Suppression and regression of choroidal neovascularization by polyamine analogues.
OBJECTIVE
Polyamine analogues inhibit tumor growth in vitro and in vivo, and oligoamines with a chain length of 10, 12, or 14 are particularly potent. This study was conducted to investigate the effect of the decamines CGC-11144 and CGC-11150 in a mouse model of choroidal neovascularization (CNV).


METHODS
Mice with laser-induced rupture of Bruch's membrane were given intraperitoneal, intravitreous, or periocular injection of CGC-11144, CGC-11150, or vehicle, and after 14 days, they were perfused with fluorescein-labeled dextran, and the area of CNV was measured on choroidal flatmounts by image analysis. In some groups of mice, treatments were started 7 days after rupture of Bruch's membrane to determine the effect of the agent on established CNV. Electroretinograms (ERGs) were performed to assess the effects on retinal function, and histopathology was used to evaluate retinal structure.


RESULTS
Intraperitoneal injection of 10 or 20 mg/kg CGC-11144 or CGC-11150 resulted in small but significant reductions in the area of CNV. Intravitreous injection of 20 microg CGC-11144 or CGC-11150 on days 0 and 7 after rupture of Bruch's membrane resulted in a approximately 40% reduction in the area of CNV, with a similar reduction after periocular injections of 0.2 mg CGC-11144 three times a week for 2 weeks. Both intravitreous and periocular delivery of CGC-11144 also caused significant regression of established CNV. Within 2 days of periocular injection of CGC-11144, there was apoptosis in CNV lesions, but not in normal blood vessels or other retinal cells. Periocular injections of d,l-alpha-difluoromethyl-ornithine (DFMO), which decreases polyamine levels by a different mechanism, also inhibited CNV. There was no decline in ERG amplitudes or abnormal retinal morphology after daily injections of 0.2 mg CGC-11144 for 2 weeks, but a single intravitreous injection compromised retinal structure and function.


CONCLUSIONS
Periocular delivery of the polyamine analogues may be a useful approach for the treatment of CNV.
Lima e Silva
Raquel
R
Department of Ophthalmology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277, USA.
Saishin
Yoshitsugu
Y
Saishin
Yumiko
Y
Akiyama
Hideo
H
Kachi
Shu
S
Aslam
Sadia
S
Rogers
Brian
B
Deering
Tye
T
Gong
Yuan Yuan
YY
Hackett
Sean F
SF
Lai
Hong
H
Frydman
Benjamin J
BJ
Valasinas
Aldonia
A
Marton
Laurence J
LJ
Campochiaro
Peter A
PA
D000818:Animals; D017209:Apoptosis; D015317:Biogenic Polyamines / Q000008:administration & dosage / Q000627:therapeutic use*; D016570:Bruch Membrane / Q000601:surgery; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D003911:Dextrans; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D000518:Eflornithine / Q000627:therapeutic use; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005452:Fluoresceins; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D053685:Laser Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009915:Orbit; D012160:Retina / Q000502:physiology; D014822:Vitreous Body
D015317:Biogenic Polyamines; C505025:CGC-11144; C505024:CGC-11150; D003911:Dextrans; D005452:Fluoresceins; C052526:fluorescein-dextran; D000518:Eflornithine