Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

Abstract

SU6668 (TSU-68) is a small-molecule synthetic inhibitor of the angiogenic related receptor tyrosine kinases Flk-1/KDR, PDGFR␤, 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.

Combination therapy of tyrosine kinase receptor inhibitor TSU-68 (SU6668) and paclitaxel inhibits subcutaneous xenografts of endometrial cancer

“…We previously reported the inhibitory and survivalprolonging effects of orally-administered TSU-68 on tumor angiogenesis and peritoneal dissemination using a peritoneallydisseminated ovarian cancer model in mice (21). The current study, also using a mouse model, demonstrated the antitumor effects of TSU-68 on subcutaneously implanted endometrial cancer, suggesting the usefulness of molecule-targeting therapy with TSU-68 for endometrial cancer.…”

Pazopanib, a Novel Multitargeted Kinase Inhibitor, Shows PotentIn VitroAntitumor Activity in Gastric Cancer Cell Lines withFGFR2Amplification

“…The complete clinical data of this trial will be available in the late 2014, and the significance of FGFR2 amplification and other biomarkers on clinical outcomes in this context of the trial will be also investigated. As several FGFR kinase inhibitors are now in clinical trials, including brivanib, dovitinib, BIBF 1120, and SU-6668, it may be useful to test these inhibitors on patients with gastric cancer harboring focal FGFR2 amplifications (28)(29)(30)(31).…”

Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells

“…These studies suggest that VEGF secreted by the ROSE199 cells is necessary for the tumor growth. Similarly, SU6668, a kinase inhibitor with broader specificity, was effective in limiting ovarian tumor growth (20,49). Because SU5416 targets host endothelial cells, this treatment may be effective in escaping development of drug resistance common to many chemotherapeutic agents.…”