Drug-containing lipid vesicles render drug-resistant tumour cells sensitive to actinomycin D

George Poste, Demetrios Papahadjopoulos

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Abstract

DEVELOPMENT of cellular resistance to actinomycin D (AD) has been reported in tumour cell populations in vivo1,2 and in vitro3-6. Such cells have a lower capacity than normal to incorporate AD3,6-8, prompting suggestions that the AD-resistant phenotype is determined by changes in plasma membrane function that reduce cellular permeability to this drug. Support for this proposed mechanism of drug resistance has been provided by experiments showing that treatment of AD-resistant cells with membrane-active detergents, to increase plasma membrane permeability, enhances AD uptake by resistant cells and reduces the concentration of AD required to inhibit cell growth8,9. This approach, while instructive, has the disadvantage that the detergent causes significant alteration in cell viability and also impairs cell growth8. We now report a new method for enhancing drug uptake by permeability restriction, drug-resistant cells which uses lipid vesicles as carrier agents to introduce AD directly into cells. As reported elsewhere10,11, negatively-charged lipid vesicles composed of lipids or lipid mixtures that are "fluid" at 37 °C are incorporated into cultured cells by fusion with the cellular plasma membrane. Entrapment of drugs inside such vesicles and subsequent fusion of the vesicles with cells offers a potential method for bypassing the plasma membrane transport barrier to introduce drugs directly into the intracellular compartment. Since vesicles are not cytotoxic10-12, their use as drug carriers allows direct evaluation of the cellular response to the introduced drug, free from the complications8,9,13 associated with the use of detergents. The results presented here indicate that uptake of vesicles containing AD by AD-resistant cells produces inhibition of cellular RNA synthesis and cell growth at AD concentrations that have no effect on cells when added as free drug to the culture medium.

Original languageEnglish (US)
Pages (from-to)699-701
Number of pages3
JournalNature
Volume261
Issue number5562
DOIs
StatePublished - Dec 1 1976
Externally publishedYes

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