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5-Fluorouracil toxicity to the ocular surface epithelium
Abstract:
The antimetabolite, 5-fluorouracil (5-FU), has been used to control proliferation of retinal pigment epithelial cells and fibrocytes, and is currently the subject of a multicenter clinical trial of its value in the control of scarring after glaucoma operations. To evaluate possible ocular surface toxicity, the effect of 5-FU on the mitotic rate and differentiation of the ocular surface epithelium in rabbits was measured. 5-FU was instilled into eyes with 10-mm diameter central epithelial wounds and into nonwounded eyes at a dose of 9 mg per day for 4 days. Saline treated control wounded eyes healed within 4 days (n = 5) while 40% (4 of 10) of the 5-FU treated wounded eyes had defects at 4 days. The normal mitotic rate of the corneal epithelium was 1.0 +/- 0.3 (n = 4) tritiated thymidine labeled cells per 100 basal corneal epithelial cells after 2.5 hr incubation. Saline treated control wounded eyes had an increased mitotic rate, 7.1 +/- 1.3 (n = 5) labeled cells per 100 basal corneal epithelial cells after 2.5 hr incubation. Topical 5-FU decreased both of those rates to about 1% of normal. The normal conjunctival epithelial mitotic rate was 1.8 +/- 0.4 (n = 4) labeled cells per 60 basal cells after per 2.5 hr incubation. This rate was the same in wounded eyes, but was decreased in eyes treated with 5-FU. Thus, 5-FU (9 mg/day topically) has serious toxic effects to ocular surface epithelium which must be carefully considered if this drug is to be used clinically.
Insights
The antimetabolite 5-fluorouracil (5-FU) shows significant ocular surface toxicity, impairing wound healing and reducing mitotic rates in corneal and conjunctival epithelium. Careful consideration of these toxic effects is crucial for its clinical use.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- 5-fluorouracil (5-FU) is an antimetabolite used to control cell proliferation.
- It is being investigated for controlling scarring after glaucoma surgery.
- Potential ocular surface toxicity requires evaluation.
Purpose of the Study:
- To assess the ocular surface toxicity of 5-FU.
- To measure the effect of 5-FU on the mitotic rate and differentiation of rabbit ocular surface epithelium.
Main Methods:
- 5-FU (9 mg/day) was topically applied to wounded and non-wounded rabbit eyes for 4 days.
- Mitotic rates were measured using tritiated thymidine labeling in corneal and conjunctival epithelium.
- Wound healing was assessed over 4 days.
Main Results:
- 5-FU treatment resulted in persistent epithelial defects in 40% of wounded eyes.
- Topical 5-FU significantly reduced corneal epithelial mitotic rates to approximately 1% of normal.
- 5-FU also decreased mitotic rates in conjunctival epithelium.
Conclusions:
- Topical 5-FU (9 mg/day) exhibits serious toxic effects on the ocular surface epithelium.
- These toxic effects include impaired wound healing and reduced cell proliferation.
- The risks of ocular surface toxicity must be carefully considered for clinical applications of 5-FU.