The effect of crown ethers, tetraalkylammonium salts, and polyoxyethylene amphiphiles on pirarubicin incorporation in K562 resistant cells.
The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance (P-gp-MDR) is a decrease in steady-state accumulation drug levels as compared to drug-sensitive controls. In an attempt to identify mechanism(s) by which MDR can be circumvented, we examined the cellular accumulation, in resistant cells, of 4'-O-tetrahydropyranyl-doxorubicin (pirarubicin) alone and in conjunction with various molecules belonging to three different classes: the crown ethers, the tetraalkylammonium salts, and the polyoxethylene amphiphiles. The present study was performed using a spectrofluorometric method which enabled us to follow the uptake and release of fluorescent molecules by living cells while the cells were being incubated with the drug. Erythroleukemia K562 cell lines were used. Our data show that the compounds of these three completely different classes were able to increase the incorporation of pirarubicin provided they had a minimum degree of lipophilicity. Study of the growth inhibitory activity of these compounds revealed that cross-resistance to the tetraalkyl ammonium salt increased with the lipophilicity and was equal to 58 for tetraoctylammonium salt, the most lipophilic compound of this series. This demonstrates that neither the presence of a positive charge nor an aromatic moiety is required for MDR recognition.
Borrel
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MN
Laboratoire de Physico-chimie Biomoléculaire et Cellulaire (URA CNRS 2056) UFR Léonard de Vinci, Université Paris Nord, Bobigny, France.
Fiallo
M
M
Veress
I
I
Garnier-Suillerot
A
A
D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004988:Ethers, Cyclic / Q000494:pharmacology*; D006801:Humans; D011092:Polyethylene Glycols / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004988:Ethers, Cyclic; D000644:Quaternary Ammonium Compounds; D013757:Tetraethylammonium Compounds; D011092:Polyethylene Glycols; D004317:Doxorubicin; C027260:pirarubicin