Metronomic scheduling of a cyclic hexapeptide Ra-VII for anti-angiogenesis, tumor vessel maturation and anti-tumor activity.
RA-VII, a cyclic hexapeptide isolated from Rubiae radix, binds to actin, causing a conformational change in the actin molecule and inducing G2 arrest by inhibiting cytokinesis. Here we examined the effect of RA-VII, its water-soluble derivative, and related RA-III and RA-V on endothelial cells. Among the four compounds tested, RA-VII most potently inhibited angiogenesis-related properties of endothelial cells (i.e. migration and proliferation) in vitro. We confirmed the anti-angiogenic activity of RA-VII in vivo by using a mouse corneal model. We then applied RA-VII for the treatment of tumors in mice. Daily intraperitoneal injection of RA-VII (1.5 or 3 mg/kg/day) exhibited no toxic effect on the animals, but significantly and dose dependently inhibited the growth of Lewis lung carcinoma cells previously inoculated into the mice. Interestingly, although two doses of RA-VII decreased the tumor vascular area to a similar extent, a higher dose of RA-VII led to tumor vessel maturation together with a significant increase in tumor cell apoptosis. Also, RA-VII showed a cytotoxic effect on Lewis lung carcinoma cells. These results indicate that metronomic scheduling of RA-VII is efficient for cancer treatment. A careful dose setting of RA-VII is crucial to obtain therapeutic superiority, possibly through tumor vessel maturation and a better distribution of the compound in the tumor tissue.
Koizumi
Takayuki
T
Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-857, Japan.
Abe
Mayumi
M
Yamakuni
Tohru
T
Ohizumi
Yasushi
Y
Hitotsuyanagi
Yukio
Y
Takeya
Koichi
K
Sato
Yasufumi
Y
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy*; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D010456:Peptides, Cyclic; C512414:RA III peptide, Rubiae radix; C043547:RA V; C043548:RA VII