Tyrosine kinase inhibitor SU6668 inhibits peritoneal dissemination of gastric cancer via suppression of tumor angiogenesis.
BACKGROUND
Peritoneal dissemination of cancer involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. Tumor angiogenesis is a prerequisite for the growth of disseminated tumor. Vascular endothelial growth factor (VEGF) and its receptor are major regulators of angiogenesis.


OBJECTIVE
We examined the cytotoxic effects of SU6668, an inhibitor of VEGF tyrosine kinase receptors, on in vitro gastric cancer cell lines and human umbilical vascular endothelial cells (HUVEC); we also examined the antitumor effects of SU6668 on human gastric cancer cells administered intraperitoneally into nude mice.


METHODS
Direct cytotoxicity to gastric cancer cells (TMK-1, MKN-45 and MKN-74) and normal cells (HUVEC) was determined by the MTT assay and the bromodeoxyuridine (BrdU) incorporation assay, with and without VEGF-evoked growth stimulation in vitro. TMK-1 cells were transplanted intraperitoneally into nude mice, followed by twice daily oral administration of SU6668 (200 mg/kg/day) for two weeks starting on the first day after transplantation. Both the number and the wet weight of disseminated peritoneal tumor nodules were assessed.


RESULTS
In the MTT assay, SU6668 demonstrated low-grade cytotoxicity to the cell growth of three gastric cancer cells, with a 50% inhibitory concentration (IC50) of 22.6 microg/ml for TMK-1, 31.8 microg/ml for MKN-45 and 26.7 microg/ml for MKN-74; HUVEC was sensitive to SU6668 with an IC50 of 8.9 microg/ml. In the BrdU assay, VEGF stimulated DNA synthesis in HUVEC, while the incorporation of BrdU was not affected by VEGF in gastric cancer cell lines. SU6668 inhibited VEGF-induced DNA synthesis in HUVEC, while BrdU incorporation of gastric cancer cell lines was inhibited by SU6668 without correlation to VEGF stimulation. Peritoneal dissemination of cancer in nude mice was significantly suppressed by SU6668 compared with a control group at the p<0.05 level.


CONCLUSIONS
The mechanism of the antitumor activity of SU6668 may not involve direct toxicity to cancer cells, but may rather be an inhibitory effect on tumor angiogenesis, resulting in the inhibition of tumor dissemination in the peritoneum.
Tokuyama
Jo
J
Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Kubota
Tetsuro
T
Saikawa
Yoshiro
Y
Yoshida
Masashi
M
Furukawa
Toshiharu
T
Otani
Yoshihide
Y
Kumai
Koichiro
K
Kitajima
Masaki
M
D000328:Adult; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000078183:Oxindoles; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D004247:DNA; C412603:orantinib; D011505:Protein-Tyrosine Kinases; C022616:thiazolyl blue