Su5416, a receptor tyrosine kinase inhibitor, is active in preclinical models of acute myeloid leukemia

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Abstract

SU5416 is a molecule highly active in inhibiting the KDR receptor tyrosine kinase (RTK) expressed by endothelial cells. This drug, now in phase HI clinical studies, is well tolerated and active in a number of solid tumors, possibly because of anti-angiogenic properties. We and others have described that angiogenesis is relevant in most hematological malignancies, that KDR is expressed in about 50% of acute myeloid leukemia (AML) cells, and that autocrine KDR stimulation by VEGF activates AML proliferation and migration (Cancer Res 2000;60:2527 and JCI 2000;106:5i 1). Since SU5416 has been recently found to inhibit also c-kit, another RTK expressed in a large proportion of AML, we evaluated SU5416 in vitro in a panel of hematopoietic neoplastic cell lines. Inhibition of proliferation and induction of apoptosis were minimal in KDR-, c-kit- lines. Conversely, proliferation of lines expressing KDR and/or c-kit was significantly inhibited by 5-10 uM SU5416, at median levels ranging from 5% (KDR+, c-kit- myeloma line JJN3) to 68% (KDR+, c-kit+ line K-562). Culture in the presence of 10 uM SU5416 induced a significant increase of apoptosis. Thus, we evaluated SU5416 in preclinical AML models by means of NOD/SCID mice transplanted with AML cells (n=6 per study group). As we recently described (Cancer Res 2000;60:2527), this model underlines the relevance of angiogenesis in hematological malignancies including AML and shows neo-vascularization patterns similar to human diseases. Mice transplanted with KDR-, c-kit- AML line KG 1A were treated with 50 mg/Kg SU5416 ip every other day. Control mice received drug vehicle. In SU5416 treated mice, tumor growth was delayed of one week, tumor weight was significantly reduced, and tumors had significantly larger necrotic areas. In a second series of studies, mice were transplanted with KDR-,c-kit+ AML line MEG-01. In vehicletreated mice, median survival time was 52 days and all mice died of leukemia within day 60. MEG-01 leukemia growth was significantly delayed in mice given SU5416 (median survival time 66 days), and 33% of mice given SU5416 are still alive 100 days after transplantation (p

Original languageEnglish
JournalBlood
Volume96
Issue number11 PART I
Publication statusPublished - 2000

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ASJC Scopus subject areas

  • Hematology

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