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.
Original language | English (US) |
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Pages (from-to) | 1368-1376 |
Number of pages | 9 |
Journal | Leukemia |
Volume | 20 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2006 |
Keywords
- Acute lymphoblastic leukemia
- CEP-701
- FLT3
- MLL
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research