5-Fluorouracil enhances Protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses: A mechanism-based clinical trial

PURPOSE: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. EXPERIMENTAL DESIGN: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days; the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 h, and PpIX levels measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months post-PDT. RESULTS: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (CPO and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates (CR) after PDT with or without 5FU pretreatment were 75% vs. 45% at 3 months, and 67% vs. 39% at 6 months, respectively; these differences were statistically significant. CONCLUSIONS: Serial 5FU and PDT improves AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. ClinicalTrials.gov NCT01525329.

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