The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic Leukemia Cells In vitro and In vivo

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BlankThe Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors

Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic

Leukemia Cells In vitro and In vivo

1.. n Paesler,

2.. Iris Gehrke,

3.. Rajesh Kumar Gandhirajan,

4.. andra Filipovich,

5.. Magdalena Hertweck,

6.. Felix Erdfelder,

7.. Uhrmacher,

8.. Simon Jonas Poll-Wolbeck,

9.. Hallek, and

10.. Karl-Anton Kreuzer

+ Author Affiliations

1.. Authors' Affiliation: Department I of Internal Medicine, University at

Cologne, Cologne, Germany

1.. Corresponding Author:

Karl-Anton Kreuzer, Department I of Internal Medicine, University at Cologne,

Kerpener Strasse 62, 50937 Cologne, Germany. Phone: 49-221-478-97382; Fax:

49-221-478-97383; E-mail: karl-anton.kreuzer@....

1.. J. Paesler and I. Gehrke contributed equally to this work.

Abstract

Purpose: There is evidence that vascular endothelial growth factor (VEGF) is a

critical microenvironmental factor that exerts angiogenesis-independent effects

on the survival of chronic lymphocytic leukemia (CLL) cells. Vatalanib and

pazopanib are potent orally available VEGF receptor tyrosine kinase inhibitors.

We investigated the efficacy and selectivity of both compounds in CLL cells,

simulated potential combination with conventional cytostatics, and tested the

effect of both substances on CLL-like tumor xenografts.

Experimental Design: Primary CLL and normal peripheral blood cells were tested

for viability after incubation with varying concentrations of both inhibitors.

Further, phosphorylation status of VEGF receptor on treatment, caspase

activation, and poly(ADP-ribose) polymerase cleavage were assessed. Combinations

of each inhibitor with fludarabine, vincristine, and doxorubicin were analyzed

for possible synergistic effects in vitro. For in vivo testing, mice grafted

with the CLL-like cell line JVM-3 were treated orally with each inhibitor.

Results: Vatalanib and pazopanib decreased phosphorylation of the VEGF receptor,

along with induction of apoptosis in CLL cells in clinically achievable

concentrations. Healthy B cells were only mildly affected. Immunoblots showed

downregulation of the antiapoptotic proteins XIAP and MCL1, whereas

poly(ADP-ribose) polymerase cleavage was increased. Combinations with

conventional cytostatic agents resulted in synergistic effects. Treatment of

xenografted mice with 100 mg/kg of body weight for 21 days resulted in tumor

inhibition rates of 76% (vatalanib) and 77% (pazopanib). In two mice, a total

tumor eradication could be observed. No gross systemic toxicity occurred.

Conclusion: We conclude that VEGF inhibition is a promising new therapeutic

approach in CLL. Vatalanib and pazopanib seem to be effective and safe

candidates to be further evaluated for this purpose. Clin Cancer Res; 16(13);

3390–8. ©2010 AACR.