Abstract |
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.
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Authors | Kyung Won Kim, Jeong Min Lee, Yong Sik Jeon, In Joon Lee, YoonSeok Choi, Jisuk Park, Berthold Kiefer, Chin Kim, Joon Koo Han, Byung Ihn Choi |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 31
Issue 5
Pg. 1097-106
(Oct 2013)
ISSN: 1573-0646 [Electronic] United States |
PMID | 23299389
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Benzophenones
- N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide
- Tubulin
- Tubulin Modulators
- Valine
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Benzophenones
(pharmacology, therapeutic use)
- Cells, Cultured
- Human Umbilical Vein Endothelial Cells
(drug effects, metabolism)
- Humans
- Magnetic Resonance Imaging
(methods)
- Neoplasms, Muscle Tissue
(blood supply, drug therapy, metabolism, pathology)
- Neovascularization, Pathologic
(drug therapy, metabolism, pathology)
- Rabbits
- Tubulin
(metabolism)
- Tubulin Modulators
(pharmacology, therapeutic use)
- Valine
(analogs & derivatives, pharmacology, therapeutic use)
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