Abstract
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.
Highlights
Non–small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome
Cultured human umbilical vein endothelial cells (HUVECs) expressed total VEGFR2 in all three culture conditions and phosphorylated VEGFR2 in full-serum conditions which was further increased after stimulation with recombinant human Vascular endothelial growth factor (VEGF) (Figure 1A)
Microarray analyses showed that A549, Calu-6, NCI-H1299, and NCI-H1650 tumors expressed similar levels of VEGF mRNA; and that A549, Calu-6, NCI-H1299, and NCIH1650 tumors expressed VEGFR1, 2, and 3 mRNA
Summary
Non–small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. Lung cancer is the primary cause of cancer death and the second most frequent cause of new cancer cases in the United States [1]. The majority of these cases are non–small-cell lung cancer (NSCLC) [2], which comprises nonsquamous carcinoma (including adenocarcinoma, large cell carcinoma, and other cell types) and squamous cell carcinoma [3]. Bevacizumab, a monoclonal antibody targeting VEGF-A, has been shown to improve overall survival when administered with carboplatin/paclitaxel [10] and to prolong progression-free survival in combination with gemcitabine/cisplatin [11] in patients with nonsquamous histology
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