Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU-68).
SU6668 (TSU-68) is a small-molecule synthetic inhibitor of the angiogenic related receptor tyrosine kinases Flk-1/KDR, PDGFRbeta, and FGFR1. Using a mouse model of peritoneally disseminated ovarian cancer, we investigated whether SU6668 inhibits peritoneal dissemination and prolongs survival time. BALB/c nude mice were intraperitoneally (i.p.) inoculated with SHIN-3 (VEGF-hypersecretory) or KOC-2S (PDGF-hypersecretory) ovarian serous adenocarcinoma cells with marked peritoneal dissemination ability. From the day after i.p. inoculation of tumor cells, SU6668 was orally administered 6 times weekly at a daily dose of 100 mg/kg or 400 mg/kg. The SU6668-administered group and the vehicle-administered control group were compared for the number of tumor vascular endothelial cells, weight of peritoneally disseminated tumors, amount of ascitic fluid and survival time. As a result, these 3 parameters were significantly smaller in the SHIN-3-inoculated, SU6668-administered mice than in the control group (p = 0.03, p = 0.002, and p = 0.02, respectively). The mean survival time was significantly longer, at 58.1 +/- 11.2 days, in the SU6668-administered mice than that (34.5 +/- 8.8 days) in the control group (p = 0.002). Similarly, in the KOC-2S-inoculated mice, the oral administration of SU6668 significantly reduced these 3 parameters (p = 0.04, p = 0.04, and p = 0.03, respectively), and significantly prolonged survival (16.6 +/- 1.7 days vs. 11.0 +/- 0.7 days, p = 0.008). Thus, the oral administration of SU6668 inhibited angiogenesis and peritoneal dissemination and prolonged survival in mice with peritoneally disseminated ovarian cancer. These effects were observed with both the VEGF- and PDGF-hypersecretory cell lines. Our results suggest that molecular targeting with oral SU6668 will become a new therapeutic strategy targeting peritoneally disseminated ovarian cancer.
Machida
Shizuo
S
Department of Obstetrics and Gynecology, Jichi Medical School, Yakushiji, Minami-kawachi, Tochigi 329-0498, Japan. smachi@jichi.ac.jp
Saga
Yasushi
Y
Takei
Yuji
Y
Mizuno
Izumi
I
Takayama
Takeshi
T
Kohno
Takahiro
T
Konno
Ryo
R
Ohwada
Michitaka
M
Suzuki
Mitsuaki
M
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000473:pathology*; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor; D011422:Propionates; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C412603:orantinib; D011505:Protein-Tyrosine Kinases