Antiangiogenic activity of TZT-1027 (soblidotin) on chick chorioallantoic membrane and human umbilical vein endothelial cells.
BACKGROUND
TZT-1027 (Soblidotin), a microtubule-depolymerizing agent, has antivascular activity which disrupts newly formed tumor vasculature. In this study, it was investigated whether TZT-1027 has also antiangiogenic activity preventing neovascularization.


METHODS
Antiangiogenic activities were evaluated in vivo in a chick embryo chorioallantoic membrane (CAM) assay and in vitro in a tube formation assay on human umbilical vein endothelial cells (HUVEC). RT-PCR and skimmed milk zymography analyses were performed to clarify the involvement of angiogenesis-related proteolytic enzymes and transcription factors.


RESULTS
TZT-1027 at doses of 0.01 and 0.06 microg/egg showed potent antiangiogenic activities in the CAM assay (80% and 100% inhibition, respectively), with no lethal toxicity to the chick embryo. TZT-1027 at doses of 0.01-10 ng/mL prevented tube formation, while 1-100 ng/mL disrupted the preformed vascular tube. However, mRNA and protein expression were unchanged.


CONCLUSIONS
TZT-1027 showed antiangiogenic activity at lower doses than it exhibited its antivascular activity. We believe it would exert its antiangiogenic activity, even if kept in a tumor at reduced concentrations to keep its antivascular activity to a minimum.
Watanabe
Junichi
J
ASKA Pharmaceutical Co., Ltd., Research and Development Division, 1604 Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan. watanabe-j@askapharma.co.jp
Endo
Yoshio
Y
Shimada
Nami
N
Natsume
Tsugitaka
T
Sasaki
Takuma
T
Kobayashi
Motohiro
M
D000482:Allantois / Q000187:drug effects*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002642:Chick Embryo; D002823:Chorion / Q000187:drug effects*; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017931:DNA Primers; D009842:Oligopeptides; C105791:soblidotin; D014568:Urokinase-Type Plasminogen Activator