SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy

• DOI: 10.4149/neo_2012_062
• Publication Date: 2012-06-18T15:41:30Z
• Authors: G. Shen; Y. Li; T. Du; G. Shi; L. Dai; X. Chen; R. Zheng; W. Li; X. Su; S. Zhang; Y. Wei; S. Yang; H. Deng
• Keywords: Mice, Inbred BALB C; Antibiotics, Antineoplastic; Neovascularization, Pathologic; Fluorescent Antibody Technique; Mammary Neoplasms, Experimental; Mice, Nude; Angiogenesis Inhibitors; Drug Synergism; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays; Tumor Burden; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols; Tumor Cells, Cultured; Animals; Female; Neoplasm Invasiveness; Hypoxia; Signal Transduction

Vascular endothelial growth factor receptor (VEGFR) or vascular (VEGF) inhibitors have shown only modest clinical activity for most tumor types when used as single agents.However, present evidence indicates that these antiangiogenic drugs can cause transient "normalization" of the vasculature, thereby improving delivery systemic chemotherapy.We examined temporal changes in function response to novel VEGFR2 inhibitor, SKLB1002.Established tumor-bearing animals were evaluated at serial time points treatment-associated architecture and function.As a result, blocking VEGF signaling by SKLB1002 produced morphologically functionally "normalized" network.Consistent with our observations, 2.2 fold increase intratumoral doxorubicin levels was determined pretreatment compared administration alone.Finally, combined exhibited significant antitumor (49% control size) antimetastatic effects (12% metastatic nodules) vivo.Our results showed induced normalization enhanced anticancer drug delivery, which associated observed synergistic effect vivo.