Document Detail


Paclitaxel-2'-Ethylcarbonate prodrug can circumvent P-glycoprotein-mediated cellular efflux to increase drug cytotoxicity.
MedLine Citation:
PMID:  17245652     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The aim of the study was to investigate whether 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et) circumvents P-glycoprotein (P-gp)-mediated cellular efflux and cytotoxicity enhanced by TAX-2'-Et activation within human culture cells transfected with a rabbit liver carboxylesterase (Ra-CES) cDNA. MATERIALS AND METHODS: TAX-2'-Et transport was characterized in a human colon carcinoma cell line (Caco-2) and paclitaxel (TAX)-resistant ovarian carcinoma cells (SKOV3/TAX60). Expression of P-gp, multidrug resistance protein (MRP) 2 and Ra-CES was detected by Western blotting. Cytotoxicity against Ra-CES-expressing cells and cellular amount of TAX produced were determined by MTT assay and using HPLC, respectively. RESULTS: Unlike rhodamine123 and TAX, TAX-2'-Et did not exhibit polarized transport in the Caco-2 cells in the absence or presence of verapamil. P-gp levels were expressed much higher in the SKOV3/ TAX60 cells than in the Caco-2 cells. MRP2 protein was not detectable in the SKOV3/TAX60 cells. Uptake by the SKOV3/TAX60 cells was similar in quantity to the amount internalized by P-gp-negative SKOV3 cells. In the SKOV3/TAX60 cells, cellular uptake of TAX-2'-Et was not altered regardless of the absence or presence of verapamil. The cytotoxicity to the untransfected SKOV3 cells induced by TAX-2'-Et was significantly lower than that induced by TAX. In the Ra-CES-expressing SKOV3 line, the EC50 value of TAX (10.6 nM) was approximately four-fold higher than that of TAX-2'-Et (2.5 nM). Transfection of Ra-CES into another TAX-resistant ovarian carcinoma cells (KOC-7c) conferred a high level of TAX-2'-Et cytotoxicity via prodrug activation. The intracellular levels of TAX produced from TAX-2'-Et in the Ra-CES-positive KOC-7c cells significantly increased compared with the levels seen in exposure of the untransfected KOC-7c cells to TAX. CONCLUSIONS: TAX-2'-Et can circumvent P-gp-associated cellular efflux of TAX. TAX-2'-Et is converted into TAX by the Ra-CES, supporting its potential use as a theoretical GDEPT strategy for cancer cells expressing high levels of P-gp. The TAX-2'-Et prodrug efficiently increased the amount of intracellular TAX, which mediates tumor cell death.
Authors:
Tadatoshi Tanino; Akihiro Nawa; Eisaku Kondo; Fumitaka Kikkawa; Tohru Daikoku; Tatsuya Tsurumi; Chenhong Luo; Yukihiro Nishiyama; Yuki Takayanagi; Katuhiko Nishimori; Seiji Ichida; Tetsuyuki Wada; Yasuyoshi Miki; Masahiro Iwaki
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmaceutical research     Volume:  24     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-05-31     Completed Date:  2007-09-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  555-65     Citation Subset:  IM    
Affiliation:
School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Phytogenic / chemistry,  pharmacokinetics,  pharmacology
Biological Transport
Blotting, Western
Caco-2 Cells
Carboxylesterase / genetics,  metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects,  genetics
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Humans
Membrane Transport Proteins / genetics,  metabolism
Molecular Structure
Multidrug Resistance-Associated Proteins / genetics,  metabolism
P-Glycoprotein / genetics,  metabolism*
Paclitaxel / chemistry,  pharmacokinetics*,  pharmacology
Plasmids / genetics
Prodrugs / chemistry,  pharmacokinetics*,  pharmacology
Rabbits
Transfection
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Membrane Transport Proteins; 0/Multidrug Resistance-Associated Proteins; 0/P-Glycoprotein; 0/Prodrugs; 0/multidrug resistance-associated protein 2; 33069-62-4/Paclitaxel; EC 3.1.1.1/Carboxylesterase

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


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