title: In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy.
abstract: We demonstrate here that cytarabine and daunorubicin, a standard drug combination used in the treatment of leukaemia, exhibits drug ratio-dependent synergistic antitumor activity in vitro and in vivo. A cytarabine:daunorubicin molar ratio of 5:1 displayed the greatest degree of synergy and minimum antagonism in a panel of 15 tumor cell lines in vitro. Co-encapsulating cytarabine and daunorubicin inside liposomes maintained the synergistic drug ratio in plasma for 24h post-injection. Liposome-encapsulated cytarabine:daunorubicin combinations exhibited drug ratio-dependent in vivo efficacy with the 5:1 molar drug ratio (designated CPX-351) having the greatest therapeutic index, despite using sub-MTD daunorubicin doses. CPX-351 exhibited superior therapeutic activity compared to free-drug cocktails, with high proportions of long-term survivors, consistent with in vivo synergy. The therapeutic advantage of CPX-351 was associated with prolonged maintenance of synergistic drug ratios in bone marrow. These results indicate that in vitro informatics on cytarabine:daunorubicin cytotoxicity can be translated in vivo to optimize the efficacy of anticancer drug combinations by controlling the exposure of drug ratios with drug delivery vehicles.
authors.affiliation: Celator Pharmaceuticals Corporation, 1779 West 75th Avenue, Vancouver, BC, Canada V6P 6P2. ptardi@celatorpharma.com
authors.forename: Paul
authors.initials: P
authors.lastname: Tardi
authors.forename: Sharon
authors.initials: S
authors.lastname: Johnstone
authors.forename: Natashia
authors.initials: N
authors.lastname: Harasym
authors.forename: Sherwin
authors.initials: S
authors.lastname: Xie
authors.forename: Troy
authors.initials: T
authors.lastname: Harasym
authors.forename: Natalia
authors.initials: N
authors.lastname: Zisman
authors.forename: Pierrot
authors.initials: P
authors.lastname: Harvie
authors.forename: David
authors.initials: D
authors.lastname: Bermudes
authors.forename: Lawrence
authors.initials: L
authors.lastname: Mayer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D003561:Cytarabine; D003630:Daunorubicin