5-Fluorouracil as an enhancer of aminolevulinate-based photodynamic therapy for skin cancer: New use for a venerable agent?

Abstract

was developed in the 1950s as an anticancer drug and is now widely used to treat many cancers, including colon and breast carcinoma. 5-FU causes fluoronucleotide misincorporation into RNA and DNA, inhibits thymidylate synthase, and leads to growth arrest and apoptosis. For skin precancers (actinic keratoses; AK), 5-FU is prescribed as a topical agent and was essentially the only option for treating widespread AK of the skin prior to FDA approval of photodynamic therapy (PDT) in 1999. PDT is now gradually replacing 5-FU as a preferred treatment for AK, but neither PDT nor 5-FU are effective for true skin cancers (basal or squamous cell), particularly for tumors >1 mm in depth. In our ongoing work to improve the efficacy of PDT for skin cancer, we previously showed that PDT efficacy can be significantly enhanced by preconditioning tumors with methotrexate (MTX), which leads to increased production of protoporphyrin IX (PpIX) in target cells. However, because MTX must be given orally or intravenously, it is considered unacceptable for widespread human use due to potential toxicity. MTX and 5-FU exert similar effects on the thymidylate synthesis pathway, so we reasoned that topical 5-FU could be a potential alternative to MTX. In this paper, exploratory studies that test 5-FU as a preconditioning agent for PDT are presented. In a cutaneous model of squamous cell carcinoma (chemically-induced papillomatous tumors in mice), 5-FU significantly enhances PpIX accumulation and therefore emerges as a new candidate agent for combination therapy with PDT.

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

“…In our studies in murine models of UV-induced skin cancer, a brief period of 5FU application (only 3 days) was sufficient to increase PpIX levels and improve the tumor treatment response. PpIX elevations were accompanied by significant changes in CPO and FC enzyme levels, as well as in E-cadherin (21,26). In addition, p53 was increased after 5FU pretreatment.…”

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.…”

Vitamin D and Other Differentiation‐promoting Agents as Neoadjuvants for Photodynamic Therapy of Cancer

“…Importantly, topical 5‐FU is approved by the FDA and is widely used for the treatment of skin precancers (so‐called “actinic keratoses”). Therefore, there are no regulatory barriers when using topical 5‐FU (31).…”