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CEP-701, a selective FLT3 tyrosine kinase inhibitor that is cytotoxic to FLT3/ITD-expressing leukemia cells, is synergistic with chemotherapeutic agents in vitro when used in time-sequential fashion



CEP-701, a selective FLT3 tyrosine kinase inhibitor that is cytotoxic to FLT3/ITD-expressing leukemia cells, is synergistic with chemotherapeutic agents in vitro when used in time-sequential fashion



Blood 102(11): 66a, November 16



Acute myeloid leukemia (AML) patients harboring internal tandem duplication mutations of the FLT3 receptor (FLT3/ITD mutations) have a poor prognosis. Incorporation of FLT3 inhibitors into existing chemotherapeutic regimens has tremendous potential to improve clinical outcomes in this high-risk group of patients. CEP-701, an indolocarbazole-derived selective FLT3 inhibitor, potently induces apoptosis, associated with a G1/S cell cycle arrest, in FLT3/ITD-expressing cell lines and primary leukemic blasts. The drug has minimal effect on cell lines that lack FLT3 protein expression, such as HL60. In a series of in vitro cytotoxicity experiments using the FLT3/ITD-expressing cell lines MV4-11 and BaF3/ITD as well as primary blast samples harboring FLT3/ITD mutations (HL60 cells were used as a control), we found that CEP-701 induced cytotoxicity in synergistic fashion with daunorubicin, mitoxantrone, and etoposide if used simultaneously or immediately following exposure to the chemotherapeutic agent. In BaF3/ITD cells pre-treated for one hour with 10 nM mitoxantrone, 14 uM etoposide, or 175 nM daunorubicin (all IC50 values for the chemotherapeutic agent alone) the IC50 for CEP-701 decreased from 7 nM to 4 nM. Likewise, simultaneous exposure to IC50 levels of these same chemotherapeutic agents increased the sensitivity of the FLT3/ITD, cell lines to CEP-701. Median effect analysis using the method of Chou and Talalay confirmed that these results reflected synergistic interaction between CEP-701 and the chemotherapeutic agents. In contrast, the combination of pre-treatment with CEP-701 followed by chemotherapy was antagonistic with CEP-701, particularly with the more cell-cycle-dependent agents such as cytarabine. For example, in experiments using MV4-11 cells pre-treated with CEP-701 followed by exposure to chemotherapy, the IC50 for cytarabine increased from 3.0 uM to 10+ uM, the IC50 for etoposide increased from 0.2 uM to 3.4 uM, and the IC50 for daunorubicin increased from 14 nM to 30 nM. This chemoresistance may have been due to the cell cycle arresting properties of CEP-701. If cells are treated with CEP-701 alone for a brief period prior to exposure to chemotherapy, the resultant cell cycle arrest apparently protects them from the full effect of the more cell-cycle specific agents. As expected, no interactions were observed between CEP-701 and chemotherapy in the control HL60 cells. We conclude that in FLT3/ITD-expressing leukemia cells, CEP-701 is synergistic with standard AML chemotherapeutic agents, but only if used simultaneously or immediately following the chemotherapy. On the basis of these findings, we have designed a treatment regimen combining CEP-701 in a time-sequential fashion with selected chemotherapeutic agents for a phase II trial scheduled to begin accrual shortly.

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Accession: 034515705

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