title: Interstitial 5-ALA photodynamic therapy and glioblastoma: Preclinical model development and preliminary results.
abstract: OBJECTIVE
  Photodynamic therapy (PDT) has become a well-established modality for the treatment of many cancers. Photodynamic eradication of tumor cells depends on the presence of a photosensitizer, oxygen and light. However, oxygen depletion during PDT is a well known problem. Modulation of light delivery could address this issue by counteracting tumor hypoxia, thereby improving tumor cell killing. This preclinical study was designed to validate an animal model incorporating 5-aminolaevulinic acid (5-ALA)-PDT using U87 glioblastoma cells. We aimed to evaluate the effects of light modulation for inducing specific tumoral lesions in this model (i.e., necrosis or apoptosis).
  
  
  METHODS
  U87 glioblastoma cells were stereotactically engrafted into the brains of male fox1 rnu/rnu rats. Light delivery was studied after 5-ALA injection (100 mg/kg i.p.). 26J of 635 nm light was interstitially delivered to U87 tumor-bearing rats at a radiant power of either 30 mW (high fluence rate) or 4.8 mW (low fluence rate). In each group, half of the population received illumination in 2 fractions with a refractory interval of 120 s, whereas the other half received continuous illumination.
  
  
  RESULTS
  Twenty-two animals received 5-ALA-PDT, and the level of necrosis was scored. In the high-fluence-rate group, we observed a greater degree of tumor necrosis in rats receiving fractionated delivery than in rats receiving continuous illumination. Similar differences were not observed in the low-fluence-rate group, which exhibited only sparse necrosis. Higher morbidity and mortality rates were observed in the high-fluence-rate group.
  
  
  CONCLUSIONS
  We have developed a reproducible and reliable rodent model for interstitial 5-ALA PDT. We found that the effects of 5-ALA-PDT are dependent on light delivery conditions. Although the low-fluence-rate treatment was better tolerated, 5-ALA-PDT induced more necrosis using fractionated delivery at a high fluence rate. These results require confirmation with further studies involving larger populations and additional fractionation schemes.
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Neurosurgery, CHU Lille, F-5900 Lille, France.
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Tetard
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Neurosurgery, CHU Lille, F-5900 Lille, France. Electronic address: m-vermandel@chru-lille.fr.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Vermandel
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Neurosurgery, CHU Lille, F-5900 Lille, France.
authors.forename: Henri-Arthur
authors.initials: HA
authors.lastname: Leroy
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leroux
authors.affiliation: Univ. Lille, CHU Lille, F-5900 Lille, France.
authors.forename: Claude-Alain
authors.initials: CA
authors.lastname: Maurage
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Neurosurgery, CHU Lille, F-5900 Lille, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Lejeune
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Mordon
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Neurosurgery, CHU Lille, F-5900 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Reyns
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005240:Feasibility Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D010865:Pilot Projects; D051381:Rats; D011923:Rats, Nude; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid
keywords: 5-ALA; High-grade glioma; Photodynamic therapy; PpIX; Rodent model; U87