Document Detail


Cell-cycle alterations underlie cyclophosphamide-induced teratogenesis in the chick embryo.
MedLine Citation:
PMID:  12962288     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Cyclophosphamide (CP) embryotoxicity was documented in several studies on different experimental models. We investigate quantitatively the relationship between the embryotoxic effect of CP and the disturbance of the cell-cycle using flow cytometry. METHODS: Chick embryos on Days 2-4 were treated with 0.5, 1, 2, 4, 8, and 16 microg doses of pure substance of CP by intraamniotic or subgerminal administration routes. Cell-cycle analysis was carried out in the brain, limb buds, hearts, and facial outgrowths dissected from the embryos 6 hr after administration. Samples of nuclear suspensions were obtained by enzymatic and mechanical disintegration of solid tissues in collagenase-dispase, followed by detergent and RNA-ase mediated cytolysis. Nuclei were stained by ethidium bromide. RESULTS: A dose-dependent increase of S-phase cells followed by decrement of G2M cell compartment was observed. The significant block of S-phase cells, however, was not always associated with malformations. The degree of cell-cycle disturbance was expressed more readily by the ratio G2M/S that demonstrated consistently the threshold character of both teratogenic and lethal effects. CONCLUSION: CP-induced cytotoxicity manifested by dose-dependent disturbance of cell-cycle resulted in an overall depression of proliferation activity clearly associated with the occurrence of malformations and embryonic death. Although a non-significant depression of mitotic activity appeared sufficient to produce malformations on Day 2, remarkably deeper disturbance was needed to interfere with the development of the embryos in more advanced stages. Changes in proliferation rate appear to be a primary and most important event in teratogenesis induced by general toxic agents.
Authors:
L Heringová; R Jelínek; M Dostál
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Birth defects research. Part A, Clinical and molecular teratology     Volume:  67     ISSN:  1542-0752     ISO Abbreviation:  Birth Defects Res. Part A Clin. Mol. Teratol.     Publication Date:  2003 Jun 
Date Detail:
Created Date:  2003-09-09     Completed Date:  2004-02-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  101155107     Medline TA:  Birth Defects Res A Clin Mol Teratol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  438-43     Citation Subset:  IM    
Affiliation:
Charles University, 3rd Faculty of Medicine, Center of Biomedical Studies, Prague, Czech Republic. lucie.heringova@lf3.cuni.cz
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MeSH Terms
Descriptor/Qualifier:
Abnormalities, Drug-Induced*
Animals
Antineoplastic Agents, Alkylating / toxicity*
Cell Cycle / drug effects*
Cell Division / drug effects
Chick Embryo
Cyclophosphamide / toxicity*
Dose-Response Relationship, Drug
Embryo, Nonmammalian / cytology,  drug effects*,  embryology
Teratogens / toxicity*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Teratogens; 50-18-0/Cyclophosphamide

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


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