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Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells.

Abstract
The present study demonstrated that poly(oxypropylene) and poly(oxyethylene) block copolymer pluronic L61 (L61)-hypersensitized multidrug-resistant CHRC5 Chinese hamster ovary cells and MCF-7/ADR human breast carcinoma cells to the cytotoxic action of doxorubicin (Dox). CHRC5 and MCF-7/ADR cells manifested 290- and 700-fold increases, respectively, in their sensitivity to Dox/L61 formulation compared with free Dox. Their sensitive counterparts Aux-B1 and MCF-7 displayed only marginal or no increase at all in their response to Dox/L61. The study of the drug transport performed by flow cytometry showed that L61 enhanced the drug uptake and reduced the P-glycoprotein-mediated drug efflux. Visualization of Dox subcellular distribution in CHRC5 cells by fluorescent microscopy revealed that Dox was sequestered in cytoplasmic vesicles, whereas incubation of the cells with Dox/L61 altered the drug compartmentalization by releasing the drug from these vesicles and shifting it to the nucleus. These findings suggested that the hypersensitive response of multidrug-resistant cells to the action of Dox/L61 was caused by an increase in the drug accumulation and changes in its subcellular distribution.
AuthorsA Venne, S Li, R Mandeville, A Kabanov, V Alakhov
JournalCancer research (Cancer Res) Vol. 56 Issue 16 Pg. 3626-9 (Aug 15 1996) ISSN: 0008-5472 [Print] United States
PMID8705995 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Polymers
  • Doxorubicin
  • Poloxalene
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (physiology)
  • Animals
  • Antibiotics, Antineoplastic (pharmacology)
  • Biological Transport
  • CHO Cells
  • Cricetinae
  • Doxorubicin (administration & dosage, pharmacokinetics, pharmacology)
  • Drug Resistance, Multiple
  • Female
  • Humans
  • Poloxalene (pharmacology)
  • Polymers (pharmacology)

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