Mitomycin-C

Structure and mechanism of action

Mitomycin-C is an antibiotic, usually classified as an alkylating agent, isolated from Streptomyces caespitosus. It has a molecular weight of 334 daltons and is soluble in water and organic solvents. When applied topically, it mainly acts under aerobic conditions generating free radicals causing cytotoxicity, DNA, and protein damage via lipid peroxidation.12 13 MMC also inhibits cell migration and production of extracellular matrix.14 15

Pharmacokinetics

Studies in rabbit models have found that topical MMC clears quite rapidly from the ocular tissues including the anterior chamber (0.18–0.45 h).16 Mietz et al17 found aqueous concentrations of 0.02 μg/ml MMC after topical use at a concentration of 0.5 mg/ml. A potential bioactivating enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase) for MMC has been detected in OSSN and in normal tissues from human donor eyes.18 MMC may be stored at room temperature (22°C) for up to 1 week and refrigerated (4°C) for up to 3 months, and still preserve 90% of its activity.19 20

Published studies

The use of topical MMC for OSSN was first described by Frucht-Pery et al in 1994.21 Since then, several case series using different treatment concentrations and duration have been published.22 23 The most widely used protocol consists of 0.02% of topical MMC given four times a day to the affected eye for 2 weeks and repeated until the lesion regresses. Others have demonstrated that an even smaller concentration of 0.002% of MMC may be effective.22 Overall, excellent response rates ranging from 87.5% to 100% have been reported.

Side effects

It is important to wait for complete healing after the biopsy prior to starting the topical chemotherapy so as to avoid the risk of corneo-scleral melt. Mitomycin C is usually well tolerated by patients when taken daily for 1–2 weeks with a recovery period of 1 week. The cellular toxicity is dose-dependent. Patients with MMC toxicity may present with signs of conjunctival hyperaemia, blepharospasm,13 corneal punctate erosions, punctal stenosis24 and limbal stem cell deficiency with higher doses.25 Some of these side effects may be managed by stopping the medication and adding a topical steroid drop three or four times daily. To prevent punctal stenosis, punctal plugs are placed in both the superior and inferior puncti. This also allows for the drug to permeate the affected tissue for a longer period of time and reduces the drug absorption by the nasal mucosa. MMC may also cause allergic blepharoconjunctivitis.

5-Fluorouracil

Structure and mechanism of action

5-Fluorouracil (5-FU) is a pyrimidine analogue, structurally similar to thymine and uracil.26 The main mechanism of action is by inhibiting the production and incorporation of thymidine into DNA during the S phase of the cell cycle. 5-FU also inhibits RNA synthesis, destroys actin cytoskeleton and promotes apoptosis of the Tenon capsule fibroblasts.26 27

Pharmacokinetics

The minimum concentration required to achieve a 50% inhibitory effect on human dermal fibroblasts is only 0.35 mg/ml.28 Fantes et al demonstrated in rabbit models that 5-FU achieved intraocular penetration when applied topically,29 with aqueous concentration levels reaching 0.9 μg/ml in 12 h after one drop containing 2.4 mg of 5-FU. This intraocular level is non-toxic to the optic nerve or retina.30

Published studies

The use of topical 5-FU in the treatment of premalignant ocular surface lesions was first described by de Keizer et al in 1986.31 5-FU is prescribed as a 1% topical solution typically applied four times a day for 4 weeks continuously or in cycles of 4 days ‘on’ followed by 30 days ‘off’ until resolution of the lesion is achieved.8 9 32 Some authors have described effectiveness of 5-FU in cases refractory to topical MMC.33

Side effects

The ocular side effects of topical 5-FU are similar to those with MMC. The most common side-effects described in the literature are conjunctival and corneal inflammation, corneal epithelial defects and eyelid skin erythema.8 Patient complaints can range from irritation and discomfort to frank pain. In an effort to decrease the toxicity of 5-FU to the ocular surface, cycling of the antimetabolite is suggested by applying it four times a day for 2–4 days and stopping it for 30–45 days, followed by a new cycle until resolution of the lesion is accomplished. The side effects of conjunctival irritation may be managed by either stopping the drug or adding a topical corticosteroid and non-preserved artificial tears.

Interferon-α2b (IFN-α2b)

Structure and mechanism of action

The glycoprotein IFN-α 2b is a type 1 interferon consisting of 165 amino acid residues with arginine in position 23. It is produced by recombinant DNA technology (Intron-A, Schering, Bloomfield, New Jersey) and it is used for the treatment of Hepatitis B and C, condyloma acuminata, hairy cell leukaemia and Kaposi sarcoma in AIDS.34 35 The mechanism of action of IFN- α 2b in the treatment of ocular tumours is only partially understood. Kim et al36 found that IL-10 was strongly expressed in basal cell and squamous cell carcinoma of the skin. IL-10 is a known potent immunosuppressive cytokine which may contribute to immune dysregulation and suppression of antitumour T cell responses and perhaps facilitating tumour growth.37 It has been observed that the intralesional injection of IFN-α2b suppresses the expression of IL-10 and stimulates the expression of IL-2 and IFN-γ mRNA, which are type 1 cytokines important in T cell immunity.36 38 This evidence suggests that the expression of IL-10 by tumour cells provides a mechanism to evade the local immune response.36

Pharmacokinetics

The exact ocular pharmacokinetics is not well understood. The intraocular levels reached after topical application is unknown as well as its minimum inhibitory levels required for ocular tumour suppression. When applied subconjunctivally, systemic side effects similar to systemic application may occur.10

Published studies

Because of its success in the treatment of epidermal squamous tumours and cervical intraepithelial neoplasia related to human papilloma virus infection, it was first investigated by Maskin et al in 1994 for therapeutic value in OSSN.10 39–43 The typical dose of IFN- α 2b given topically is 1 million IU/ml. It may also be given as a subconjunctival injection of 3 million IU/ml.10 Schechter et al44 have evaluated the recurrence rate after treatment with IFN-α 2b and found it to be 3.7% in patients followed for more than a year, and a resolution rate of 96.4% in this same group of patients.

In this issue, Galor et al report a retrospective study of 33 eyes with non-invasive OSSN and two eyes with SCC, treated with topical IFN-α2b. Neither eye with SCC responded to interferon therapy.45 However, 85% of the patients with non-invasive OSSN responded with no significant differences between those treated with 1 million IU/ml (21 eyes) and those with 3 million IU/ml (12 eyes). After a median follow-up of 24 months, three recurrences were observed. Topical interferon therapy was well tolerated, with most common side effects being ocular discomfort and photophobia. There was a trend towards a greater frequency of side effects with a dose of 3 million IU/ml. The authors recommend using the 1 million IU/ml dose for the treatment of non-invasive OSSN.45

In another retrospective but comparative interventional case series of 29 consecutive patients with OSSN, 15 elected topical interferon (1–3 million IU/ml), and 14 chose surgical excision.46 Two patients in the interferon group subsequently underwent surgical excision for lack of response. No patient in either group developed a recurrence during the mean study period of almost 3 years. The authors concluded that both topical interferon α-2b and aggressive surgical excision offer comparable disease-free interval.46

Side effects

Topical IFN-α 2b has fewer ocular side effects than the other topical chemotherapeutic agents used in OSSN. The side effects range from none to a mild and transient keratitis and follicular conjunctivitis.10 34 35 41 Unusual complications of corneal epithelial microcysts have also been observed with both topical47 and systemic use of interferon α-2b.48 Although rare, systemic side effects such as fevers, myalgias and fatigue may occur when the drug is injected subconjunctivally.10 Retinopathy and neuropathy after systemic use of IFN- α 2b have been reported.49 50