The Synergistic Antitumor Effect of Irinotecan and Flavonoids on Human Colon Cancer Xenograft Mice

Abstract ID 53806 Poster Board 44 Camptothecin (CPT)-11 (irinotecan), a DNA topoisomerase I inhibitor, is one of the first-line therapeutic agents in the treatment of metastatic colorectal cancer, but its efficacy and safety can be compromised because of its severe side effects, such as gastrointestinal injury/inflammation and severe diarrhea. Previous studies reported that natural flavonoids such as wogonin and chrysin have anticancer and anti-diarrheal activities. The purpose of this study is to investigate the efficacy and safety of irinotecan when co-administered with flavonoids in the human colon cancer xenograft model. The human colorectal adenocarcinoma cell line HT-29 was cultured, and 2 x 106 cells/mouse were administered subcutaneously to 6 weeks old nude mice. When the tumor volume was around 500-600 mm3, the flavonoids (wogonin and chrysin mix) were administered by oral gavage at 100 mg per kg of mouse body weight (100mg/kg) per day for three days and then co-administered with CPT-11. CPT-11 was administered intraperitoneally at two different doses i.e., 50 mg/kg and 75mg/kg per day for seven consecutive days as a bolus injection. Mice that received CPT-11 monotherapy served as control. Our study demonstrated that the combination therapy of CPT-11 co-administered with flavonoids had no major impact on mouse body weights. Furthermore, the combination therapy resulted in lower tumor volume when compared with single-agent treatment. Tumor volume decreased by 36 % with the treatment of 50 mg/kg CPT-11 plus 100mg/kg/day wogonin/chrysin and 57 % with 75 mg/kg/day CPT-11 plus 100mg/kg/day wogonin/chrysin compared to conventional irinotecan treated animals. Interestingly, female mice that received the combination therapy, either with a low dose or high dose of CPT-11, showed a 2-fold decrease in tumor volume when compared to CPT-11 only treated group. This confirms the previous reports that females mount a more robust cellular and humoral response, resulting in greater anti-tumor efficacy. Furthermore, monotherapy and combination therapy led to the same CPT-11 disposition in blood or tumor tissues, as demonstrated by the Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) analysis. Taken together, our data show that CPT-11 and flavonoids (wogonin and chrysin) exhibit a synergistic anti-tumor effect and can be safely administered together for metastatic colon cancer treatment. Therefore, this combination therapy could be a promising approach in an