLC cell lines. The effects of etoposide on the classic SCLC line H209 were potentiated by TNF with a decrease in the IC50 from 3.3 microM to 1.0 microM as determined by FDA/PI. Tumor necrosis factor alone had little effect on the growth or cloning efficiency of H209 cells. Tumor necrosis factor alone stimulated the growth and cloning of variant SCLC line N417, but the cytotoxicity of etoposide was not potentiated by TNF in N417 cells. Tumor necrosis factor alone inhibited the growth and cloning of the NSCLC line H125 but exerted a marked protective effect against higher concentrations of etoposide. It appears that the interaction of TNF with etoposide varies between cell lines and between subclasses of human lung cancer.
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PMID:Interaction of recombinant human tumor necrosis factor and etoposide in human lung cancer cell lines. 217 61

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.
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PMID:Potentiation of TNF-mediated cell killing by mitoxantrone. Relationship to DNA single-strand break formation. 821 70