Reversal of multi-drug resistancein vitro by fatty acid PEG fatty acid diesters

Autor: Ahmad R. Safa, R. Martin Emanuele, Pavel G. Komarov, Lela Buckingham, Mannarsamy Balasubramanian, John S. Coon, Himanshu Shah
Rok vydání: 1996
Předmět:
Zdroj: International Journal of Cancer. 65:74-79
ISSN: 1097-0215
0020-7136
Popis: 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 I 337, 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 oxidederived 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 I .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 I pg/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. o 1996 Wiley-Liss, Inc. Multidrug resistance (MDR) entails simultaneous crossresistance to a distinct group of seemingly unrelated chemotherapeutic agents through a common mechanism (Pastan and
Databáze: OpenAIRE
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