In combination photodynamic therapy (cPDT), a small-molecule drug is used to modulate the physiological state of
tumor cells prior to giving aminolevulinate (ALA; a precursor for protoporphyrin IX, PpIX). In our laboratory we have
identified three agents (methotrexate, 5-fluorouracil, and vitamin D) that can enhance therapeutic effectiveness of ALAbased
photodynamic therapy for cutaneous squamous cell carcinoma (SCC). However, only one (5-fluorouracil; 5-FU) is
FDA-approved for skin cancer management. Here, we describe animal and human studies on 5-FU mechanisms of
action, in terms of how 5-FU pretreatment leads to enhanced PpIX accumulation and improves selectivity of ALA-PDT
treatment. In A431 subcutaneous tumors in mice, 5-FU changed expression of heme enzyme (upregulating
coproporphyrinogen oxidase, and down-regulating ferrochelatase), inhibited tumor cell proliferation (Ki-67), enhanced
differentiation (E-cadherin), and led to strong, tumor-selective increases in apoptosis. Interestingly, enhancement of
apoptosis by 5-FU correlated strongly with an increased accumulation of p53 in tumor cells that persisted for 24 h post-
PDT. In a clinical trial using a split-body, bilaterally controlled study design, human subjects with actinic keratoses (AK;
preneoplastic precursors of SCC) were pretreated on one side of the face, scalp, or forearms with 5-FU cream for 6 days,
while the control side received no 5-FU. On the seventh day, the levels of PpIX in 4 test lesions were measured by
noninvasive fluorescence dosimetry, and then all lesions were treated with PDT using methyl-aminolevulinate (MAL)
and red light (635 nm). Relative amounts of PpIX were found to be increased ~2-fold in 5-FU pretreated lesions relative
to controls. At 3 months after PDT, the overall clinical response to PDT (reduction in lesion counts) was 2- to 3-fold
better for the 5-FU pretreated lesions, a clinically important result. In summary, 5-FU is a useful adjuvant to
aminolevulinate-based PDT for actinic keratoses of the skin.
Edward V. Maytin and Sanjay Anand, "Combination photodynamic therapy using 5-fluorouracil and aminolevulinate enhances tumor-selective production of protoporphyrin IX and improves treatment efficacy of squamous skin cancers and precancers," Proc. SPIE 9694, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXV, 96940E (Presented at SPIE BiOS: February 13, 2016; Published: 1 March 2016); https://doi.org/10.1117/12.2218138.
Combination photodynamic therapy using 5-fluorouracil and aminolevulinate enhances tumor-selective production of protoporphyrin IX and improves treatment efficacy of squamous skin cancers and precancers
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