Enhancement of murine tumor cell sensitivity to adriamycin by presentation of the drug in phosphatidylcholine-phosphatidylserine liposomes.
In vitro incubation of mouse UV-2237M fibrosarcoma cells with liposomes containing Adriamycin (ADR) produced significant cytotoxicity in drug-sensitive cells and in multidrug-resistant variants of this tumor. ADR was encapsulated in the aqueous space of multilamellar liposomes composed of phosphatidylcholine and phosphatidylserine. The preparation was stable in medium at 37 degrees C for up to 7 days. Free unencapsulated ADR produced cytostasis in parental ADR-sensitive cells but not in variant lines selected for resistance to the drug. In contrast, ADR encapsulated in multilamellar liposomes (MLV) produced high levels of cytostasis in both ADR-sensitive and ADR-resistant cells. The phospholipid composition of the MLV influenced the outcome of ADR-mediated cytostasis. ADR encapsulated in MLV consisting of only phosphatidylcholine did not produce cytostasis. Increasing the proportion of phosphatidylserine in the MLV increased the level of ADR-mediated cytotoxicity in cells resistant to free ADR. This effect was not due to simple modification of tumor cell surface by liposomes since ADR added to resistant cells together with liposomes containing buffer produced less cytostasis. The cytostasis of resistant cells by ADR in liposomes was not due to appreciable changes in the intracellular ADR concentration or localization within the cells because ADR-induced DNA cleavage was not found in ADR-resistant cells treated with cytostatic amounts of liposomal ADR. Whether the enhanced sensitivity of tumor cells to ADR was due to localized damage to the plasma membrane through a phosphatidylserine-mediated release of the drug to the cell surface is now under active investigation.
Fan
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D
Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Bucana
C D
CD
O'Brian
C A
CA
Zwelling
L A
LA
Seid
C
C
Fidler
I J
IJ
D000818:Animals; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004273:DNA, Neoplasm; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin