title: Calcitriol enhances 5-aminolevulinic acid-induced fluorescence and the effect of photodynamic therapy in human glioma.
abstract: BACKGROUND
  Glioma recurrence frequently occurs close to the marginal area of the surgical cavity as a result of residual infiltrating glioma cells. Fluorescence-guided surgery with 5-aminolevulinic acid (ALA) for resection of gliomas has been used as an effective therapeutic approach to discriminate malignant tissue from brain tissue and to facilitate patient prognosis. ALA-based photodynamic therapy is an effective adjuvant treatment modality for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the applicability of fluorescence-guided resection and photodynamic therapy in the marginal areas of gliomas.
  
  
  METHODS
  To be able to understand how to overcome these issues, human glioma cells and normal astrocytes were used as the model system. Glioma cells and astrocytes were preconditioned with calcitriol for 48 hours and then incubated with ALA. Changes in ALA-induced PpIX fluorescence and cell survival after light exposure were assessed. Furthermore, expression of porphyrin synthetic enzymes in pretreated glioma cells was analyzed.
  
  
  RESULTS
  Calcitriol can be administered prior to ALA as a non-toxic preconditioning regimen to significantly enhance ALA-induced PpIX levels and fluorescence. This increase in PpIX level was detected preferentially in glioma versus normal cells. Also, calcitriol pretreated glioma cells exhibited increased cell death following ALA-based photodynamic therapy. Furthermore, mechanistic studies documented that expression of the porphyrin synthesis enzymes coproporphyrinogen oxidase was increased by calcitriol at the mRNA level.
  
  
  CONCLUSIONS
  We demonstrated for the first time a simple, non-toxic and highly effective preconditioning regimen to selectively enhance PpIX fluorescence and the response of ALA-PDT in glioma cells. This finding suggests that the combined treatment of glioma cells with calcitriol plus ALA may provide an effective and selective therapeutic modality to enhance ALA-induced PpIX fluorescent quality for improving discrimination of tumor tissue and PDT efficacy.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University , Harbin , People's Republic of China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Chen
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Teng
authors.forename: Yaohua
authors.initials: Y
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Ligang
authors.initials: L
authors.lastname: Wang
authors.forename: Huailei
authors.initials: H
authors.lastname: Liu
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Liu
authors.forename: Dongzhi
authors.initials: D
authors.lastname: Zhang
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Guan
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.forename: Changyu
authors.initials: C
authors.lastname: Fu
authors.forename: Boxian
authors.initials: B
authors.lastname: Zhao
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.forename: Shiguang
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004798:Enzymes / Q000235:genetics; D005453:Fluorescence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D057054:Molecular Imaging / Q000379:methods*; D010778:Photochemotherapy / Q000379:methods*; D011524:Protoporphyrins / Q000378:metabolism
chemical_list: D004798:Enzymes; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D002117:Calcitriol