Background
Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to improve PDT efficacy, through direct interaction with PpIX formation or through an independent response, both of which may improve PDT treatment.

Objective
To present the currently available clinical evidence of pharmacological pretreatments prior to PDT and to associate potential clinical benefits with the pharmacological mechanisms of action of the individual compounds.

Methods
A comprehensive search on the Embase, MEDLINE, and Web of Science databases was performed.

Results
In total, 16 studies investigated 6 pretreatment compounds: 5-fluorouracil (5-FU), diclofenac, retinoids, salicylic acid, urea, and vitamin D. Two of these, 5-FU and vitamin D, robustly increased the efficacy of PDT across multiple studies, illustrated by mean increases in clearance rates of 21.88% and 12.4%, respectively. Regarding their mechanisms, 5-FU and vitamin D both increased PpIX accumulation, while 5-FU also induced a separate anticarcinogenic response. Pretreatment with diclofenac for four weeks improved the clearance rate in one study (24.9%), administration of retinoids had a significant effect in one of two studies (16.25%), while salicylic acid and urea did not lead to improved PDT efficacy. Diclofenac and retinoids demonstrated independent cytotoxic responses, whereas salicylic acid and urea acted as penetration enhancers to increase PpIX formation.

Conclusion
5-FU and vitamin D are well-tested, promising candidates for pharmacological pretreatment prior to PDT. Both compounds affect the haem biosynthesis, providing a target for potential pretreatment candidates. Key Words: Photodynamic Therapy, Actinic Keratosis,Pre-tretment,Review,enhancement