Abstract 13269: The Tyrosine Kinase Inhibitor Nilotinib Induces Vascular Adverse Events in Patients With Chronic Myeloid Leukemia and Inhibits Endothelial Function and Angiogenesis
The second-generation BCR/ABL tyrosine kinase inhibitor nilotinib (nilo) is used for treatment of patients (pts) with chronic myeloid leukemia. Nilo has been considered a well-tolerated drug however the occurrence of peripheral arterial disease (PAD) has been reported in several centers. We therefore analyzed our patients treated with nilo, performed a mouse model of hindlimb ischemia (HLI) and examined the in-vitro effects on endothelial cells (ECs).
A total number of 34 pts receiving nilo were examined (median observation time: 2 years). Vascular events were recorded in 9 pts (26.5%) and the majority (6 pts, 17.6%) had PAD. The frequency of PAD in matched control (ctr) cohorts (CML pts receiving imatinib (ima), lymphoproliferative and myeloproliferative neoplasms, each n=34 pts) was significantly lower (<5%) than in the nilo group (P<0.05).
In mouse HLI nilo but not ima inhibited blood perfusion 4 weeks after ischemia (laser Doppler perfusion ratio ischemic/ctr leg: ctr: 0.81±0.03, ima:
0.79±0.04, nilo: 0.68±0.04; n=13/group; P<0.05 nilo vs. ctr and ima) and increased tissue necrosis (necrosis scores: ctr 1.15±0.08, ima 1.17±0.05, nilo 1.54±0.18; n=13, P<0.05 nilo vs. ctr and ima). Capillary density was reduced by nilo but not by ima (capillaries/high powered field: ctr: 212±9, nilo: 160±7, ima: 218±16; n=13, P<0.05 nilo vs. ctr and ima).
As assessed by 3H-thymidine incorporation, nilo was found to dose-dependently inhibit the proliferation of human ECs, with pharmacologically relevant IC50 values between 100 nM (coronary artery ECs) and 1.0 μM (umbilical vein ECs). By contrast, ima showed only little if any effects. Moreover, nilo increased caspase activity suggesting induction of apoptosis and inhibited migration of ECs in a wound-scratch assay as well as angiogenesis in a tube formation assay (rel. capillary tubes: VEGF+ctr:
1.8±0.1, VEGF+nilo (100 nM): 1.3±0.1, VEGF+ima (100 nM): 1.7±0.05; n=3, P<0.01 for VEGF+ima vs. VEGF+nilo).
Our data indicate that nilotinib inhibits EC function in-vitro as well as angiogenesis in-vivo. In patients with CML, nilotinib might be associated with an increased risk of adverse vascular events. Future evaluations should identify the mechanism of nilotinib-induced vasculopathy and endothelial dysfunction.
- © 2013 by American Heart Association, Inc.