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5-Fluorouracil (5-FU) 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.
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