title: Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) is a genetically heterogeneous cancer that frequently exhibits aberrant kinase signaling. We investigated a treatment strategy combining sorafenib, a multikinase inhibitor with limited single-agent activity in AML, and cytarabine, a key component of AML chemotherapy.
  
  
  METHODS
  Using 10 human AML cell lines, we determined the effects of sorafenib (10 μM) on antileukemic activity by measuring cell viability, proliferation, ERK1/2 signaling, and apoptosis. We also investigated the effects of sorafenib treatment on the accumulation of cytarabine and phosphorylated metabolites in vitro. A human equivalent dose of sorafenib in nontumor-bearing NOD-SCID-IL2Rγ(null) mice was determined by pharmacokinetic studies using high performance liquid chromatography with tandem mass spectrometric detection, and steady-state concentrations were estimated by the fit of a one-compartment pharmacokinetic model to concentration-time data. The antitumor activity of sorafenib alone (60 mg/kg) twice daily, cytarabine alone (6.25 mg/kg administered intraperitoneally), or sorafenib once or twice daily plus cytarabine was evaluated in NOD-SCID-IL2Rγ(null) mice bearing AML xenografts.
  
  
  RESULTS
  Sorafenib at 10 μM inhibited cell viability, proliferation and ERK1/2 signaling, and induced apoptosis in all cell lines studied. Sorafenib also increased the cellular accumulation of cytarabine and metabolites resulting in additive to synergistic antileukemic activity. A dose of 60 mg/kg in mice produced a human equivalent sorafenib steady-state plasma exposure of 10 μM. The more dose-intensive twice-daily sorafenib plus cytarabine (n = 15) statistically significantly prolonged median survival in an AML xenograft model compared with sorafenib once daily plus cytarabine (n = 12), cytarabine alone (n = 26), or controls (n = 27) (sorafenib twice daily plus cytarabine, median survival = 46 days; sorafenib once daily plus cytarabine, median survival = 40 days; cytarabine alone, median survival = 36 days; control, median survival = 19 days; P < .001 for combination twice daily vs all other treatments listed).
  
  
  CONCLUSIONS
  Sorafenib in combination with cytarabine resulted in strong anti-AML activity in vitro and in vivo. These results warrant clinical evaluation of sorafenib with cytarabine-based regimens in molecularly heterogeneous AML.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Niu
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.forename: Shelley
authors.initials: S
authors.lastname: Orwick
authors.forename: Charles
authors.initials: C
authors.lastname: Rose
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Shengping
authors.initials: S
authors.lastname: Yang
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.forename: Christopher
authors.initials: C
authors.lastname: Calabrese
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015986:Confounding Factors, Epidemiologic; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D001557:Benzenesulfonates; D003561:Cytarabine; D053631:Interleukin Receptor Common gamma Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077157:Sorafenib; C421142:ABCC10 protein, human; C435500:ABCC11 protein, human; C507941:IL2RG protein, human; C535150:MAPK1 protein, human