(T1030-04-28) Co-administration of Irinotecan with Naturally Occurring Flavonoids Exhibits Synergistic Antitumor Effects on Colon Xenograft Tumors

Purpose: Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. 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 (GI) injury/inflammation and severe diarrhea. CPT-11 is a prodrug that is converted to the active cytotoxic molecule SN-38 by the action of liver carboxylesterases. SN-38 is subsequently conjugated primarily by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite (SN-38G). However, SN-38G is susceptible to β-linkage cleavage in the intestinal tract, producing free SN-38 which can be reabsorbed leading to GI toxicity. Previous studies reported that natural flavonoids such as wogonin and chrysin have anticancer and anti-diarrheal activities. This study aims to investigate the efficacy and safety of irinotecan when co-administered with a naturally occurring flavonoids mixture in human colon cancer xenograft model.

Methods: Xenograft model was established using the human colon adenocarcinoma HT-29 cell line. When the tumor volume was around 500-600 mm³, the flavonoids mixture (wogonin plus chrysin) was administered by oral gavage at 100mg/kg/day for three days and then co-administered with CPT-11, intraperitoneally, at two different doses i.e., 50mg/kg and 75mg/kg per day for seven consecutive days. Mice that received CPT-11 monotherapy served as control. The body weights and tumor volumes were measured daily, and tumor percentage changes were assessed between groups and between genders. Plasma samples were collected on days 3 and 7 by blood collection via tail snip, post-dosing, and tumor samples were collected on day 7, immediately after scarifying the mice, for measuring the changes in the drug disposition of CPT-11, SN-38, and SN-38G using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) analysis. A t-test was used for all statistical analyses.

Results: Our study demonstrated that the tumor volume decreased by 36 % with the treatment of 50mg/kg/day CPT-11 plus 100mg/kg/day wogonin/chrysin and by 57 % with 75mg/kg/day CPT-11 plus 100mg/kg/day wogonin/chrysin compared to conventional irinotecan treated animals with no major impact on body weights. Interestingly, female mice showed a 2-fold decrease in tumor volume compared to the monotherapy group which is statistically significant with p< 0.05. 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 plasma and tumor samples, as demonstrated by the LC-MS/MS analysis.

Conclusion: Taken together, our data show that co-administration of CPT-11 and flavonoids mixture (wogonin and chrysin) exhibit a gender-specific synergistic anti-tumor effect with no changes in drug disposition rates and hence can be safely administered together for metastatic colon cancer treatment. Therefore, this combination therapy could be a promising approach in anti-tumor chemotherapy for better clinical outcomes.

Acknowledgements: NIGMS grant award 1SC2GM135111-01, NIMHD grant award U54MD007605, CPRIT grant RP180748 and RCMI – CBMHR.