期刊
LEUKEMIA
卷 20, 期 8, 页码 1368-1376出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.leu.2404277
关键词
FLT3; MLL; CEP-701; acute lymphoblastic leukemia
资金
- NCI NIH HHS [CA70970, CA100632] Funding Source: Medline
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.
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