Additive effect of PTK787/ZK 222584, a potent inhibitor of VEGFR phosphorylation, with Idarubicin in the treatment of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a disease with a poor prognosis. It has been demonstrated that AML cells express vascular endothelial growth factor (VEGF) as well as Flt-1 and KDR, resulting in an autocrine pathway for cell survival. PTK787/ZK 222584 is a new oral antiangiogenic molecule that inhibits tyrosine kinase activity of all known VEGF receptors. The present study aimed to investigate the therapeutic efficacy of combining PTK787/ZK 222584 with a chemotherapeutic agent, such as Idarubicin, for treatment of AML. We have analyzed in four AML cell lines and seven AML patient samples, cell proliferation, apoptosis, angiogenesis. and activation of several related intracellular pathways after treatment with PTK787/ZK 222584 alone or combined with Idarubicin. PTK787/ZK 222584 decreased VEGF levels and VEGF receptor phosphorylation in the AML cells showing Fms-like tyrosine kinase 3/internal tandem duplication mutation (Flt3/ITD). Both drugs, given separately, inhibited cell proliferation and promoted apoptosis. Moreover, combined treatment promoted more apoptosis and inhibition of cell proliferation than each compound administered separately in all AML cells. In conclusion, PTK787/ZK 222584 combined with Idarubicin achieved a better therapeutic efficacy than chemotherapy alone in AML cells, especially in those with Flt3/ITD, in which the combination further prevented activation of the angiogenic process.