Abstract
Abstract: :
Purpose: Polyamines play a critical role in cell proliferation. Two synthetic polyamine analogs (oligoamines), SL11144 and SL11150, decrease levels of natural polyamines, inhibit proliferation of cancer cells in culture, and exhibit antitumor effects in animal models. In this study, these agents were tested in a mouse model of CNV. Methods: Adult C57BL/6 mice had laser–induced rupture of Bruch’s membrane at 3 locations in each eye. They were treated with intraperitoneal injection of SL11144, SL11150, or vehicle, or they were treated with intraocular injection of SL11144 or SL11150 in one eye and vehicle in the other eye. After 2 weeks, the mice were perfused with fluorescein–labeled dextran and the area of CNV at Bruch’s membrane rupture sites was measured by image analysis. Results: Intraperitoneal injection of 20 mg/kg of SL11144 or SL11150 three times a week had substantial toxicity with 40% and 40% mortality, respectively. In surviving mice there was a modest, but significant decrease in area of CNV (mm2 x 10–3) compared to injection of vehicle (SL11144: 20.89±1.21 vs 26.08±0.73, P=0.0002; SL11150: 22.70±1.33 vs 26.84±0.58, P=0.001). Intraperitoneal injection of 10 mg/kg of SL11144 or SL11150 twice a week was well tolerated and resulted in significant reduction in area of CNV compared to injection of vehicle (22.58±0.77 vs 25.33±0.63, P=0.0007; 23.13±0.82 vs 25.81±0.53, P=0.0006). Intravitreous injection of 20 µg of SL11144 or SL11150 on the day of rupture of Bruch’s membrane and 7 days later resulted in prominent reduction in area of CNV compared to vehicle injection in the fellow eye (15.86±1.11 vs 25.95±1.33; 16.92±1.01 vs 25.96±1.23, P<0.00001). Conclusions: Local administration of polyamine analogs suppresses the development of CNV at Bruch’s membrane rupture sites. These agents are likely to work by mechanisms different from those of VEGF antagonists, and may be useful for single agent and/or combination therapy.
Keywords: choroid: neovascularization • drug toxicity/drug effects • neovascularization