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Norwegian Radium Hospital, Comprehensive Cancer Center The influence of photodynamic therapy on folate and vitamin D levels Biophysics and PDT group, Department of Radiation Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet HF Group leader: Johan Moan, Prof., PhD Tel:22934268 E-mail: [email protected] PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) involves administration of a tumour-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid (ALA) or its methyl ester (MAL)) and the subsequent activation of the photosensitizer by light in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumour microvasculature and stimulate the host immune system. ALA or MAL Light Cell destruction TOPICAL PHOTODYNAMIC THERAPY IN DERMATOLOGY In dermatology, PDT with topical ALA or MAL is very effective in the treatment of actinic keratosis, basal cell carcinomas and Bowen's disease. In addition, very promising results have been obtained in inflammatory pathologies like morphea, sarcoidosis and infections like warts. Bowen’s disease Basal cell carcinoma Actinic keratosis Folate is an essential vitamin for cell division and cell Morphea Warts A high vitamin D status (serum 25(OH)vitamin D3) correlates with a decreased risk of breast-, prostate-, colon-, lung cancer and lymphomas. growth. Since cancer cells divide more often than normal cells they need more folate. Therefore, several of the chemotherapeutic agents used against cancer are antifolates. The most common one is Methotrexate, which binds to the folate enzyme dihydrofolate reductase. O O Me N H N N H2 N CO 2 H S CO 2 H N H N H Folate N H Jablonski and Chaplin, Sci. Am. 2002 Experiments carried out by us indicate that folate is degraded during PDT, both in vivo, in patient treated with PDT, and in vitro, in folate solutions exposed to visible light in the presence of photosensitizers. The most common folate derivative in the human body, 5methyltetrahydrofolate, is oxidized to the biological inactive folate 5-methyldihydrofolate, because of it’s antioxidant activity. Multivariable relative risks and 95% confidence intervals for an increment of 25 nmol/L in predicted plasma 25-hydroxy-vitamin D level for individual cancers in the Health Professionals Followup Study (1986–2000). Giovannucci, E. et al. J Natl Cancer Inst 2006;98:451-459 CAN PDT HAVE SYSTEMIC EFFECTS LIKE FOLATE DEGRADATION AND INCREASED VITAMIN D PRODUCTION? The aim of this study is to investigate the level of folate and vitamin D in serum of rats before and after PDT. A cream containing ALA will be applied topically for 6 h on shaved rat skin. Subsequently the cream will be removed and rats will be exposed to blue light. Blood will be sampled before light exposure and after at different time points. Serum will be separated and vitamin D derivatives and folate will be quantified by standard methods. Furthermore, cream may be enriched with vitamin D precursors that will be absorbed in the skin and activated during light exposure in PDT. By this means, vitamin D production might be locally increased leading to a better treatment outcome. If the experimental results are encouraging, a clinical study will be designed. Blood from patients undergoing PDT treatment on extended skin areas will be drawn and vitamin D and folate levels will be assessed.