Effects of fluorouracil and fluorouridine on protein synthesis in rabbit retina.
5-Fluorouracil (5-FU) and its active metabolite 5-fluorouridine (FUR) are currently being evaluated for the treatment of proliferative vitreoretinopathy and the control of scarring after glaucoma filtering procedures. To test for retinal toxicity, the authors examined the effect of intravitreal injections of 5-FU and FUR on protein synthesis in rabbit retinal photoreceptors and ganglion cells. In addition, the toxic effect of subconjunctival 5-FU injections, after a trephine filtering procedure, on ganglion cell protein synthesis was examined. Albino rabbit eyes were given either unilateral intravitreal injections of 1 mg of 5-FU, 2.5 mg of 5-FU, or 0.1 mg of FUR, or subconjunctival injections of 3 mg of 5-FU twice daily after a trephine procedure. Quantitative autoradiography was used to study ganglion cells and photoreceptor outer segment renewal, and scintillation counting was used to quantify newly synthesized protein transported axonally from ganglion cell bodies to the superior colliculus (SC). Marked reduction of labeled protein reaching the SC was noted after either intravitreal 0.1 mg of FUR (41% inhibition after a single injection and 53% after two injections) or 2.5 mg of 5-FU (41% after one injection and 26% after two injections). This reduction was still present after 8 days in eyes receiving 0.1 mg of FUR (32%) and 2.5 mg of 5-FU (22%). Quantitative autoradiography of retinal photoreceptors and ganglion cells corroborated these data, demonstrating inhibition of outer segment renewal after one or two injections of either 0.1 mg of FUR or 2.5 mg of 5-FU. This inhibitory effect was statistically significant using the paired t-test for both drugs. No mean inhibition was observed after intravitreal 1 mg of 5-FU injections or after subconjunctival injections of 5-FU.
Department of Ophthalmology, University of Washington School of Medicine, Seattle 98195.
J A
JA
Leon
J M
JM
Britt
R H
RH
Hopp
R P
RP
Mills
A H
AH
Milam
D000818:Animals; D001345:Autoradiography; D001370:Axonal Transport / Q000187:drug effects; D003228:Conjunctiva / Q000187:drug effects; D005136:Eye Proteins / Q000378:metabolism*; D005472:Fluorouracil / Q000633:toxicity*; D010786:Photoreceptor Cells / Q000187:drug effects; D011817:Rabbits; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects; D012374:Rod Cell Outer Segment / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives* / Q000633:toxicity; D014822:Vitreous Body / Q000187:drug effects
D005136:Eye Proteins; C001943:5-fluorouridine; D005472:Fluorouracil; D014529:Uridine