Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner

Leukemia. 2006 Aug;20(8):1368-76. doi: 10.1038/sj.leu.2404277. Epub 2006 Jun 8.

Abstract

Mixed lineage leukemia (MLL) rearrangements occur in 80% of infants and 5% of older children with acute lymphoblastic leukemia (ALL). These cases have a poor prognosis with current therapy. The FLT3 kinase is overexpressed and constitutively activated in MLL-rearranged ALL cells. The FLT3 inhibitor CEP-701 selectively kills these cells, but is unlikely to be curative if used as monotherapy. To identify potentially synergistic combination strategies, we studied CEP-701 and six standard chemotherapeutic agents in three sequences of exposure (S1: chemotherapy followed by CEP-701, S2: simultaneous exposure to both; and S3: CEP-701 followed by chemotherapy) using MLL-rearranged ALL cell lines and patient bone marrow samples. MTT cytotoxicity and annexin V binding apoptosis assays were used to assess antileukemic effects. Combination indices (CI) were calculated for each combination (CI<0.9 - synergistic; CI 0.9-1.1 - additive; CI>1.1 - antagonistic). A striking pattern of sequence-dependent synergy was observed: S1 was markedly synergistic (mean CI=0.59+/-0.10), S2 was additive (mean CI=0.99+/-0.09) and S3 was antagonistic (mean CI=1.23+/-0.10). The sequence dependence is attributable to the effect of CEP-701 on cell cycle kinetics, and is mediated specifically by FLT3 inhibition, as these effects are not seen in control cells without activated FLT3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Carbazoles / administration & dosage*
  • Carbazoles / pharmacology
  • Cell Line, Tumor
  • Child
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Furans
  • G1 Phase / drug effects
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Indoles / administration & dosage*
  • Indoles / pharmacology
  • Infant
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Protein Kinase Inhibitors / administration & dosage*
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Carbazoles
  • Furans
  • Indoles
  • KMT2A protein, human
  • Protein Kinase Inhibitors
  • Myeloid-Lymphoid Leukemia Protein
  • lestaurtinib
  • Histone-Lysine N-Methyltransferase
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3