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. Amon...

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Published in:Cancer science 2006-07, Vol.97 (7), p.665-674
Main Authors: Koizumi, Takayuki, Abe, Mayumi, Yamakuni, Tohru, Ohizumi, Yasushi, Hitotsuyanagi, Yukio, Takeya, Koichi, Sato, Yasufumi
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Blood Vessels - cytology
Blood Vessels - drug effects
Blood Vessels - growth & development
Carcinoma, Lewis Lung - blood supply
Carcinoma, Lewis Lung - drug therapy
Cattle
Cell Movement - drug effects
Cell Proliferation - drug effects
Chemotherapy
Endothelial Cells - drug effects
Medical sciences
Mice
Neovascularization, Pathologic - drug therapy
Original
Peptides, Cyclic - administration & dosage
Peptides, Cyclic - pharmacology
Peptides, Cyclic - therapeutic use
Pharmacology. Drug treatments
Tumors
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Summary: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. (Cancer Sci 2006; 97:665–674)
ISSN:1347-9032
1349-7006
DOI:10.1111/j.1349-7006.2006.00229.x