Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia.
We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 micromol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 micromol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by > or =50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML.
Hu
Shuiying
S
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale Street, DTRC Room D1034, Mail Stop 314, Memphis, TN 38105, USA.
Niu
Hongmei
H
Minkin
Patton
P
Orwick
Shelley
S
Shimada
Akira
A
Inaba
Hiroto
H
Dahl
Gary V H
GV
Rubnitz
Jeffrey
J
Baker
Sharyn D
SD
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077157:Sorafenib; D000077210:Sunitinib
D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib