Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program.
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.
Maris, JM; Courtright, J; Houghton, PJ; Morton, CL; Gorlick, R; Kolb, EA; Lock, R; Tajbakhsh, M; Reynolds, CP; Keir, ST; Wu, J; Smith, MA
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