5-Fluorouracil Enhances Protoporphyrin IX Accumulation and Lesion Clearance during Photodynamic Therapy of Actinic Keratoses: A Mechanism-Based Clinical Trial

Abstract

Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents 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. A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT. PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant. Serial 5FU and PDT improve 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. .

Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta‐analysis

“…Four of the 10 studies investigated a combination of PDT with imiquimod cream 21,[26][27][28] and three studies a combination of PDT with 5-FU cream. 19,24,25 The remaining three studies assessed a combination of PDT with ingenol mebutate 0.015% gel, 16 tazarotene 0.1% gel 17 and calcipotriol ointment, 30 respectively. Six studies assessed PDT monotherapy 17,19,24,25,27,30 and one study diclofenac monotherapy 21 as comparison.…”

Photodynamic Therapy and the Biophysics of the Tumor Microenvironment

“…Cells that are poorly differentiated and rapidly proliferating, as is common in many tumors, may produce insufficient amounts of PpIX . One area of investigation to address this issue involves the use of cellular differentiators such as vitamin D or its analogues, methotrexate, retinoic acid, 5‐fluorouracil acid, iron chelators and the androgens 5α‐dihydrotestosterone (DHT) and R1881 .…”

“…Actinic keratoses, melanoma, cervical cancer, mucosal lesions, intraepithelial squamous cell carcinoma (193)(194)(195)(196)(197) (215)(216)(217) dilated (53). This vascular network often exhibits large pores, enabling increased extravasation of nanoparticle drug carriers into the tumor site for heightened drug accumulation.…”

Probe‐based fluorescence dosimetry of an antibody‐dye conjugate to identify head and neck cancer as a first step to fluorescence‐guided tissue preselection for pathological assessment

“…However, the decision on which tissue to sample for margin status assessment remains highly subjective as it mainly depends on the surgeon's experience, visualization of the tumor, and tactile feedback, which can lead to significant sampling errors. 20,21 Building on this technique, we have developed a novel contact probe-based fluorescence dosimeter device that allows optical measurements of protoporphyrin IX concentration in a targeted region on the surface of human tissue. [9][10][11][12][13][14][15] In head and neck squamous cell carcinoma (HNSCC), the epidermal growth factor receptor (EGFR) is overexpressed in >90% of tumor cells, making it ideal for optical targeted imaging.…”

“…Dosimetry has proven itself valuable for monitoring drug delivery in photodynamic therapy (PDT), where it provides a quantitative measurement of photoactivatable drug dose within the targeted region. 20,21 Building on this technique, we have developed a novel contact probe-based fluorescence dosimeter device that allows optical measurements of protoporphyrin IX concentration in a targeted region on the surface of human tissue. 20,22 We hypothesize that fluorescence dosimetry using such a contact probe could quantify the fluorescence signal of superficial human tissue to discriminate between head and neck cancer and healthy adjacent tissue utilizing panitumumab-IRDye800CW.…”