Aims: 5-fluorouracil (5FU) is a chemotherapy agent known to cause gastrointestinal mucositis (GM), a side effect of cancer treatment, for which there is currently no effective treatment. Vitamin D has been widely shown to have immunomodulatory and anti-inflammatory effects in the intestine, and therefore may reduce severity of GM. Since the use of vitamin D and vitamin D analogues have an associated risk of hypercalcaemia, we considered whether competitive vitamin D catabolism inhibitor (VDCI) could be used for reducing 5FU-induced GM, without causing hypercalcaemia.
Methods: C57Bl6 mice (n=36) received a single intraperitoneal injection of 450mg/kg 5-fluorouracil (5FU) or saline (vehicle control), and subcutaneous 500ng/kg VDCI or saline (vehicle control) daily for five days prior and two days following 5FU administration, before being euthanized at 48 h following 5FU administration. Routine H&E, RT-PCR and immunohistochemistry was carried out on duodenum sections. NDP.view 2 was used to quantify villi and crypt parameters. Serum calcium levels were measured via KONE analysis. One-way ANOVA, with Tukey’s test, was used for statistical analysis.
Results: Calcium levels were unaltered in the presence of VDCI. 5FU significantly reduced villous height (VH, p=0.0002) and villous area (VA, p=0.0006) in the duodenum, compared to saline. 5FU + VDCI significantly increased VH compared to 5FU (p=0.043), and was not significantly different to saline. 5FU treatment decreases transient receptor potential cation channel subfamily v member 6 (TRPV6) RNA expression, while VDCI/5-FU doesn’t upregulate TRPV6 in duodenum, suggesting a mechanism for normocalcemia.
Conclusions: Inhibition of vitamin D catabolism alleviates intestinal damage in 5FU-treated mice without causing hypercalcemia and may provide a promising new avenue for anti-mucotoxic therapy.