Intestinal alkaline phosphatase (IAP) is an endogenous intestinal enzyme that promotes gastrointestinal (GI) homeostasis by detoxifying inflammatory mediators, tightening the gut barrier and promoting a healthy microbiome. In previous reports, oral delivery of IAP ameliorated colitis in animals and in a human pilot study. The commonly used chemotherapy, 5-Fluorouracil (5-FU), can cause severe GI damage potentially resulting in dose limiting toxicities. Given the recent implication of the gut microbiome in modulating the anti-cancer response and the role of IAP in mitigating GI toxicity, we sought to evaluate the role of IAP in ameliorating 5-FU related GI side effects and to assess the impact of IAP therapy on anti-cancer efficacy.
BALB/c mice were inoculated with CT26 murine colorectal cancer cells into the right flank. 5-FU (30 mg/kg) was given IP QD for 5 consecutive days. IAP (0.5 mg/kg) or vehicle was administered PO BID throughout the study. Mice were evaluated for stool consistency, tumor growth and survival. A cohort of mice was sacrificed at day 5 for histopathology analysis.
5-FU administration caused loose stools/diarrhea in all the treated animals, which peaked at day 6 and recovered by day 9. Interestingly, mice that received IAP showed a significantly faster recovery (p < 0.03). As expected, 5-FU slowed tumor progression compared to controls (no 5-FU). Surprisingly, IAP addition significantly improved anti-cancer efficacy. Mice treated with IAP showed diminished tumor growth compared to vehicle (at day 19, 1066 vs 1968 mm3, p < 0.05). Furthermore, IAP administration significantly prolonged animal survival when compared to vehicle-treated animals (p < 0.02). Mechanistically, 5-FU led to goblet cell loss whereas IAP treatment protected the goblet cells.
Oral administration of IAP in mice not only improved some of the side effects associated with 5-FU, such as diarrhea and potentially mucositis, but also enhanced the anti-tumor efficacy of 5-FU leading to significantly prolonged survival. Overall, IAP has the potential to become a new therapeutic agent intended to mitigate cancer-treatment side effects and to enhance the overall anti-tumor response.
The authors.
Synthetic Biologics.
C. Furlan Freguia: Full / Part-time employment: Synthetic Biologics. M. Kaleko: Full / Part-time employment: Synthetic Biologics.