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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

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

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Angela Coxon, Beth Ziegler, Stephen Kaufman, Man Xu, Hongyu Wang, Dawn Weishuhn, Joanna Schmidt, Heather Sweet, Charlie Starnes, Douglas Saffran, Anthony Polverino
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-70) contains supplementary material, which is available to authorized users.

Competing interests

AC, BZ, SK, MX, HW, DW, JS, HS, CS, DS, and AP are employees of and shareholders in Amgen Inc.

Authors’ contributions

AC: Study conception and design, data analysis and interpretation, writing and revising the manuscript. BZ: Xenograft experiments, data analysis, and revising the manuscript. SK: Histomorphometric analysis of xenograft studies, data analysis, and revising the manuscript. MX: Xenograft experiments and revising the manuscript. HW: Xenograft experiments and revising the manuscript. DW: Xenograft experiments and revising the manuscript. JS: In vitro proliferation assays and Western blots; data analysis, and revising the manuscript. HS: Xenograft experiments and revising the manuscript. CS: Study conception and design, data analysis and interpretation, revising the manuscript. DS: Study conception and design, data analysis and interpretation, revising the manuscript. AP: Study conception and design, data analysis and interpretation, writing and revising the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Non–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.

Results

Motesanib 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.

Conclusions

These 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.
Zusatzmaterial
Additional file 1: Figure S1. Effects of treatment with an Amgen proprietary small-molecule VEGF receptor inhibitor (“Compound 72”) on lung mass in a KRAS-driven genetically engineered mouse model of lung adenocarcinoma. In this model, development of lung tumors was induced by intratracheal delivery of adenovirus containing the Cre-recombinase to KRAS LSL-G12D mice. Animals with established lung tumors were treated with (A) vehicle (n = 12) or (B) small-molecule VEGF receptor inhibitor 30 mg/kg QD (n = 10). Figure S2 Representative computed tomography images of mice with mutant KRAS G12D lung cancer (as described in Additional file 1) 11 weeks after induction of disease and 3 weeks after treatment with an Amgen proprietary small-molecule VEGF receptor inhibitor (“Compound 72”). (A) Vehicle. The image shows wide-spread tumor burden and minimal viable lung space. (B) Treatment with a small-molecule VEGF receptor inhibitor resulted in visible preservation of normal, viable lung with less tumor burden. (DOC 218 KB)
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