The tumor growth delay was calculated as the time difference between each treatment group and Selinexor (KPT-330)? the control group when the average tumor size reached 1000 mm3. Combination treatment with oxaliplatin and/or dovitinib did not show any gross signs of toxicity and/or possible adverse side effects as measured by two profiles, that is, body weight and diet consumption. Also, the necropsy report showed no abnor mality in these mice at the end of the experiment. Reports have shown that Dovitinib as high as 120 mg/Kg for con tinuous 25 days exerted no toxicity in animals. In an attempt to understand some of the details of the mechanism of action of combination, the tumors were removed from mice and processed for immunohistochem ical expression of Ki 67 and CD 31.

Ki 67 antigen is the prototypic cell cycle related nuclear protein, expressed by proliferating cells in all phases of the active cell cycle and absent in resting cells. It is routinely used as a marker for proliferating cells. Representative photomicrographs of Ki 67 antigen stained sections from untreated, oxaliplatin and/or dovitinib tumors are shown in Figures 4C a d. Staining for Ki 67 decreased immensely with the treat ment of oxaliplatin combined with dovitinib compared to untreated tumors as well as either of oxaliplatin or doviti nib administered groups. Angiogenesis is crucial for tumor development and CD31 is widely used as a marker to highlight the density of intra tumoral vessels and the degree of neoangiogen esis.

Its immunoexpression was mainly localized in the junction between cells and is clearly positive in tumors from the vehicle control group with slight inhibition in the oxaliplatin and dovitinib treated tumors and almost negli gible staining in combination treatment group a d. Figures 4C a d show the H E staining in tu mors from all the groups. The quantitative data for immu nostaining is shown in Figure 4D. These results suggest an in Batimastat vivo antitumor efficacy of the combination against colorectal cancer without any ap parent signs of toxicity. Also, antitumor effect of the com bination of oxaliplatin and dovitinib is due to inhibition of both proliferation and angiogenesis. Discussion In this study, we evaluated the growth inhibitory effects of dovitinib and oxaliplatin combination in cell culture and xenograft models of colon cancer, and our goal for this investigation was to elucidate potential molecular mechanisms of action for the compounds contributing to the antiproliferative and anticancer capacity of human colon cancer cells.

We found that selleck chemicals both oxaliplatin and dovitinib effectively di minished the growth of colon cancer cell lines regardless of their RAS RAF mutation status. Of greater interest, we found that this combination showed a syner gistic antiproliferative activity and inhibition of angio genesis in a colon cancer xenograft model with a bRAF mutation and multi drug resistant phenotype.