The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro.
BACKGROUND
Combretastatin A-4-phosphate (CA-4-P) is a microtubule depolymerising agent currently in clinical trial as a tumour vascular-targeting agent. In vivo, CA-4-P causes rapid shutdown of tumour blood flow (within minutes) and a significant neutrophil infiltration at later times.


METHODS
Using an in vitro flow-cell assay, we investigated neutrophil-endothelial cell interactions and associated mechanisms, following endothelial cell exposure to CA-4-P. Cellular adhesion molecule (CAM) expression was examined using immunoblotting and immunofluorescence, and the role of CAM in neutrophil recruitment was investigated using specific blocking antibodies.


RESULTS
Exposure of HUVEC to CA-4-P, resulted in significant neutrophil recruitment, and increased expression of endothelial CAM. Results of antibody studies demonstrated that endothelial CAM expression induced by CA-4-P is responsible for the observed neutrophil recruitment.


CONCLUSIONS
This study demonstrated that the tumour vascular targeting agent, CA-4-P, directly induces endothelial CAM expression and subsequent neutrophil recruitment. In vivo, neutrophil infiltration probably contributes to CA-4-P-induced tumour cell kill. Therefore, increasing neutrophil recruitment into tumours may have potential for optimising vascular-targeted strategies for cancer therapy.
Brooks
Andrew C
AC
Tumour Microcirculation Group, Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middx. HA6 2JR, U.K. brooks@gci.ac.uk
Kanthou
Chryso
C
Cook
Ian H
IH
Tozer
Gillian M
GM
Barber
Paul R
PR
Vojnovic
Boris
B
Nash
Gerard B
GB
Parkins
Charles S
CS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology*; D014404:Tubulin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D015815:Cell Adhesion Molecules; D013267:Stilbenes; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; C058728:fosbretabulin; D017239:Paclitaxel; D003078:Colchicine