title: Molecular determinants of photodynamic therapy for lung cancers.
abstract: OBJECTIVE
  PDT induces apoptosis, inflammatory reactions, immune reactions, and damage to the microvasculature around the tumors. The mechanisms responsible for the anticancer effects of Photofrin-PDT and NPe6-PDT differ somewhat. To select a photosensitizer for lung cancer treatment and to improve the efficacy of PDT, the mechanisms of action for PDT using Photofrin or NPe6 must be elucidated and the phenomena validated by analyzing molecular determinants from clinical samples.
  
  
  METHODS
  We examined the role of immunological reactions in the anti-tumor effects of PDT using cytokine-overexpressing cells and investigated whether the anti-apoptotic protein Bcl-2 may be a molecular target. Moreover, we investigated the association between ATP-binding cassette transporter proteins such as breast cancer-resistant protein (BCRP), which can pump out some types of photosensitizer, and the efficacy of PDT using clinical samples from 81 early lung cancer lesions treated with PDT between 1998 and 2006 at the Tokyo Medical University Hospital.
  
  
  RESULTS
  Photofrin-PDT damaged Bcl-2 and rapidly induced apoptosis, but NPe6-PDT did not damage Bc-2 nor did it induce morphologically typical apoptosis. However, NPe6-PDT exerted a strong anti-tumor effect, regardless of the overexpression of Bcl-2. By analyzing the BCRP-overexpressing cells, Photofrin, but not NPe6, was found to be a substrate of BCRP. All 81 lung cancer lesions were BCRP-positive; as Photofrin was found to be a substrate of BCRP, the expression of BCRP significantly affected the efficacy of Photofrin-PDT. However, NPe6-PDT exerted a strong antitumor effect regardless of BCRP expression, and the complete response rate after NPe6-PDT was much higher than that after Photofrin-PDT.
  
  
  CONCLUSIONS
  Our translational research suggests that NPe6-PDT may be superior to Photofrin-PDT for the treatment of lung caner, and individualized approaches to PDT based on the expression status of Bcl-2 and/or BCRP may improve the efficacy of PDT in patients with lung cancers.
authors: Department of Thoracic Surgery, Tokyo Medical Universiry, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. jusuda@tokyo-med.ac.jp
authors: Jitsuo
authors: J
authors: Usuda
authors: Shuji
authors: S
authors: Ichinose
authors: Taichirou
authors: T
authors: Ishizumi
authors: Keishi
authors: K
authors: Ohtani
authors: Tatsuya
authors: T
authors: Inoue
authors: Sachio
authors: S
authors: Maehara
authors: Kentarou
authors: K
authors: Imai
authors: Kiyoteru
authors: K
authors: Shima
authors: Tatsuo
authors: T
authors: Ohira
authors: Harubumi
authors: H
authors: Kato
authors: Norihiko
authors: N
authors: Ikeda
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D017323:Dihematoporphyrin Ether / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011166:Porphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; D011166:Porphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; D017323:Dihematoporphyrin Ether; C053434:Talaporfin