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

Abstract

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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.