Vascular targeting effect of combretastatin A-4 phosphate dominates the inherent angiogenesis inhibitory activity.
The current research aimed to define hypothesis-based anti-angiogenic properties of the vascular targeting agent combretastatin A-4 phosphate (combreAp). The in vitro wound assay indicated that combreAp potently inhibited migration of endothelial cells (EC). A significant inhibition of migration could already be measured after 2 hr of treatment. In a three-dimensional (3D) tube formation assay, combreAp inhibited sprout formation at concentrations that did not inhibit the proliferation of EC. At sub-ng concentrations the half-maximal response was reached. Interestingly, although combreAp is considered a vascular targeting agent, the human tumor cell lines tested were found to be 20-30 times more sensitive for combreAp than the human umbilical vein endothelial cells (HUVEC). A similar response difference between rat EC and R1 rat rhabdomyosarcoma tumor cells was observed. The growth inhibition in EC was only in part mediated by induction of apoptosis. The growth delay results obtained with the in vivo rodent tumor models involving repeat dosing of combreAp can partly be explained by anti-angiogenic activity of the compound. The results obtained with the various in vitro and in vivo assays substantiate an anti-angiogenic profile of combreAp, largely at the level of EC migration. This mechanism may operate to a different extent in different tumor types.
Ahmed
Bisan
B
Research Institute for Growth and Development (GROW), Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands.
Van Eijk
Loes I
LI
Bouma-Ter Steege
Jessica C A
JC
Van Der Schaft
Daisy W J
DW
Van Esch
Anita M
AM
Joosten-Achjanie
Susan R
SR
Lambin
Philippe
P
Landuyt
Willy
W
Griffioen
Arjan W
AW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D051381:Rats; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology; D014945:Wound Healing
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C058728:fosbretabulin