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Updated: Jul 15, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program
John M Maris1, Joshua Courtright, Peter J Houghton
1Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA. maris@chop.edu
Background:
Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP).
Procedures:
AZD2171 was tested at concentrations from 0.1 nM to 1.0 microM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle.
Results:
One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 microM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models.
Conclusions:
AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.
Insights
AZD2171 showed significant anti-angiogenic effects, inhibiting solid tumor growth in preclinical childhood cancer models. While effective in vivo, its in vitro activity was limited, suggesting a primary anti-angiogenesis mechanism.
Area of Science:
- Oncology
- Pharmacology
Background:
- Vascular endothelial growth factor (VEGF) signaling is a key target for anti-angiogenic cancer therapy.
- AZD2171 is an orally bioavailable inhibitor of VEGF receptors.
Purpose of the Study:
- To evaluate the antitumor activity of AZD2171 in preclinical childhood cancer models.
- To screen AZD2171's efficacy in vitro and in vivo using the Pediatric Preclinical Testing Program (PPTP) models.
Main Methods:
- AZD2171 was tested in vitro against 22 cell lines and in vivo against solid tumor xenografts and leukemia models.
- In vivo studies involved 6-week daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle.
Main Results:
- Limited in vitro activity observed (1/22 cell lines sensitive).
- Significant in vivo antitumor activity (tumor growth delay) in 78% of solid tumor xenografts across various types.
- Objective responses (complete responses) seen in 6% of solid tumor xenografts; no activity against acute lymphoblastic leukemia models.
Conclusions:
- AZD2171 demonstrated broad tumor growth inhibition in solid tumor xenografts, primarily via anti-angiogenesis.
- The dissociation between in vitro and in vivo efficacy supports an anti-angiogenesis mechanism of action for AZD2171.
