Investigational New Drugs

, Volume 30, Issue 2, pp 468–479

Vandetanib mediates anti-leukemia activity by multiple mechanisms and interacts synergistically with DNA damaging agents

PRECLINICAL STUDIES

DOI: 10.1007/s10637-010-9572-6

Cite this article as:
Macy, M.E., DeRyckere, D. & Gore, L. Invest New Drugs (2012) 30: 468. doi:10.1007/s10637-010-9572-6

Summary

Vandetanib is an orally active small molecule tyrosine kinase inhibitor (TKI) with activity against several pathways implicated in malignancy including the vascular endothelial growth factor receptor pathway, the epidermal growth factor receptor pathway, the platelet derived growth factor receptor β pathway, and REarranged during Transfection pathway. To determine if vandetanib-mediated inhibition of receptor tyrosine kinases is a potential therapeutic strategy for pediatric acute leukemia, these studies aimed to characterize the activity of vandetanib against acute leukemia in vitro. Treatment of leukemia cell lines with vandetanib resulted in a dose-dependent decrease in proliferation and survival. Vandetanib’s anti-leukemic activity appeared mediated by multiple mechanisms including accumulation in G1 phase at lower concentrations and apoptosis at higher concentrations. Alterations in cell surface markers also occurred with vandetanib treatment, suggesting induction of differentiation. In combination with DNA damaging agents (etoposide and doxorubicin) vandetanib demonstrated synergistic induction of cell death. However in combination with the anti-metabolite methotrexate, vandetanib had an antagonistic effect on cell death. Although several targets of vandetanib are expressed on acute leukemia cell lines, expression of vandetanib targets did not predict vandetanib sensitivity and alone are therefore not likely candidate biomarkers in patients with acute leukemia. Interactions between vandetanib and standard chemotherapy agents in vitro may help guide choice of combination regimens for further evaluation in the clinical setting for patients with relapsed/refractory acute leukemia. Taken together, these preclinical data support clinical evaluation of vandetanib, in combination with cytotoxic chemotherapy, for pediatric leukemia.

Keywords

Acute leukemia Vandetanib Vascular endothelial growth factor Tyrosine kinase inhibitor Combination therapy 

Abbreviation

ALL

acute lymphoblastic leukemia

AML

acute myelogenous leukemia

DMSO

dimethyl sulfoxide

EGFR

epidermal growth factor receptor

FBS

fetal Bovine Serum

Flt-3

fms-like tyrosine kinase 3

KDR

kinase-insert domain containing region

MLL

mixed lineage leukemia

PDGFRβ

platelet derived growth factor β

RET

Rearranged during transfection

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

Supplementary material

10637_2010_9572_MOESM1_ESM.pdf (23 kb)
Supplemental Figure 1Leukemia cell lines differentially express vandetanib targets. RNA was obtained from actively growing cultures of the indicated acute leukemia cell lines. For VEGFR2, RET, EGFR expression cDNA was synthesized and receptor expression was determined by RT-PCR. GAPDH was used as control. Expression was determined relative to HUVECS. Expression of VEGFR-1, VEGFR-3 and PDGFRB was determined by real-time RT-PCR. Expression was determined by average Ct values. Ct values greater than 35 were considered minimal expression. (PDF 534 kb)

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Margaret E. Macy
    • 3
  • Deborah DeRyckere
    • 1
  • Lia Gore
    • 1
    • 2
  1. 1.Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow TransplantationUniversity of Colorado DenverAuroraUSA
  2. 2.Division of Medical OncologyUniversity of Colorado DenverAuroraUSA
  3. 3.Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow TransplantationUniversity of Colorado DenverAuroraUSA

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