Combination of Oral Vitamin D3 with Photodynamic Therapy Enhances Tumor Cell Death in a Murine Model of Cutaneous Squamous Cell Carcinoma

Photodynamic therapy (PDT), in which 5‐ALA (a precursor for protoporphyrin IX, PpIX) is administered prior to exposure to light, is a nonscarring treatment for skin cancers. However, for deep tumors, ALA‐PDT is not always effective due to inadequate production of PpIX. We previously developed and reported a combination approach in which the active form of vitamin D₃ (calcitriol) is given systemically prior to PDT to improve PpIX accumulation and to enhance PDT‐induced tumor cell death; calcitriol, however, poses a risk of hypercalcemia. Here, we tested a possible strategy to circumvent the problem of hypercalcemia by substituting natural dietary vitamin D₃ (cholecalciferol; D₃) for calcitriol. Oral D₃ supplementation (10 days of a 10‐fold elevated D₃ diet) enhanced PpIX levels 3‐ to 4‐fold, and PDT‐mediated cell death 20‐fold, in subcutaneous A431 tumors. PpIX levels and cell viability in normal tissues were not affected. Hydroxylated metabolic forms of D₃ were only modestly elevated in serum, indicating minimal hypercalcemic risk. These results show that brief oral administration of cholecalciferol can serve as a safe neoadjuvant to ALA‐PDT. We suggest a clinical study, using oral vitamin D₃ prior to PDT, should be considered to evaluate this promising new approach to treating human skin cancer.