Article

Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors.

Department of Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.
Clinical Cancer Research (impact factor: 7.74). 02/2009; 15(1):110-8. DOI:10.1158/1078-0432.CCR-08-1155 pp.110-8
Source: PubMed

ABSTRACT Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes.
Athymic nude mice were implanted with MCF-7 (luminal) or MDA-MB-231 (mesenchymal) tumor fragments or Cal-51 (mixed/progenitor) tumor cells. Once tumors were established, animals were randomized to receive increasing doses of motesanib alone or motesanib plus cytotoxic chemotherapy (docetaxel, doxorubicin, or tamoxifen).
Across all three xenograft models, motesanib treatment resulted in significant dose-dependent reductions in tumor growth, compared with vehicle-treated controls, and in marked reductions in viable tumor fraction and blood vessel density. No significant effect on body weight was observed with compound treatment compared with control-treated animals. Motesanib did not affect the proliferation of tumor cells in vitro. There was a significantly greater reduction in xenograft tumor growth when motesanib was combined with docetaxel (MDA-MB-231 tumors) or with the estrogen receptor modulator tamoxifen (MCF-7 tumors), compared with either treatment alone, but not when combined with doxorubicin (Cal-51 tumors).
Treatment with motesanib alone or in combination with chemotherapy inhibits tumor growth in vivo in various models of human breast cancer. These data suggest that motesanib may have broad utility in the treatment of human breast cancer.

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Keywords

Athymic nude mice
 
breast cancer development
 
Cal-51 tumors
 
chemotherapy inhibits tumor growth
 
estrogen receptor modulator tamoxifen
 
human breast cancer
 
Kit receptor
 
MCF-7 tumors
 
MDA-MB-231 tumors
 
platelet-derived growth factor receptor
 
potent angiogenic factor
 
regulates endothelial cell proliferation
 
significant effect
 
three xenograft models
 
tumor growth
 
various human breast cancer subtypes
 
Vascular endothelial growth factor
 
VEGF receptors 1
 
viable tumor fraction
 
xenograft tumor growth