Chemotherapy causes gastrointestinal mucositis (GM), a damaging side effect of cancer treatment, which is associated with vitamin D deficiency. Previously, we have identified that reduced vitamin D activity in the intestine, via CYP24A1 activity, exacerbates GM. Thus, enhanced intestinal vitamin D activity may reduce GM during chemotherapy exposure. As such, we have developed a low-calcemic vitamin D analogue, VD1-6, to assess whether promoting vitamin D activity reduces the severity of chemotherapy-induced GM, without causing hypercalcaemia.
VD1-6 (500ng/kg/day) or saline was administered, in two independent studies, either subcutaneously or orally, to C57Bl6 mice daily five days before, and two days following, chemotherapy (5FU I.P. 450mg/kg) exposure. Histological and mRNA analyses of the duodenum and colon sections were performed to assess intestinal damage and intestinal barrier function. Serum biochemical markers of vitamin D metabolites, PTH, FGF23, ALP, calcium and phosphate were measured. Other measures of kidney and bone structure and function were also assessed.
In both studies, acute 5FU exposure caused intestinal damage (ie reduced duodenal villous height, reduced colon crypt depth, goblet cell ablation, and reduced intestinal barrier function markers including Zonulin-1). 5FU exposure markedly reduced colon VDR mRNA levels, indicating impaired vitamin D activity. However, subcutaneous VD1-6 treatment prevented 5-FU-induced colon crypt damage without hypercalcemia, in part, through the maintenance of crypt cell proliferation, as measured by Ki67. In contrast, VD1-6 did not consistently prevent 5-FU-induced duodenal damage when administered either subcutaneously or orally.
Vitamin D therapies, using low-calcemic analogues, may provide a promising new strategy to assist in the prevention of GM. Further investigations are required to elucidate the key pathways involved.