The Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Possess Strong Inhibitory Effect on Tumor Growth In a CLL-Like Xenograft Mouse Model

Abstract 1393

As chronic lymphocytic leukemia (CLL) is still mainly treated using unspecific chemotherapy, new targeted therapies are highly desirable. Vatalanib and Pazopanib are potent orally available receptor tyrosine kinase inhibitors with high selectivity towards the vascular endothelial growth factor (VEGF)-receptor. VEGF-signaling is critically involved in the microenvironment-mediated prolonged survival of CLL cells. We investigated the efficacy and selectivity of both compounds in CLL cells and tested their effect on CLL like tumor xenografts in nude mice. Primary CLL cells (n=20) and healthy B-cells (n=5) were treated with Vatalanib and Pazopanib ranging from 1 to 200 μM. Both substances were tested for their apoptosis-inducing efficiency in a CLL cell coculture with the bone marrow-derived stromal cell line HS5 (n=4), which provides a strong survival support for CLL cells and mimick the in vivo situation. Apoptosis induction was monitored flow cytometrically by Annexin V-FITC/PI staining and by immunoblotting of caspases and PARP. Further, both compounds were administered daily via oral gavage at 100 mg/kg bodyweight to nude mice engrafted with CLL-like JVM3 cells for 21 days (n=10/group). Both substances effectively induced apoptosis in primary CLL cells with lethal concentration (LC) 50 of 48.4 μM and 32.7 μM for Vatalanib and Pazopanib, respectively. Healthy B-cells were largely unaffected. Furthermore, both substances showed similar apoptosis-inducing capacity when CLL cells were maintained on a survival-supporting HS5 feederlayer. In a CLL-like xenograft mouse model tumor growth was significantly inhibited by 76% and 77% after a treatment period of 21 days for Vatalanib and Pazopanib, respectively. In two mice complete tumor eradication could be observed after treatment with Vatalanib. No adverse side effects were observed during the treatment period. We conclude that the receptor tyrosine kinase inhibitors Vatalanib and Pazopanib have strong and selective anti-neoplastic activity towards CLL cells. As they are orally available and in general well tolerated they deserve further evaluation as a potential new therapeutic option for treatment of CLL.