ZK 304709, the orally active Multi-target Tumor Growth Inhibitor™ (MTGI™), inhibits key enzymes required for tumor growth and metastasis, such as: cyclin-dependent kinase 1, 2, 4, 7 and 9; vascular endothelial growth factor receptor 1, 2 and 3; and platelet-derived growth factor receptor β. Previous studies have shown that the simultaneous blockade of cell cycle progression and angiogenesis with ZK 304709 provides improved efficacy over alternative monotherapies. Treatment with ZK 304709, paclitaxel (a tubulin active inhibitor), or 5-FU (a uracil analog anti-metabolite compound) alone inhibits tumor growth in a human estrogen-independent mammary carcinoma xenograft model (MaTu), in a dose-dependent manner. The aim of this study was to investigate the effect of combined treatment with ZK 304709 and either paclitaxel or 5-FU on tumor growth in this model. MaTu mammary tumor cells were implanted subcutaneously in the inguinal region of female NMRI nude mice (n=8/group). Mice were randomized to treatment, which was started when the tumors were approximately 20 mm2. ZK 304709 treatment (60 mg/kg/d) was combined with two doses of either paclitaxel (6 or 9 mg/kg) for 5 days followed by a 10-day break, or 5-FU (50 or 100 mg/kg) three times once weekly and then either once weekly (50 mg/kg) or once fortnightly (100 mg/kg). The treatment groups were sacrificed when the mean tumor area in a group was approximately 150 mm2, except in the groups with combined ZK 304709 and paclitaxel treatment, due to total tumor eradication. In these groups, both treatments were discontinued on day 60 to observe possible tumor regrowth. ZK 304709, 5-FU and paclitaxel were also administered as monotherapies. In the monotherapy groups, the time for tumors to reach 150 mm2 for ZK 304709, paclitaxel (6 or 9 mg/kg) and 5-FU (100 mg/kg) was extended by 25, 5, 15 and 10 days, respectively, compared with control. The lower dose of 5-FU was not significantly different from control. ZK 304709 combined with paclitaxel totally eradicated tumors, and after treatment was discontinued, only one tumor remission was observed. The combination of ZK 304709 and 5-FU (50 or 100 mg/kg) produced significant inhibition of tumor growth, resulting in an extended time for tumors to reach 150 mm2 (60 or >100 days respectively). The combination of ZK 304709 and either paclitaxel or 5-FU was well tolerated.The data presented here indicates that the combination of the MTGI™ ZK 304709 with paclitaxel or 5-FU is well tolerated and provides marked antitumor activity. The combination of ZK 304709 and paclitaxel resulted in total tumor eradication, while the combination of ZK 304709 and 5-FU demonstrated a clear synergistic effect with increased time to progression. These data suggest that the combination of ZK 304709 and either paclitaxel or 5-FU offer a potent and well-tolerated treatment for breast cancer.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]