Document Detail


Cell cycle checkpoint models for cellular pharmacology of paclitaxel and platinum drugs.
MedLine Citation:
PMID:  18446502     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A pharmacokinetic-pharmacodynamic mathematical model is developed for cellular pharmacology of chemotherapeutic drugs for which the decisive step towards cell death occurs at a point in the cell cycle, presumably corresponding to a cell cycle checkpoint. For each cell, the model assumes a threshold level of some intracellular species at that checkpoint, beyond which the cell dies. The threshold level is assumed to have a log-normal distribution in the cell population. The kinetics of formation of the lethal intracellular species depends on the drug, and on the cellular pharmacokinetics and binding kinetics of the cell. Specific models are developed for paclitaxel and for platinum drugs (cisplatin, oxaliplatin and carboplatin). In the case of paclitaxel, two separate mechanisms of cell death necessitate a model that accounts for two checkpoints, with different intracellular species. The model was tested on a number of in vitro cytotoxicity data sets for these drugs, and found overall to give significantly better fits than previously proposed cellular pharmacodynamic models. It provides an explanation for the asymptotic convergence of dose-response curves as exposure time becomes long.
Authors:
Ardith W El-Kareh; Rachel E Labes; Timothy W Secomb
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2008-02-05
Journal Detail:
Title:  The AAPS journal     Volume:  10     ISSN:  1550-7416     ISO Abbreviation:  AAPS J     Publication Date:  2008  
Date Detail:
Created Date:  2008-04-30     Completed Date:  2008-09-22     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  101223209     Medline TA:  AAPS J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15-34     Citation Subset:  IM    
Affiliation:
ARL-Microcirculation Division, University of Arizona, PO Box 245051, Tucson, AZ 85724-5051, USA. elkareh@u.arizona.edu
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle / drug effects*,  physiology
Cell Line, Tumor
Dose-Response Relationship, Drug
Humans
Models, Biological*
Paclitaxel / pharmacology*
Platinum Compounds / pharmacology*
Grant Support
ID/Acronym/Agency:
CA040355/CA/NCI NIH HHS; CA098671/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Platinum Compounds; 33069-62-4/Paclitaxel
Comments/Corrections

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


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