Carboxyamidotriazole orotate and cytotoxic chemotherapy have a synergistic effect on tumor inhibition in glioblastoma and colon xenograft mouse models

Abstract

The purpose of this study was to evaluate the antitumor efficacy of carboxyamidotriazole orotate (CTO) alone or in combination with cytotoxic chemotherapy in glioblastoma and colon cancer xenograft mouse models. CTO targets VEGF and PI3K via Ca++ signaling pathways. Combination therapy with VEGF inhibitors and chemotherapy is reported to have a synergistic effect in these models. CTO was administered alone and in combination with temozolomide against U251 human glioblastoma xenografts in male, athymic NCr-nu/nu mice. CTO was administered alone and in combination with 5-fluorouracil (5-FU) and compared to 5-FU or bevacizumab given alone or in combination against HT29 human colon tumor xenografts in male, athymic NCr-nu/nu mice. Efficacy was measured by the time delay to doubling or tripling of the tumor, delay in tumor growth, and tumor weight relative to controls. The combination of CTO and chemotherapy exhibited significant antitumor effects that were more efficacious than chemotherapy alone in U251 and HT29 xenograft mouse models. CTO combined with temozolomide had synergistic activity resulting in significantly greater inhibition than temozolomide monotherapy in the GBM xenograft mouse model; however, high-dose CTO was toxic. Low-and high-dose CTO in combination with 5-FU had greater efficacy than the combination of bevacizumab and 5-FU in the colon cancer xenograft mouse model. This study supports the growing body of data reporting the efficacy of combination therapy with Calcium-VEGF-PI3K inhibitors and cytotoxic chemotherapy in GBM and colorectal cancer. Our findings establish a therapeutic approach to tumors using CTO combined with cytotoxic chemotherapy for the treatment of GBM and colon cancer.