Liposomal encapsulation of a synergistic molar ratio of cytarabine and daunorubicin enhances selective toxicity for acute myeloid leukemia progenitors as compared to analogous normal hematopoietic cells

• Published in: Experimental hematology 2011-07, Vol.39 (7), p.741-750
• Main Authors: Kim, Hyun Pyo, Gerhard, Brigitte, Harasym, Troy O, Mayer, Lawrence D, Hogge, Donna E
• Format: Article
• Language: English
• Subjects: Acute Disease; Advanced Basic Science; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Colony-Forming Units Assay; Cytarabine - pharmacology; Daunorubicin - pharmacology; Dose-Response Relationship, Drug; Drug Combinations; Drug Compounding; Drug Synergism; Flow Cytometry; Hematology, Oncology and Palliative Medicine; Humans; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Liposomes; Stem Cells - drug effects; Stem Cells - metabolism; Tumor Cells, Cultured
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2011.04.001

Objective To evaluate the possibility of improved selective killing of acute myeloid leukemia (AML) cells with CPX-351 (a liposomal formulation of cytarabine and daunorubicin). CPX-351 and the same molar ratio of free drugs were compared for cytotoxicity against colony-forming cells (CFCs) and subpopulations of cells enriched for primitive progenitors from AML patients and normal granulocyte colony-stimulating factor−mobilized peripheral blood (PB) and bone marrow (BM) donors. Materials and Methods AML blasts (n = 13) and normal PB and BM cells (n = 7) were incubated for 24 hours in various concentrations of CPX-351 or free drugs before plating in CFC assay or staining with anti-CD34 and anti-CD38 antibodies, Annexin-V, and propidium iodide followed by fluorescence-activated cell sorting analysis. High performance liquid chromatography was used to measure intracellular daunorubicin accumulation. Results AML blasts and progenitors from patients who achieved complete remission were more sensitive to both CPX-351 and free drugs than the same cells from patients with chemotherapy refractory leukemia. However, AML CFCs and CD34+ CD38− AML blasts (enriched for candidate leukemia stem cells) from the same patient showed similar sensitivity to the liposomal or free drug formulations. In contrast, CFCs and CD34+ CD38− cells from normal PB and BM were fivefold more sensitive to the free drugs than to CPX-351. Consistent with these observations, preferential intracellular accumulation of CPX-351 in AML over normal cells was observed, while there was little difference in drug uptake between AML and normal cells with the free drug cocktail. Conclusions CPX-351, as compared to free cytarabine:daunorubicin, shows enhanced selective in vitro cytotoxicity for AML rather than normal progenitors.