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

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.
AuthorsKyung 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
JournalInvestigational new drugs (Invest New Drugs) Vol. 31 Issue 5 Pg. 1097-106 (Oct 2013) ISSN: 1573-0646 [Electronic] United States
PMID23299389 (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
  • 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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