title: Synergistic interaction of 5-aminolevulinic acid-based photodynamic therapy with simultaneous hyperthermia in an osteosarcoma tumor model.
abstract: In this study, the effectiveness and mechanism of combination therapy of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) with simultaneous hyperthermia (HT) on human-derived osteosarcoma in vivo were examined. A tumor model was prepared by subcutaneously implanting human osteosarcoma into nude mice and local injection of ALA was selected as the administration route. This study demonstrated that both ALA-PDT and the combination of ALA-PDT with HT exhibited significant inhibitory effects on tumor growth. In the group with high total energy, the growth inhibition rates of tumor were 52.3% in ALA-PDT, and 27.3% in ALA-PDT with simultaneous HT (PDT+HT), and the synergetic index was 1.76, demonstrating that the inhibitory effect on tumor growth in ALA-PDT was significantly increased by simultaneous use of HT. In the histological findings, after ALA-PDT, necrosis was observed in the area from the surface to a depth of 2 mm, and only a slight effect was confirmed in deeper layers. On the other hand, after PDT+HT, necrosis was observed in layers even deeper than 2 mm below the surface. Furthermore, based on the immunohistochemical findings of the expression of carbonic anhydrase IX, while weak expression of CAIX was observed after ALA-PDT in an area relatively close to the surface, a positive area extended to the deeper layers after PDT+HT compared with ALA-PDT. In conclusion, PDT+HT demonstrated a significant inhibitory effect on tumor growth of human-derived osteosarcoma, and a synergistic interaction of simultaneous HT. This suggests the possibility that ALA-PDT is useful, not only for the treatment of superficial tumors but also for deep-seated mesenchymal tumors, such as osteosarcoma. Furthermore, the mechanism of the synergistic interaction suggested that ALA-PDT was effective in the deep area of tumors due to the increase of blood flow by mild hyperthermia.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Mie University, Tsu, Mie 514-8507, Japan. shigeaki@clin.medic.mie-u.ac.jp
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Yanase
authors.forename: Jouji
authors.initials: J
authors.lastname: Nomura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nagata
authors.forename: Tasuku
authors.initials: T
authors.lastname: Fujii
authors.forename: Toshiro
authors.initials: T
authors.lastname: Tagawa
mesh_terms: D000622:Aminolevulinic Acid / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000473:pathology* / Q000628:therapy*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases