Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death.
Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death.
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DOI：
10.1158/1535-7163.mct-16-0608
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发表时间：
2017-06
影响因子：
5.7
通讯作者：
Maytin EV
中科院分区：
文献类型：
--
作者：
Anand S;Rollakanti KR;Brankov N;Brash DE;Hasan T;Maytin EV
使用5-氨基乙酰丙酸（ALA）驱动原卟啉IX（PpIX）合成的光动力疗法（PDT）是皮肤癌手术的一种有前途的无疤痕替代疗法，包括鳞状细胞癌（SCC）和称为光化性角化病（AK）的SCC前体。在美国，PDT仅被FDA批准用于治疗AK;如果PDT疗效得到改善，这种狭窄的适应症范围可能会扩大。为了实现这一目标，我们开发了一种基于机制的组合方法，使用5-氟尿嘧啶（5-FU）作为新辅助剂用于基于ALA的PDT。在SCC小鼠模型（原位UV诱导的病变和皮下A431和4 T1肿瘤）中，用5-FU预处理3天，然后用ALA预处理4小时，导致PpIX水平的大的肿瘤选择性增加，并增强光照后的细胞死亡。确定了几种可能解释相对改善的治疗反应的机制。首先，血红素合成途径中的关键酶的表达被改变，包括粪卟啉原氧化酶的上调和亚铁螯合酶的下调。其次，在5-FU预处理的肿瘤中，观察到3- 6倍的p53诱导。A431含有突变型p53的事实并不能阻止新佐剂5-FU作用的发展。此外，4 T1肿瘤（完全缺乏p53的细胞）的5-FU预处理仍然导致显著的有益诱导，即，2.5-倍的PpIX和PDT诱导的细胞死亡。因此，新辅助5-FU联合PDT代表了一种新的治疗方法，甚至对p53突变型和p53缺失型肿瘤也有用。
Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses (AK). In the United States, PDT is only FDA approved for treatment of AK; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneous A431 and 4T1 tumors), pretreatment with 5-FU for 3 days followed by ALA for 4 hours led to large, tumor-selective increases in PpIX levels, and enhanced cell death upon illumination. Several mechanisms were identified that might explain the relatively improved therapeutic response. Firstly, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Secondly, a 3- to 6-fold induction of p53 in 5-FU pretreated tumors was noted. The fact that A431 contains a mutant form p53 did not prevent the development of a neoadjuvantal 5-FU effect. Furthermore, 5-FU pretreatment of 4T1 tumors (cells that completely lack p53), still led to significant beneficial inductions, i.e., 2.5-fold for both PpIX and PDT-induced cell death. Thus, neoadjuvantal 5-FU combined with PDT represents a new therapeutic approach that appears useful even for p53-mutant and p53-null tumors.