Vascular disrupting effect of CKD-516: preclinical study using DCE-MRI.

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.

• 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)

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

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)