Photodynamic therapy in retinoblastoma: effects of verteporfin on retinoblastoma cell lines.
OBJECTIVE
In contrast to the excellent survival rates of the malignant childhood tumor retinoblastoma (RB), morbidity is high in patients with this disease because of the enucleation or loss of retinal areas caused by current bulb-saving therapies. The authors aimed to preclinically assess the effects of photochemotherapy using second-generation photochemotherapeutics as a prerequisite to develop a promising therapeutic alternative. This therapy implies intravenous application of a photosensitizer activated locally by light of the appropriate wavelength. Activation leads to the formation of free radicals, vascular occlusion, and death of affected cells in the area of irradiation. The photosensitizer verteporfin is approved for the therapy of neovascularizations, such as age-related maculopathy.


METHODS
The uptake of verteporfin in RB cell lines was investigated. Established RB cell lines, an RB subline resistant to etoposide, and dissociated cells from a primary RB were incubated with verteporfin and irradiated with activating laser light. Proliferation was measured at different time points after application.


RESULTS
All five RB cell lines investigated incorporated verteporfin, and nanomolar concentrations were sufficient for effective killing. At lower doses, surviving cells started to proliferate again after several days, but verteporfin 50 ng/mL and 100 J/cm(2) were sufficient for irreversible killing. High verteporfin concentrations caused cell death with little to no irradiation. Etoposide-resistant cells and primary tumor cells had a comparable susceptibility to photodynamic therapy (PDT) as established parental cell lines.


CONCLUSIONS
PDT using verteporfin efficiently kills chemotherapy-resistant and nonresistant retinoblastoma cell lines and primary tumor cells in vitro, and it warrants further preclinical evaluation as a therapeutic option for the treatment of retinoblastoma.
Stephan
Harald
H
Department of Hematology and Oncology, University Children's Hospital, Essen, Germany. harald.stephan@uni-due.de
Boeloeni
Réka
R
Eggert
Angelika
A
Bornfeld
Norbert
N
Schueler
Andreas
A
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D009994:Osmolar Concentration; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D011166:Porphyrins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000077362:Verteporfin
D000972:Antineoplastic Agents, Phytogenic; D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D005047:Etoposide