In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy

Leuk Res. 2009 Jan;33(1):129-39. doi: 10.1016/j.leukres.2008.06.028. Epub 2008 Aug 3.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytarabine / administration & dosage
  • Cytarabine / pharmacokinetics
  • Cytarabine / pharmacology*
  • Daunorubicin / administration & dosage
  • Daunorubicin / pharmacokinetics
  • Daunorubicin / pharmacology*
  • Flow Cytometry
  • Humans
  • Liposomes
  • Mice

Substances

  • Antineoplastic Agents
  • Liposomes
  • Cytarabine
  • Daunorubicin