Document Detail


Melding a New 3-Dimensional Agarose Colony Assay with the E(max) Model to Determine the Effects of Drug Combinations on Cancer Cells.
MedLine Citation:
PMID:  19334798     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The goal of our study was two-fold: (i) develop a robust 3D colony assay methodology to interrogate drug combinations using GelCount and (ii) to develop 2-drug combinations that might be useful in the clinic for the treatment of high-grade gliomas. We used three glioma cell lines (U251MG, SNB19, and LNZ308) and two adenocarcinoma cell lines (MiaPaCa and SW480) grown as colonies in a two-tiered agarose cultures. We evaluated two-drug combinations of difluoromethylornithine (DFMO), carboplatin, vorinostat (SAHA), and docetaxel. To analyze for antitumor efficacy we used GelCount to measure the area under the curve for tumor colony volumes (microm(2) x OD) in each plate. The non-linear dose-response E(max) model and the interaction index based on the Loewe additivity are applied to calculate two-drug synergy, additive, and antagonistic interactions. For glioblastoma cell lines, (i) carboplatin followed by DFMO was synergistic or additive in 2/3 cell lines, (ii) carboplatin before SAHA was synergistic in 1 cell line, (iii) carboplatin before docetaxel was synergistic in 2/3 cell lines and partially additive in the third, (iv) SAHA before docetaxel was synergistic in 1/3 cell lines, (v) docetaxel before DFMO was additive or partially active in 3/3 cell lines, and (vi) DFMO plus SAHA was inactive regardless of order. In the MiaPaCA cell line, synergy occurred when DFMO followed carboplatin and, at short exposure times, when SAHA was combined with carboplatin (regardless of order). In the SW480 cell line synergy occurred only in short exposures for carboplatin followed by docetaxel; additive and mixed partial effects were also seen with DFMO plus carboplatin or docetaxel (regardless of order), carboplatin before DFMO, carboplatin before SAHA, and docetaxel before carboplatin. In conclusion, by applying the Gelcount automated counting and sizing of colonies and the use of E(max) and Loewe models to define drug interactions, we can reliably define drug combination efficacy as a function of log dose and duration of drug exposure.
Authors:
Yoshinori Kajiwara; Sonali Panchabhai; Diane D Liu; Maiying Kong; J Jack Lee; Victor A Levin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Technology in cancer research & treatment     Volume:  8     ISSN:  1533-0346     ISO Abbreviation:  Technol. Cancer Res. Treat.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-01     Completed Date:  2009-08-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101140941     Medline TA:  Technol Cancer Res Treat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  163-76     Citation Subset:  IM    
Affiliation:
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77230-1402, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Cell Culture Techniques
Cell Line, Tumor
Cell Survival / drug effects
Drug Screening Assays, Antitumor / instrumentation,  methods*
Humans
Sepharose
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 9012-36-6/Sepharose

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


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