| S-Phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine. | |
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MedLine Citation:
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PMID: 11221834 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanisms of resistance to nucleoside analogues established in preclinical models are rarely found in primary tumors resistant to therapy with these agents. We tested the hypothesis that cells sense sublethal incorporation of analogues into DNA during replication and react by arresting further DNA synthesis and cell cycle progression. After removal of drug, cells may be able to repair damaged DNA and continue proliferation, thus escaping nucleoside analogue toxicity. As a corollary, we evaluated whether dysregulation of this mechanism causes cell death. Using gemcitabine as a model of S-phase-specific nucleoside analogues in human acute myelogenous leukemia ML-1 cells, we found that DNA synthesis decreased, cells arrested in S-phase transit, and 60-70% of the population accumulated in S-phase in response to cytostatic conditions. Proliferation continued after washing the cells into drug-free medium. S-phase-arrested cells were then treated with otherwise nontoxic concentrations of UCN-01, which caused rapid onset of apoptosis without cell cycle progression specifically in cells with an S-phase DNA content. Thus, S-phase arrest by nucleoside analogues sensitizes cells to UCN-01, which appears to activate signaling for death mechanisms and/or inhibit survival pathways. These results differ from those in cells arrested at the G2 checkpoint, in which UCN-01 abrogates cell cycle arrest, permitting cells to progress in the cell cycle before apoptosis. |
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Authors:
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Z Shi; A Azuma; D Sampath; Y X Li; P Huang; W Plunkett |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 61 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2001 Feb |
Date Detail:
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Created Date: 2001-02-26 Completed Date: 2001-03-15 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1065-72 Citation Subset: IM |
Affiliation:
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Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center and The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alkaloids
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pharmacology* Antimetabolites, Antineoplastic / pharmacology* Antineoplastic Agents / pharmacology* Apoptosis / drug effects Cell Cycle / drug effects Cell Survival / drug effects Deoxycytidine / analogs & derivatives, pharmacology* Dose-Response Relationship, Drug Drug Synergism Humans Leukemia, Myeloid, Acute / drug therapy, pathology S Phase / drug effects* Staurosporine / analogs & derivatives Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA28596/CA/NCI NIH HHS; CA32839/CA/NCI NIH HHS; CA55164/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Alkaloids; 0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents; 103882-84-4/gemcitabine; 112953-11-4/7-hydroxystaurosporine; 62996-74-1/Staurosporine; 951-77-9/Deoxycytidine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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