Inability of liposome encapsulated 1-β- d-arabinofuranosylcytosine nucleotides to overcome drug resistance in L1210 cells

Youcef M. Rustum; Eric Mayhew; Francis Szoka; Joel Campbell

doi:10.1016/0014-2964(81)90237-1

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Journal article

Inability of liposome encapsulated 1-β- d-arabinofuranosylcytosine nucleotides to overcome drug resistance in L1210 cells

Youcef M. Rustum, Eric Mayhew, Francis Szoka and Joel Campbell

European journal of cancer & clinical oncology, Vol.17(7), pp.809-817

1981

DOI: 10.1016/0014-2964(81)90237-1

PMID: 7199474

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Abstract

The uptake, metabolism and antitumor activity of 1-β- d-arabinofuranosylcytosine nucleotides encapsulated in liposomes were investigated in L1210 cells sensitive and resistant to the drug. These studies were carried out in order to determine whether encapsulation of the presumed active component of the drug, namely, arabinofuranosylcytosine 5′ triphosphate will convert resistant cells to sensitive. The results indicate that liposome entrapment of Ara-CMP and Ara-CTP did not result in increased delivery of these metabolites into L1210 cells. The amount of nucleotide found intracellularly following an in vitro incubation of encapsulated drugs with L1210 cells did not exceed the level expected from a simple extracellular breakdown of liposome releasing their contents with subsequent uptake and phosphorylation of the released nucleoside. Further evidence for lack of enhancement of drug uptake by liposome encapsulation were obtained when the rate of incorporation of TdR into DNA of L1210/Ara-C was not significantly affected by Ara-CTP encapsulation in liposome. The data presented herein also demonstrated that the in vivo sensitivity of L1210 cells resistant to Ara-C could not be modified by encapsulation of Ara-CTP in liposomes. The results strongly suggest that encapsulation of drugs unmodified or untargeted liposomes will not be able to overcome drug resistance related to transport defect and/or deletion of intracellular activating enzyme(s).

Ara-C

Ara-CMP Ara-CDP and Ara-CTP

Ara-UMP

arabinofuranosylcytosine

arabinofuranosyluridine 5′ monophosphate

CHOL

cholesterol

HEPES/MOPS

high pressure liquid chromatograph

HPLC

KOH

L1210/0, and L1210/Ara-C

leukemia L1210 cells sensitive and resistant to Ara-C, respectively

N-2-hydroxyethylpiperazine- N'-2-ethanesulfonic acid/morpholinopropane sulfonic acid

PCA

perchloric acid

phosphatidylcholine

phosphatidylserine

potassium hydroxide

REV

reverse evaporation phase vesicles

sonicated unilamellar vesicles

SUV

the 5′ mono, 5′ di-and 5′-triphosphates of Ara-C, respectively

Details

Title: Subtitle: Inability of liposome encapsulated 1-β- d-arabinofuranosylcytosine nucleotides to overcome drug resistance in L1210 cells
Creators: Youcef M. Rustum - Roswell Park Cancer Institute
Eric Mayhew - Roswell Park Cancer Institute
Francis Szoka - Roswell Park Cancer Institute
Joel Campbell - Roswell Park Cancer Institute
Resource Type: Journal article
Publication Details: European journal of cancer & clinical oncology, Vol.17(7), pp.809-817
Publisher: Elsevier Ltd
DOI: 10.1016/0014-2964(81)90237-1
PMID: 7199474
ISSN: 0277-5379
Language: English
Date published: 1981
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359671602771

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