Antiproliferative medications, also known as antimetabolites, are used in the treatment of severe ocular inflammatory diseases. They can also be used locally as antiproliferative agents in ocular surface neoplasia and as antifibrotic agents to limit scarring related to ophthalmic procedures, particularly of the ocular surface, as in glaucoma filtering procedures and pterygium surgery. The use of fluorouracil (5-FU) and mitomycin C (MMC) for these purposes, though common, is considered off-label.
Fluorouracil is a fluorinated pyrimidine nucleoside analogue that blocks production of thymidylate synthase and interrupts normal cellular DNA and RNA synthesis. Its primary action may be to cause cellular thymine deficiency and resultant cell death. The effect of 5-FU is most pronounced on rapidly growing cells, and its use as an antiviral drug is related primarily to the destruction of infected cells (eg, warts) by topical application. The drug is also thought to inhibit cellular proliferation that may otherwise occur in response to inflammation.
Two randomized clinical trials compared use of 5-FU infusion with use of low-molecular-weight heparin and placebo during vitrectomy to prevent proliferative vitreoretinopathy (PVR). One trial was conducted in patients at high risk of developing postoperative PVR and the other in unselected cases of rhegmatogenous retinal detachment (ie, including patients who were not viewed as being at risk of postoperative PVR). The results concerning the effects of these 2 agents were inconclusive.
In another study involving high-risk patients, including young patients (≤40 years of age) with glaucoma, the success rate for initial trabeculectomy with adjunctive 5-FU was higher than the rate with surgery without the adjunct. 5-FU was used postoperatively as a subconjunctival injection and intraoperatively as a topical application to the trabeculectomy site.
MMC, another antiproliferative compound, is isolated from the fungus Streptomyces caespitosus. The parent compound becomes a bifunctional alkylating agent after enzymatic alteration within the cell; it then inhibits DNA synthesis by DNA cross-linkage. Although mitomycin’s immunosuppressive properties are fairly weak, it is a potent inhibitor of fibroblast proliferation. During glaucoma filtering operations, MMC is used topically in a single application to impede scarring and prevent surgical failure (see BCSC Section 10, Glaucoma). Complications of therapy are wound leakage, hypotony, and localized scleral melting. In an animal model, severe toxicity was reported with intraocular instillation of MMC, resulting in irreversible progressive bullous keratopathy in 3 of 4 rabbits.
Both mitomycin and 5-FU have been used to treat conjunctival intraepithelial neoplasia. Mitomycin is also commonly used to reduce haze in patients undergoing phototherapeutic keratectomy and has been recommended both as single-dose topical therapy and as postoperative drops to prevent recurrence of pterygia after pterygium excision. The recommended dosage is 0.02%–0.04% 4 times daily for 1–2 weeks after surgery. The reported recurrence rate with this therapy has been as low as 0%–11%. However, several adverse effects, such as corneal edema, corneal and scleral perforation, corectopia, anterior uveitis, cataract, and intractable pain, have been reported. With a primary conjunctival graft after pterygium removal, recurrence rates may be similarly low but without these serious complications. For additional information on uses of mitomycin and 5-FU, see BCSC Section 8, External Disease and Cornea.
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Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.