Document Detail

S-Phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine.
MedLine Citation:
PMID:  11221834     Owner:  NLM     Status:  MEDLINE    
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.
Z Shi; A Azuma; D Sampath; Y X Li; P Huang; W Plunkett
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  61     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-02-26     Completed Date:  2001-03-15     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1065-72     Citation Subset:  IM    
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.
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MeSH Terms
Alkaloids / 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
Leukemia, Myeloid, Acute / drug therapy,  pathology
S Phase / drug effects*
Staurosporine / analogs & derivatives
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Alkaloids; 0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents; 62996-74-1/Staurosporine; 7BU5H4V94A/7-hydroxystaurosporine; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine

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