5-Fluorouracil photosensitising reactions induced by UVB light

The chemotherapeutic agent 5-fluorouracil (5-FU) is a pyrimidine analogue used as an antineoplastic drug both systemically and topically for a variety of cancerous and precancerous diseases. Among its side effects, phototoxic and photoallergic reactions are reported in treated patients inadvertently exposed to sunlight and higher efficacy against actinic keratosis was found when affected areas are exposed to irradiation. 5-FU and its deoxyribonucleoside monophosphate are known to undergo photodegradation under UVC and UVB light. Therefore the drug itself and its formulations are suggested to be protected from light. Phototoxicity was studied in vitro on NCTC-2544 and 3T3 cell lines. The photoallergic potential was evaluated through photosensitization reactions to model amino acids and proteins. Experiments in cancerous 5-FU resistant MCF-7 cell lines were performed in order to assess the antiproliferative effect of 5-FU in combination with UVB light. The photostability of 5-FU parenteral and topical formulations and the consequences of photolysis on therapeutic activity have been also evaluated. We have demonstrated that photolysis of 5-FU caused loss of its antiproliferative activity in HCT-15 and HeLa tumor cell lines sensitive to 5-FU. Moreover, a slight in vitro phototoxicity of 5-FU was detected on NCTC-2544 and 3T3 cell lines. The nucleophilic addition of amino acids and peptides (i.e. serine, cysteine, angiotensin fragment) to the 5,6 double bond of 5-FU (detected by Mass Spectrometry) as well as photooxidation of proteins (BSA carbonyl content assay) were shown, possibly explaining the occurrence of photoallergy and other undesired light–induced side effects of this drug. A little improvement of the antiproliferative activity of 5-FU in combination with UVB irradiation on MCF-7 resistant cells was also evidenced, but not enough effective to justify its use as a phototherapeutic agent.