title: Defining the therapeutic window of vertebral photodynamic therapy in a murine pre-clinical model of breast cancer metastasis using the photosensitizer BPD-MA (Verteporfin).
abstract: Breast cancer is known to cause metastatic lesions in the bone, which can lead to skeletal-related events. Currently, radiation therapy and surgery are the treatment of choice, but the success rate varies and additional adjuncts are desirable. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for numerous cancers. Earlier work has shown that the athymic rat model is suitable to investigate the effect of PDT on bone metastasis and benzoporphyrin-derivative monoacid ring A (BPD-MA; verteporfin) has been shown to be a selective photosensitizer. The aim of this study was to define the therapeutic window of photosensitizer with regard to drug and light dose. Human breast carcinoma cells (MT-1)-stable transfected with the luciferase gene-were injected intra-cardiacally into athymic rats. At 14 days, the largest vertebral lesion by bioluminescence imaging was targeted for single treatment PDT. A drug escalating-de-escalating scheme was used (starting drug dose and light energy of 0.2 mg/kg and 50 J, respectively). Outcomes included 48 h post-treatment bioluminescence of remaining viable tumour, histomorphometric assessment of tumour burden, and neurologic evaluation. The region of effect by bioluminescence and histology increased with increasing drug dose and light energy. A safe and effective drug-light dose combination in this model appears to be 0.5 mg/kg BPD-MA and applied light energy of less than 50 J for the thoracic spine and 1.0 mg/kg and 75 J for the lumbar spine. For translation to clinical use, it is an advantage that BPD-MA (verteporfin), a second-generation photosensitizer, is already approved to treat age-related macular degeneration. Overall, PDT represents an exciting potential new minimally-invasive local, safe and effective therapy in the management of patients with spinal metastases.
authors.affiliation: Division of Orthopaedic Surgery, Sunnybrook Health Science Centre, Room E2-44, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. makens@sri.utoronto.ca
authors.forename: Margarete K
authors.initials: MK
authors.lastname: Akens
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hardisty
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Joerg
authors.initials: J
authors.lastname: Schwock
authors.forename: Cari M
authors.initials: CM
authors.lastname: Whyne
authors.forename: Shane
authors.initials: S
authors.lastname: Burch
authors.forename: Albert J M
authors.initials: AJ
authors.lastname: Yee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008159:Lumbar Vertebrae / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D013125:Spinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D013904:Thoracic Vertebrae / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D000077362:Verteporfin; D023041:Xenograft Model Antitumor Assays
chemical_list: D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D008156:Luciferases