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Experimental and Molecular Therapeutics 25: Novel Approaches to Drug Delivery

Cytarabine (Cyt):Daunorubicin (Daun) combined inside liposomes at a fixed synergistic ratio leads to potent therapeutic activity against a range of preclinical leukemia models

Sharon A. Johnstone, Pierrot Harvie, Salam Kadhim, Troy Harasym, Paul Tardi, Natashia Harasym and Lawrence Mayer
Sharon A. Johnstone
Celator Pharmaceuticals, Vancouver, BC, Canada
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Pierrot Harvie
Celator Pharmaceuticals, Vancouver, BC, Canada
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Salam Kadhim
Celator Pharmaceuticals, Vancouver, BC, Canada
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Troy Harasym
Celator Pharmaceuticals, Vancouver, BC, Canada
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Paul Tardi
Celator Pharmaceuticals, Vancouver, BC, Canada
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Natashia Harasym
Celator Pharmaceuticals, Vancouver, BC, Canada
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Lawrence Mayer
Celator Pharmaceuticals, Vancouver, BC, Canada
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DOI:  Published April 2006
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Proc Amer Assoc Cancer Res, Volume 47, 2006

Abstract

3061

We have previously demonstrated that Cyt:Daun combinations can interact synergistically or antagonistically when exposed to cancer cells in vitro depending on the ratio of the two agents. We were able to maintain a synergistic 5:1 Cyt:Daun molar ratio after in vivo administration by delivering the drug combination in a liposomal carrier. In the present study we examined the therapeutic activity of this liposomal Cyt:Daun formulation (CPX-351) in a variety of preclinical leukemia models representing a range of cell lineages. The efficacy of CPX-351 was compared to that of free drugs combined in saline as well as individual drugs encapsulated in liposomes. When injected intravenously in mice, CPX-351 not only maintained the synergistic 5:1 molar ratio of Cyt:Daun in the plasma for 24h, but also provided total drug AUC values that were >500- and 4,000-fold higher than Cyt and Daun respectively, given as a free drug combination in saline. Intravenous treatment with CPX-351 resulted in >90% cure rates and maximum increase in life span (ILS) values >500% in mice bearing ascitic P388 and L1210 murine lymphocytic as well as WEHI-3B murine monomyelocytic leukemia. In contrast, Cyt:Daun administered at a molar ratio in saline at its MTD provided no long-term survivors and significantly lower ILS values of 214%, 86% and 122%, respectively, in these tumor models. In addition, dose-matched comparisons of efficacy for individual liposomal drugs at sub-curative doses indicated that CPX-351 activity was far greater than predicted based on additive contributions of the two agents. A 100% cure rate was observed for CPX-351 treatment of mice bearing engrafted CCRF-CEM human T-lymphoblastoid leukemia cells whereas the maximum tolerated dose (MTD) of the free drug combination in saline provided an ILS value of only 34%. CPX-351 was also superior to free agents against the more drug-resistant engrafted human promyelocytic leukemia HL60 model with an ILS value of 43% compared to 20% for the MTD of the free drug cocktail. These results confirm that controlled delivery of Cyt and Daun at synergistic drug:drug ratios using liposomes dramatically enhances therapeutic activity, further validating the approach of using in vitro information on drug:drug ratios and drug delivery technology to optimize therapeutic activity of drug combinations in vivo.

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Cancer Research: 66 (8 Supplement)
April 2006
Volume 66, Issue 8 Supplement
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Cytarabine (Cyt):Daunorubicin (Daun) combined inside liposomes at a fixed synergistic ratio leads to potent therapeutic activity against a range of preclinical leukemia models
Sharon A. Johnstone, Pierrot Harvie, Salam Kadhim, Troy Harasym, Paul Tardi, Natashia Harasym and Lawrence Mayer
Cancer Res April 15 2006 (66) (8 Supplement) 720;

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Cytarabine (Cyt):Daunorubicin (Daun) combined inside liposomes at a fixed synergistic ratio leads to potent therapeutic activity against a range of preclinical leukemia models
Sharon A. Johnstone, Pierrot Harvie, Salam Kadhim, Troy Harasym, Paul Tardi, Natashia Harasym and Lawrence Mayer
Cancer Res April 15 2006 (66) (8 Supplement) 720;
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