Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts.
The objective of this study was to examine the pharmacodynamic basis for the potent preclinical and clinical anti-leukemic activity of CPX-351, a nano-scale liposome formulation of cytarabine and daunorubicin co-encapsulated at a synergistic 5:1 molar ratio. A bone marrow-engrafting CCRF-CEM leukemia model in Rag2-M mice was utilized to correlate the therapeutic and myelosuppressive properties of CPX-351 with bone marrow delivery and drug uptake in leukemia cells relative to normal bone marrow cell populations. When administered to mice bearing CCRF-CEM human leukemia xenografts, CPX-351 ablated bone marrow (BM) leukemic cells to below detectable levels for multiple weeks, whereas the free-drug cocktail only transiently suppressed leukemia growth. In contrast to the activity against leukemia cells, CPX-351 and free-drug cocktail induced similar myelosuppression in non-tumor-bearing BM. In leukemia-laden BM, drug concentrations were markedly elevated for CPX-351 over free-drug cocktail and the first dose of CPX-351, but not free-drug cocktail, potentiated BM drug accumulation for subsequent doses. Confocal fluorescence microscopy revealed that CPX-351 liposomes are taken up by CCRF-CEM cells and subsequently release drugs intracellularly. The improved in vivo efficacy of CPX-351 appears related to increased and prolonged exposure of synergistic cytarabine:daunorubicin ratios in BM, and the selective killing of leukemia may arise from direct liposome-leukemia cell interactions. These features may also have broader applicability in the treatment of other haematological malignancies.
Celator Pharmaceuticals Corporation, 1779W. 75th Avenue, Vancouver, BC V6P 6P2, Canada.
Wah-Seng
WS
Lim
Paul G
PG
Tardi
Nancy
N
Dos Santos
Xiaowei
X
Xie
Mannie
M
Fan
Barry D
BD
Liboiron
Xiaoping
X
Huang
Troy O
TO
Harasym
David
D
Bermudes
Lawrence D
LD
Mayer
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001853:Bone Marrow / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D003561:Cytarabine; D003630:Daunorubicin