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1 From the Laser Laboratory, Retina Service, Massachusetts Eye and Ear Infirmary; and the 2 Schepens Eye Research Institute, Harvard Medical School, Boston.
PURPOSE. To examine the effect of combining angiostatin with photodynamic therapy (PDT) using Lutetium Texaphyrin (Lu-Tex; Alcon, Fort Worth, TX) as a photosensitizer in bovine retinal capillary endothelial (BRCE) and retinal pigment epithelial (RPE) cells and to determine the mode of PDT-induced cell death in these cell lines.
METHODS. Cultured BRCE and RPE cells were incubated with angiostatin (500 ng/ml) for 18 hours and subjected to Lu-Tex/PDT, using treatment parameters previously optimized (3 µg/ml Lu-Tex for 30 minutes followed by timed irradiation at 732 nm). Cellular survival was assessed after a 1-week cellular proliferation. Data were analyzed using Student’s t-test. Caspase 3 activity was monitored in cells after PDT using a fluorogenic substrate, (Asp-Glu-Val-Asp)-AFC (7-amino-4-trifluoromethyl coumarin) [DEVD-AFC], of caspase 3. After PDT, expression of Bcl-2, Bcl-xL, Bax, and Bak was also examined in cell lysates by Western blot analysis.
RESULTS. A synergistic cytotoxic effect of angiostatin and Lu-Tex/PDT was
observed in BRCE cells at all fluences used (5, 10, and 20
J/cm2; P 
0.05). These findings
applied only if angiostatin was delivered before PDT. No such
interactive killing effect was observed in RPE cells. Caspase 3
activity was elevated within 10 minutes of PDT in BRCE and RPE cells
and was fluence dependent. Differential modulation of Bcl-2 family
members was observed after PDT in BRCE and RPE cells.
CONCLUSIONS. The combination of angiostatin and Lu-Tex/PDT potentiates the cytotoxic effect of Lu-Tex/PDT on BRCE but not on RPE cells. This may provide a strategy to increase the selectivity of PDT in damaging capillary endothelial cells with less damage to RPE cells. Lu-Tex/PDT induces rapid caspase-dependent apoptosis in BRCE and RPE cells. Furthermore, Lu-Tex/PDT induces apoptosis through selective modulation of members of the Bcl-2 family and differs between BRCE and RPE cells.
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