title: 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.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Kyung Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Jeong Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Jeon
authors.forename: In Joon
authors.initials: IJ
authors.lastname: Lee
authors.forename: YoonSeok
authors.initials: Y
authors.lastname: Choi
authors.forename: Jisuk
authors.initials: J
authors.lastname: Park
authors.forename: Berthold
authors.initials: B
authors.lastname: Kiefer
authors.forename: Chin
authors.initials: C
authors.lastname: Kim
authors.forename: Joon Koo
authors.initials: JK
authors.lastname: Han
authors.forename: Byung Ihn
authors.initials: BI
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D009379:Neoplasms, Muscle Tissue / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; C552333:N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide; D014404:Tubulin; D050257:Tubulin Modulators; D014633:Valine