Liposome-encapsulated daunorubicin for PGP-related multidrug resistance.
The possibility that Daunoxome (DNX), a combination of daunorubicin (DNR) with a liposomal targeting system, escapes PGP was tested. Two pairs of leukaemic cell lines, each consisting of the parental non-multidrug resistance (MDR) line and of a MDR variant, were studied for cytotoxicity (MTT test) and for cellular DNR kinetic and accumulation (flow cytometry). DNX and free DNR were equally toxic against non-MDR cells, whereas the liposomal anthracycline was more toxic than the free drug against the MDR variant. Non-MDR cells accumulated DNR more rapidly when they were exposed to free DNR than to DNX, but MDR cells accumulated more DNR when they were exposed to DNX. The kinetics of DNX and free DNR were also studied in the blast cells of 41 cases of acute leukaemia and they were found to be related to blast cell PGP expression. In 15 cases with a low PGP expression intracellular DNR accumulation was faster and higher with free DNR than with DNX. In 26 cases with a high PGP expression the area under the curve was similar with DNX and free DNR, but the kinetics of intracellular DNR accumulation showed an early low plateau with free DNR and a slow and continuous increase with DNX. In MDR cell lines the ratio was more favourable to DNX than to free DNR. We conclude that liposome encapsulated DNR is partially protected from PGP and that it is worth testing for the treatment of PGP-positive acute leukaemia.
Michieli
M
M
Division of Haematology, Department of Medical and Morphological Research, Udine University Hospital, Italy.
Damiani
D
D
Ermacora
A
A
Masolini
P
P
Michelutti
A
A
Michelutti
T
T
Russo
D
D
Pea
F
F
Baccarani
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000208:Acute Disease; D003630:Daunorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D008081:Liposomes; D003630:Daunorubicin