title: Aminolevulinic acid-photodynamic therapy combined with topically applied vascular disrupting agent vadimezan leads to enhanced antitumor responses.
abstract: The tumor vascular-disrupting agent (VDA) vadimezan (5,6-dimethylxanthenone-4-acetic acid, DMXAA) has been shown to potentiate the antitumor activity of photodynamic therapy (PDT) using systemically administered photosensitizers. Here, we characterized the response of subcutaneous syngeneic Colon26 murine colon adenocarcinoma tumors to PDT using the locally applied photosensitizer precursor aminolevulinic acid (ALA) in combination with a topical formulation of vadimezan. Diffuse correlation spectroscopy (DCS), a noninvasive method for monitoring blood flow, was utilized to determine tumor vascular response to treatment. In addition, correlative CD31-immunohistochemistry to visualize endothelial damage, ELISA to measure induction of tumor necrosis factor-alpha (TNF-α) and tumor weight measurements were also examined in separate animals. In our previous work, DCS revealed a selective decrease in tumor blood flow over time following topical vadimezan. ALA-PDT treatment also induced a decrease in tumor blood flow. The onset of blood flow reduction was rapid in tumors treated with both ALA-PDT and vadimezan. CD31-immunostaining of tumor sections confirmed vascular damage following topical application of vadimezan. Tumor weight measurements revealed enhanced tumor growth inhibition with combination treatment compared with ALA-PDT or vadimezan treatment alone. In conclusion, vadimezan as a topical agent enhances treatment efficacy when combined with ALA-PDT. This combination could be useful in clinical applications.
authors.affiliation: Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Marrero
authors.forename: Theresa
authors.initials: T
authors.lastname: Becker
authors.forename: Ulas
authors.initials: U
authors.lastname: Sunar
authors.forename: Janet
authors.initials: J
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Bellnier
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000287:Administration, Topical; D000622:Aminolevulinic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D014408:Biomarkers, Tumor / Q000032:analysis; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003131:Combined Modality Therapy / Q000379:methods*; D005260:Female; D007150:Immunohistochemistry; D008027:Light; D051379:Mice; D008807:Mice, Inbred BALB C; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000276:immunology; D013057:Spectrum Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D044004:Xanthones / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017319:Photosensitizing Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D000622:Aminolevulinic Acid