| Influence of cell cycle and oncogene activity upon topoisomerase IIalpha expression and drug toxicity. | |
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MedLine Citation:
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PMID: 11094065 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The cell cycle, oncogenic signaling, and topoisomerase (topo) IIalpha levels all influence sensitivity to anti-topo II drugs. Because the cell cycle and oncogenic signaling influence each other as well as topo IIalpha levels, it is difficult to assess the importance of any one of these factors independently of the others during drug treatment. Such information, however, is vital to an understanding of the cellular basis of drug toxicity. We, therefore, developed a series of analytical procedures to individually assess the role of each of these factors during treatment with the anti-topo II drug etoposide. All studies were performed with asynchronously proliferating cultures by the use of time-lapse and quantitative fluorescence staining procedures. To our surprise, we found that neither oncogene action nor the cell cycle altered topo IIalpha protein levels in actively cycling cells. Only a minor population of slowly cycling cells within these cultures responded to constitutively active oncogenes by elevating topo IIalpha production. Thus, it was possible to study the effects of the cell cycle and oncogene action on drug-treated cells while topo IIalpha levels remained constant. Toxicity analyses were performed with two consecutive time-lapse observations separated by a brief drug treatment. The cell cycle phase was determined from the first observation, and cell fate was determined from the second. Cells were most sensitive to drug treatment from mid-S phase through G(2) phase, with G(1) phase cells nearly threefold less sensitive. In addition, the presence of an oncogenic src gene or microinjected Ras protein increased drug toxicity by approximately threefold in actively cycling cells and by at least this level in the small population of slowly cycling cells. We conclude that both cell cycle phase and oncogenic signaling influence drug toxicity independently of alterations in topo IIalpha levels. |
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Authors:
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D W Stacey; M Hitomi; G Chen |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Molecular and cellular biology Volume: 20 ISSN: 0270-7306 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2000 Dec |
Date Detail:
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Created Date: 2000-12-13 Completed Date: 2001-01-11 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 9127-37 Citation Subset: IM |
Affiliation:
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Department of Molecular Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. Staceyd@CCF.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Animals Antigens, Neoplasm Antineoplastic Agents, Phytogenic / pharmacology, toxicity Cell Cycle / drug effects*, physiology Cell Transformation, Neoplastic DNA / metabolism DNA Topoisomerases, Type II / antagonists & inhibitors, genetics, metabolism* DNA Topoisomerases, Type II, Eukaryotic* DNA-Binding Proteins Etoposide / pharmacology*, toxicity Fluorescence Humans Isoenzymes / antagonists & inhibitors, genetics, metabolism* Mice Microinjections Microscopy, Video Nucleic Acid Synthesis Inhibitors / pharmacology*, toxicity Oncogene Protein p21(ras) / metabolism Oncogenes / physiology* Signal Transduction* Video Recording |
| Grant Support | |
ID/Acronym/Agency:
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GM52271/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, Neoplasm; 0/Antineoplastic Agents, Phytogenic; 0/DNA-Binding Proteins; 0/Isoenzymes; 0/Nucleic Acid Synthesis Inhibitors; 33419-42-0/Etoposide; 9007-49-2/DNA; EC 3.6.5.2/Oncogene Protein p21(ras); EC 5.99.1.-/DNA Topoisomerases, Type II, Eukaryotic; EC 5.99.1.3/DNA Topoisomerases, Type II; EC 5.99.1.3/DNA topoisomerase II alpha |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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