Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death.
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. In the United States, PDT is only FDA approved for treatment of actinic keratoses; 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. First, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Second, 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, that is, 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.Mol Cancer Ther; 16(6); 1092-101. ©2017 AACR.
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio. anands@ccf.org maytine@ccf.org.|Department of Dermatology, Cleveland Clinic, Cleveland, Ohio.
Sanjay
S
Anand
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio.
Kishore R
KR
Rollakanti
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio.
Nikoleta
N
Brankov
Departments of Therapeutic Radiology and Dermatology, Yale School of Medicine, New Haven, Connecticut.
Douglas E
DE
Brash
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.
Tayyaba
T
Hasan
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio. anands@ccf.org maytine@ccf.org.|Department of Dermatology, Cleveland Clinic, Cleveland, Ohio.|Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.
Edward V
EV
Maytin
D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006418:Heme / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D010778:Photochemotherapy / Q000379:methods; D011524:Protoporphyrins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D011524:Protoporphyrins; D016159:Tumor Suppressor Protein p53; D006418:Heme; C028025:protoporphyrin IX; D005472:Fluorouracil