Document Detail


Permanent cell cycle arrest in asynchronously proliferating normal human fibroblasts treated with doxorubicin or etoposide but not camptothecin.
MedLine Citation:
PMID:  10413306     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Damage to DNA has been implicated in the induction of permanent cell cycle arrest or premature senescence in normal human fibroblasts. We tested the ability of a group of cancer chemotherapeutic agents or related compounds, which can cause DNA double-strand breaks (DSBs) directly or indirectly, to induce a permanent cell cycle arrest in normal proliferating fibroblasts. A brief treatment with etoposide, doxorubicin, cisplatin, or phleomycin D1 induced a block to S phase entry sustained through 15 days. Lower levels of these drugs did not induce appreciable levels of transient cell cycle arrest. Higher concentrations caused cell death that lacked the DNA degradation characteristic of apoptosis. Camptothecin, an agent that causes DNA single-strand breaks, which are converted to DSBs during S phase, was able to induce an efficient, but only transient, cell cycle arrest in these normal cells. The cells did not enter S phase until after removal of the camptothecin. These findings support the idea that permanent cell cycle arrest and cell death are typical reactions of these normal cells to drugs that can cause DSBs. In addition, we report data consistent with the concept that both actinomycin D and doxorubicin are sequestered by cells and slowly released in active form. This is consistent with the observation that both these drugs bind reversibly to intracellular components.
Authors:
S J Robles; P W Buehler; A Negrusz; G R Adami
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  58     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1999 Aug 
Date Detail:
Created Date:  1999-08-02     Completed Date:  1999-08-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  675-85     Citation Subset:  IM    
Affiliation:
Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago, 60612, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Camptothecin / pharmacology*
Cell Cycle / drug effects*
Cell Division / drug effects
Cell Survival / drug effects
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / biosynthesis
DNA Damage
Dactinomycin / pharmacology
Doxorubicin / metabolism,  pharmacology*
Etoposide / pharmacology*
Fibroblasts / cytology,  drug effects*
Humans
Tumor Suppressor Protein p53 / biosynthesis
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Tumor Suppressor Protein p53; 23214-92-8/Doxorubicin; 33419-42-0/Etoposide; 50-76-0/Dactinomycin; 7689-03-4/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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