TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti-angiogenesis.
A number of receptor tyrosine kinases (RTKs) are involved in angiogenesis. TSU-68 (SU-6668) was developed as an inhibitor of RTKs involved in VEGF, bFGF and PDGF signaling, which then inhibits endothelial cell proliferation. We investigated the antitumor effects of TSU-68 against human colon cancer xenografts in male SCID mice and its anti-angiogenic activity using a dorsal air-sac (DAS) assay. TSU-68 was administered orally at a dose of 200 mg/kg twice daily. Mice bearing human colon carcinoma, HT-29, or WiDr xenografts were treated for 16 days. To determine the effect on hepatic metastasis, cell suspensions of HT-29 or WAV-I were injected into the spleen of mice on day 0, and mice treated for 28 days starting from day 1. For the DAS assay, HT-29, WiDr or WAV-I cells suspended in PBS at 2 x 10(7) cells/Millipore chamber were implanted subcutaneously into SCID mice, which were then treated from day 0 to 5, On day 6, the anti-angiogenic effects were assessed. Results indicated that TSU-68 significantly inhibited the growth of subcutaneous tumors. In the hepatic metastasis model, liver weights of the TSU-68-treated group were significantly reduced, compared to those of control mice. In the DAS assay, the angiogenic indices of the treated groups were significantly decreased for HT-29, WiDr and WAV-I tumors, with T/C ratios of 13.4, 50 and 35.3%, respectively. As TSU-68 significantly inhibited tumor growth and liver metastasis formation of human colon cancer xenografts, probably through anti-angiogenic activity, this agent may be useful for the treatment of colon cancer.
Yorozuya
Kyoko
K
Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Kubota
Tetsuro
T
Watanabe
Masahiko
M
Hasegawa
Hirotoshi
H
Ozawa
Soji
S
Kitajima
Masaki
M
Chikahisa
Lumi Muramatsu
LM
Yamada
Yuji
Y
D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D000078183:Oxindoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D007211:Indoles; D019394:Ki-67 Antigen; D000078183:Oxindoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011422:Propionates; D011758:Pyrroles; C412603:orantinib; D011505:Protein-Tyrosine Kinases