Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non–small-cell lung cancer xenograft models

Molecular Cancer

Research

Anthony Polverino¹  Douglas Saffran²  Man Xu²  Charlie Starnes³  Beth Ziegler³  Joanna Schmidt³  Angela Coxon³  Stephen Kaufman⁴  Hongyu Wang⁵  Dawn Weishuhn⁵  Heather Sweet⁵ 

[1] Department of Oncology Research, Amgen Inc, 1201 Amgen Court West, 98119, Seattle, WA, USA;Department of Oncology Research, Amgen Inc, 360 Binney Street, 02142, Cambridge, MA, USA;Department of Oncology Research, Amgen Inc, One Amgen Centre Drive, 91320, Thousand Oaks, CA, USA;Department of Pathology, Amgen Inc, One Amgen Centre Drive, 91320, Thousand Oaks, CA, USA;Department of Protein Sciences, Amgen British Columbia, 7990 Enterprise St, V5A 1V7, Burnaby, BC, Canada;

关键词: Motesanib;    Cisplatin;    Docetaxel;    VEGF receptor;    NSCLC;    Angiogenesis;   

DOI  :  10.1186/1476-4598-11-70

 received in 2011-12-07, accepted in 2012-09-03,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundNon–small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations.ResultsMotesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro.ConclusionsThese data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.

【 授权许可】

CC BY   
© Coxon et al.; licensee BioMed Central Ltd. 2012