Vascular disrupting effect of CKD-516: preclinical study using DCE-MRI
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Vascular disrupting agents (VDAs) are new class of anti-cancer drugs targeting pre-existing tumor vasculature which lead to tumor ischemia and necrosis. An innovative tubulin polymerization inhibitor, CKD-516, was recently developed as a VDA. We attempted to evaluate its tubulin destabilizing effect using immunofluorescence staining on human endothelial cells (HUVECs) and to ascertain its antivascular effect in a rabbit VX2 tumor model using dynamic contrast-enhanced (DCE) MRI by measuring the changes in kinetic parameters such as K-trans and IAUGC. Immunofluorescence staining using anti-tubulin and anti-actin antibodies on HUVECs showed that CKD-516 selectively disrupted tubulin component of the endothelial cytoskeleton. Serial DCE-MRI showed a significant decrease in K-trans and IAUGC parameters from baseline at 4 h (39.9 % in K-trans; −45.0 % in IAUGC) and at 24 h (−32.2 % in K-trans; −36.5 % in IAUGC), and a significant recovery at 48 h (22.9 % in K-trans; 34.8 % in IAUGC) following administration of CKD-516 at a 0.7-mg/kg dose. When the tumors were stratified according to the initial K-trans value of 0.1, tumors with a high K-trans > 0.1 which was indicative of having well-developed pre-existing vessels, showed greater reduction in K-trans and IAUGC values. On histologic examination, the degree of necrosis of treated tumors was significantly greater than that of untreated tumors. In summary, CKD-516 is an effective VDA which results in rapid vascular shutdown by targeting the tubulin component of tumor vessels and thus leads to necrosis.
KeywordsCKD-516 Vascular disrupting agent Tubulin DCE-MRI
This work was partially supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (2011-0026127) and by grants from the Korean Health and Medical Technology R&DProject, Ministry of Health, Welfare, and Family Affairs (A100895, A100265). We thank Bonnie Hami, M.A. (USA) for her editorial assistance. We also thank Hyunjun Ji and Peter Gall for his technical advice regarding Tissue 4D software.
Conflict of interest
One coauthors (Berthold Kiefer), an employee of Siemens Healthcare, provided technical advice for DCE-MRI in animal experiment and has no direct or indirect conflict interests. One coauthor (Chin Kim), an employee of Chong Kun Dang Pharmaceuticals, provided CKD-516 and technical advice for making drug formulation and in vitro experiment. The other coauthors (Kyung Won Kim, Jeong Min Lee, Yong Sik Jeon, In Joon Lee, YoonSeok Choi, Jisuk Park, Joon Koo Han, Byung Ihn Choi) have no direct or indirect conflict of interest.
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