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Reversal of multi-drug resistance in vitro by fatty acid-PEG-fatty acid diesters.

Abstract：

:Fatty acid ester surfactants, e.g., Cremophor EL and Solutol HS 15, that modulate multi-drug resistance (MDR) have been described; however, the drug potential of these preparations is unclear because of the molecular heterogeneity of these and other commercial surfactants. In previous experiments, an active but still polydisperse preparation, designated CRL 1337, was synthesized by reacting purified oleic acid with a 20-fold molar excess of ethylene oxide. We have subjected this preparation to chromatographic separation, and infrared analysis of the active fractions revealed a significant component of diester structures (fatty acid-PEG-fatty acid). A new generation of diester compounds has now been synthesized. Preparations comprised of 99% diesters were significantly more potent than monoester preparations for MDR modification activity in vitro. As previously determined for ethylene oxide-derived preparations similar to CRL 1337, the nature of the fatty acid domains proved to be important for activity, as was the relative length of the polyethylene glycol domain (which determines the hydrophile-lipophile balance). The ester linkage appeared unimportant since homologous diethers and diamides had activity similar to that of diesters. Stearic acid diester was 1.5- to 7-fold more potent than CRL 1337 when tested in cell proliferation inhibition assays. In light of these structural restrictions on drug potentiation, and since these surfactants are active at relatively low concentrations (below 1 microgram/ml), investigations of their mechanism of action were initiated by exploring specific interactions with P-glycoprotein. Both active and inactive diesters inhibited azidopine labeling of P-glycoprotein, suggesting that fatty acid-PEG diesters can interfere with P-glycoprotein substrate binding. Other attributes of these preparations must contribute to their ability to reverse MDR.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Buckingham LE,Balasubramanian M,Safa AR,Shah H,Komarov P,Emanuele RM,Coon JS

doi

10.1002/(SICI)1097-0215(19960103)65:1<74::AID-IJC1

subject

Has Abstract

pub_date

1996-01-03 00:00:00

pages

74-9

issue

eissn

0020-7136

issn

1097-0215

pii

10.1002/(SICI)1097-0215(19960103)65:1<74::AID-IJC1

journal_volume

pub_type

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Reversal of multi-drug resistance in vitro by fatty acid-PEG-fatty acid diesters.