title: The effects of ultra low fluence rate single and repetitive photodynamic therapy on glioma spheroids.
abstract: OBJECTIVE
  Achieving local control of gliomas with photodynamic therapy (PDT) requires the delivery of adequate light fluences to depths of 1-2 cm in the resection margin where the majority of local recurrences originate. This is clinically impractical with current single-shot, intraoperative PDT treatments due to the length of time required to deliver adequate fluences. Multiple or extended treatment protocols would therefore seem to be required. The response of human glioma spheroids to 5-aminolevulinic acid (ALA)-mediated PDT using single or, repetitive light delivery protocols was investigated at both low and ultra low fluence rates.
  
  
  METHODS
  Human glioma spheroids (400 microm diameter) were subjected to sub-threshold light fluence (1.5, 3, or 6 J cm(-2)) ALA-PDT consisting of four light delivery schemes: single treatment given over either 1 or 24 hours, repetitive treatment given either as four 1 hour light treatments separated by a 4 day interval, or 24 hours light delivery, consisting of four 24 hours treatments separated by a 3 day interval. Treatment efficacy was evaluated using a growth assay. In some cases, confocal microscopy was used to image cell viability.
  
  
  RESULTS
  The repetitive and single light treatment protocols were most effective when delivered at ultra low (microW cm(-2)) fluence rates. In all cases, growth inhibition was light dose-dependent. The repetitive ultra low fluence rate treatment (1.5 J cm(-2); irradiance = 17 microW cm(-2)) light delivery protocol was the most effective resulting in total growth inhibition during the 2-week observation period.
  
  
  CONCLUSIONS
  Ultra low light fluence rate ALA-PDT results in significant spheroid growth inhibition. Repeated administration of ALA was required during repetitive and/or protracted single PDT treatment protocols. The existence of a lower fluence rate limit, below which the efficacy of threshold light fluences diminish was not found in these studies. Lasers Surg. Med. 41:578-584, 2009. (c) 2009 Wiley-Liss, Inc.
authors.affiliation: Beckman Laser Institute, University of California, Irvine, California 92612, USA. mmathews@ubns.com
authors.forename: Marlon S
authors.initials: MS
authors.lastname: Mathews
authors.forename: Even
authors.initials: E
authors.lastname: Angell-Petersen
authors.forename: Rogelio
authors.initials: R
authors.lastname: Sanchez
authors.forename: Chung-Ho
authors.initials: CH
authors.lastname: Sun
authors.forename: Van
authors.initials: V
authors.lastname: Vo
authors.forename: Henry
authors.initials: H
authors.lastname: Hirschberg
authors.forename: Steen J
authors.initials: SJ
authors.lastname: Madsen
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage*; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000528:radiation effects*; D014407:Tumor Cells, Cultured
chemical_list: D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid