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Published in: Advances in Therapy 4/2019

Open Access 01-04-2019 | Refractive Surgery | Review

A Critical Overview of the Biological Effects of Mitomycin C Application on the Cornea Following Refractive Surgery

Authors: Esther Arranz-Marquez, Andreas Katsanos, Vassilios P. Kozobolis, Anastasios G. P. Konstas, Miguel A. Teus

Published in: Advances in Therapy | Issue 4/2019

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Abstract

During the last 2 decades, modifying the shape of the cornea by means of laser photoablation has emerged as a successful and popular treatment option for refractive errors. Corneal surface ablation techniques such as photorefractive keratectomy (PRK) and laser-assisted subepithelial keratomileusis (LASEK) offer good refractive results while having a minimal impact on corneal biomechanical stability. Past limitations of these techniques included the long-term regression of refractive outcome and a vigorous healing response that reduced corneal clarity in some patients (giving rise to what is clinically described as “haze”). Mitomycin C (MMC) was introduced as a healing modulator and applied on the corneal surface after refractive surgery to address these drawbacks. This article critically reviews the available evidence on the biological effects, safety, and clinical benefits of the off-label use of MMC in corneal refractive surgery.
Literature
1.
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–602.
2.
Hashemi H, Fotouhi A, Yekta A, et al. Global and regional estimates of prevalence of refractive errors: systematic review and meta-analysis. J Curr Ophthalmol. 2018;30:3–22.CrossRefPubMed
3.
Kandel H, Khadka J, Goggin M, Pesudovs K. Impact of refractive error on quality of life: a qualitative study. Clin Exp Ophthalmol. 2017;45:677–88.CrossRefPubMed
4.
Mohammadi S-F, Alinia C, Tavakkoli M, et al. Refractive surgery: the most cost-saving technique in refractive errors correction. Int J Ophthalmol. 2018;11:1013–9.PubMedPubMedCentral
5.
Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol. 1983;96:710–5.CrossRefPubMed
6.
Pallikaris IG, Papatzanaki ME, Stathi EZ, et al. Laser in situ keratomileusis. Lasers Surg Med. 1990;10:463–8.CrossRefPubMed
7.
Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser refractive surgery. J Cataract Refract Surg. 1988;14:46–52.CrossRefPubMed
8.
Azar DT, Ang RT, Lee JB, et al. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol. 2001;12:323–8.CrossRefPubMed
9.
Garcia-Gonzalez M, Drake Rodriguez-Casanova P, Rodriguez-Perez I, et al. Long-term follow-up of LASEK with mitomycin C performed to correct myopia in thin corneas. J Refract Surg. 2017;33:813–9.CrossRefPubMed
10.
Li S-M, Zhan S, Li S-Y, et al. Laser-assisted subepithelial keratectomy (LASEK) versus photorefractive keratectomy (PRK) for correction of myopia. Cochrane Database Syst Rev. 2016;2:CD009799.
11.
Kuryan J, Cheema A, Chuck RS. Laser-assisted subepithelial keratectomy (LASEK) versus laser-assisted in situ keratomileusis (LASIK) for correcting myopia. Cochrane Database Syst Rev. 2017;2:CD011080.
12.
Wen D, McAlinden C, Flitcroft I, et al. Postoperative efficacy, predictability, safety, and visual quality of laser corneal refractive surgery: a network meta-analysis. Am J Ophthalmol. 2017;178:65–78.CrossRefPubMed
13.
Erie JC. Corneal wound healing after photorefractive keratectomy: a 3-year confocal microscopy study. Trans Am Ophthalmol Soc. 2003;101:293–333.PubMedPubMedCentral
14.
15.
Marino GK, Santhiago MR, Torricelli AAM, et al. Corneal molecular and cellular biology for the refractive surgeon: the critical role of the epithelial basement membrane. J Refract Surg. 2016;32:118–25.CrossRefPubMed
16.
17.
Taliana L, Evans MD, Dimitrijevich SD, Steele JG. Vitronectin or fibronectin is required for corneal fibroblast-seeded collagen gel contraction. Invest Ophthalmol Vis Sci. 2000;41:103–9.PubMed
18.
Wilson SE, Mohan RR, Hong JW, et al. The wound healing response after laser in situ keratomileusis and photorefractive keratectomy: elusive control of biological variability and effect on custom laser vision correction. Arch Ophthalmol. 2001;119:889–96.CrossRefPubMed
19.
Corbett MC, Prydal JI, Verma S, et al. An in vivo investigation of the structures responsible for corneal haze after photorefractive keratectomy and their effect on visual function. Ophthalmology. 1996;103:1366–80.CrossRefPubMed
20.
Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal wound healing explains refractive instability and haze development after photorefractive keratectomy: a 1-year confocal microscopic study. Ophthalmology. 2000;107:1235–45.CrossRefPubMed
21.
Netto MV, Mohan RR, Sinha S, et al. Stromal haze, myofibroblasts, and surface irregularity after PRK. Exp Eye Res. 2006;82:788–97.CrossRefPubMed
22.
Tomás-Juan J, Murueta-Goyena Larrañaga A, Hanneken L. Corneal regeneration after photorefractive keratectomy: a review. J Optom. 2015;8:149–69.CrossRefPubMed
23.
Seiler T, Holschbach A, Derse M, et al. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology. 1994;101:153–60.CrossRefPubMed
24.
Stojanovic A, Nitter TA. Correlation between ultraviolet radiation level and the incidence of late-onset corneal haze after photorefractive keratectomy. J Cataract Refract Surg. 2001;27:404–10.CrossRefPubMed
25.
Kaiserman I, Sadi N, Mimouni M, et al. Corneal breakthrough haze after photorefractive keratectomy with mitomycin C: incidence and risk factors. Cornea. 2017;36:961–6.CrossRefPubMed
26.
Abad JC, An B, Power WJ, et al. A prospective evaluation of alcohol-assisted versus mechanical epithelial removal before photorefractive keratectomy. Ophthalmology. 1997;104:1566–74 (discussion 1574–1575).CrossRefPubMed
27.
Stojanovic A, Ringvold A, Nitter T. Ascorbate prophylaxis for corneal haze after photorefractive keratectomy. J Refract Surg. 2003;19:338–43.PubMed
28.
Nien CJ, Flynn KJ, Chang M, et al. Reducing peak corneal haze after photorefractive keratectomy in rabbits: prednisolone acetate 1.00% versus cyclosporine A 0.05%. J Cataract Refract Surg. 2011;37:937–44.CrossRefPubMedPubMedCentral
29.
Nassaralla BA, Szerenyi K, Wang XW, et al. Effect of diclofenac on corneal haze after photorefractive keratectomy in rabbits. Ophthalmology. 1995;102:469–74.CrossRefPubMed
30.
Anitua E, de la Fuente M, Muruzabal F, et al. Plasma rich in growth factors (PRGF) eye drops stimulates scarless regeneration compared to autologous serum in the ocular surface stromal fibroblasts. Exp Eye Res. 2015;135:118–26.CrossRefPubMed
31.
32.
Anumanthan G, Sharma A, Waggoner M, et al. Efficacy and safety comparison between suberoylanilide hydroxamic acid and mitomycin C in reducing the risk of corneal haze after PRK treatment in vivo. J Refract Surg. 2017;33:834–9.CrossRefPubMed
33.
Mohan RR, Gupta R, Mehan MK, et al. Decorin transfection suppresses profibrogenic genes and myofibroblast formation in human corneal fibroblasts. Exp Eye Res. 2010;91:238–45.CrossRefPubMedPubMedCentral
34.
35.
Talamo JH, Gollamudi S, Green WR, et al. Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids. Arch Ophthalmol. 1991;109:1141–6.CrossRefPubMed
36.
Teus MA, de Benito-Llopis L, Alió JL. Mitomycin C in corneal refractive surgery. Surv Ophthalmol. 2009;54:487–502.CrossRefPubMed
37.
Hata T, Hoshi T, Kanamori K, et al. Mitomycin, a new antibiotic from Streptomyces. I. J Antibiot. 1956;9:141–6.PubMed
38.
Verweij J, Pinedo HM. Mitomycin C: mechanism of action, usefulness and limitations. Anticancer Drugs. 1990;1:5–13.CrossRefPubMed
39.
Kunimoto N, Mori S. Studies on pterygium. Part IV. A treatment of the pterygium by mitomycin-C instillation. Nippon Ganka Gakkai Zasshi. 1963;67:601–7.
40.
41.
Carones F, Vigo L, Scandola E, Vacchini L. Evaluation of the prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg. 2002;28:2088–95.CrossRefPubMed
42.
43.
Mladenov E, Tsaneva I, Anachkova B. Activation of the S phase DNA damage checkpoint by mitomycin C. J Cell Physiol. 2007;211:468–76.CrossRefPubMed
44.
Lown J. The molecular mechanism of action of the mitomycins. In: Carter S, Crooke S, editors. Mitomycin C, current status and new developments. New York: Academic; 1979. p. 5–26.
45.
Sadeghi HM, Seitz B, Hayashi S, et al. In vitro effects of mitomycin-C on human keratocytes. J Refract Surg. 1998;14:534–40.PubMed
46.
47.
Kim T, Tchah H, Lee S, et al. Apoptosis in keratocytes caused by mitomycin C. Invest Ophthalmol Vis Sci. 2003;44:1912–7.CrossRefPubMed
48.
Chou S-F, Chang S-W, Chuang J-L. Mitomycin C upregulates IL-8 and MCP-1 chemokine expression via mitogen-activated protein kinases in corneal fibroblasts. Invest Ophthalmol Vis Sci. 2007;48:2009–16.CrossRefPubMed
49.
Crowston JG, Chang LH, Daniels JT, et al. T lymphocyte mediated lysis of mitomycin C treated Tenon’s capsule fibroblasts. Br J Ophthalmol. 2004;88:399–405.CrossRefPubMedPubMedCentral
50.
Pritsos CA, Sartorelli AC. Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics. Cancer Res. 1986;46:3528–32.PubMed
51.
Pogrebniak HW, Matthews W, Pass HI. Chemotherapy amplifies production of tumor necrosis factor. Surgery. 1991;110:231–7.PubMed
52.
Goeptar AR, Groot EJ, Scheerens H, et al. Cytotoxicity of mitomycin C and adriamycin in freshly isolated rat hepatocytes: the role of cytochrome P450. Cancer Res. 1994;54:2411–8.PubMed
53.
Lee Y-J, Park S-J, Ciccone SLM, et al. An in vivo analysis of MMC-induced DNA damage and its repair. Carcinogenesis. 2006;27:446–53.CrossRefPubMed
54.
Occleston NL, Daniels JT, Tarnuzzer RW, et al. Single exposures to antiproliferatives: long-term effects on ocular fibroblast wound-healing behavior. Invest Ophthalmol Vis Sci. 1997;38:1998–2007.PubMed
55.
Song J-S, Kim J-H, Yang M, et al. Mitomycin-C concentration in cornea and aqueous humor and apoptosis in the stroma after topical mitomycin-C application: effects of mitomycin-C application time and concentration. Cornea. 2007;26:461–7.CrossRefPubMed
56.
Chang S-W. Corneal keratocyte apoptosis following topical intraoperative mitomycin C in rabbits. J Refract Surg. 2005;21:446–53.PubMed
57.
Torres RM, Merayo-Lloves J, Daya SM, et al. Presence of mitomycin-C in the anterior chamber after photorefractive keratectomy. J Cataract Refract Surg. 2006;32:67–71.CrossRefPubMed
58.
Kymionis GD, Diakonis VF, Panagopoulou SI, et al. Mitomycin C aqueous humor concentration after photorefractive keratectomy: an experimental study. Eur J Ophthalmol. 2009;19:738–42.CrossRefPubMed
59.
Kawase K, Matsushita H, Yamamoto T, Kitazawa Y. Mitomycin concentration in rabbit and human ocular tissues after topical administration. Ophthalmology. 1992;99:203–7.CrossRefPubMed
60.
Rajan MS, O’Brart DPS, Patmore A, Marshall J. Cellular effects of mitomycin-C on human corneas after photorefractive keratectomy. J Cataract Refract Surg. 2006;32:1741–7.CrossRefPubMed
61.
Kuzuya T, Yamauchi M, Ito A, et al. Pharmacokinetic characteristics of 5-fluorouracil and mitomycin C in intraperitoneal chemotherapy. J Pharm Pharmacol. 1994;46:685–9.CrossRefPubMed
62.
Kemp EG, Harnett AN, Chatterjee S. Preoperative topical and intraoperative local mitomycin C adjuvant therapy in the management of ocular surface neoplasias. Br J Ophthalmol. 2002;86:31–4.CrossRefPubMedPubMedCentral
63.
Yulish M, Khatib A, Pikkel J. Systemic absorption of Mitomycin-C when used in pterygium surgery. Cornea. 2018;37:746–7.CrossRefPubMed
64.
Crawford C, Ainbinder DJ, Davis R, et al. Systemic absorption of mitomycin-C when used in refractive surgery. J Cataract Refract Surg. 2013;39:193–6.CrossRefPubMed
65.
Majmudar PA, Schallhorn SC, Cason JB, et al. Mitomycin-C in corneal surface excimer laser ablation techniques: a report by the American Academy of Ophthalmology. Ophthalmology. 2015;122:1085–95.CrossRefPubMed
66.
Gambato C, Ghirlando A, Moretto E, et al. Mitomycin C modulation of corneal wound healing after photorefractive keratectomy in highly myopic eyes. Ophthalmology. 2005;112:208–18 (discussion 219).CrossRefPubMed
67.
de Benito-Llopis L, Cañadas P, Drake P, et al. Keratocyte density 3 months, 15 months, and 3 years after corneal surface ablation with mitomycin C. Am J Ophthalmol. 2012;153(17–23):e1.
68.
69.
Majmudar PA, Forstot SL, Nirankari VS, et al. Topical mitomycin-C for subepithelial fibrosis after corneal surgery. Ophthalmology. 2000;107:89–94.CrossRefPubMed
70.
Netto MV, Mohan RR, Sinha S, et al. Effect of prophylactic and therapeutic mitomycin C on corneal apoptosis, cellular proliferation, haze, and long-term keratocyte density in rabbits. J Refract Surg. 2006;22:562–74.CrossRefPubMedPubMedCentral
71.
Camellin M. Laser epithelial keratomileusis with mitomycin C: indications and limits. J Refract Surg. 2004;20:S693–8.PubMed
72.
Lacayo GO, Majmudar PA. How and when to use mitomycin-C in refractive surgery. Curr Opin Ophthalmol. 2005;16:256–9.CrossRefPubMed
73.
Maldonado MJ. Intraoperative MMC after excimer laser surgery for myopia. Ophthalmology. 2002;109:826 (author reply 826–828).CrossRefPubMed
74.
Daniels JT, Occleston NL, Crowston JG, Khaw PT. Effects of antimetabolite induced cellular growth arrest on fibroblast-fibroblast interactions. Exp Eye Res. 1999;69:117–27.CrossRefPubMed
75.
Khoury JM, Farah T, El-Haibi CP, Noureddin BN. Corneal light shield as a delivery system for standardized application of mitomycin C in excimer surface ablation. J Refract Surg. 2007;23:716–9.CrossRefPubMed
76.
Midena E, Gambato C, Miotto S, et al. Long-term effects on corneal keratocytes of mitomycin C during photorefractive keratectomy: a randomized contralateral eye confocal microscopy study. J Refract Surg. 2007;23:S1011–4.CrossRefPubMed
77.
Qazi MA, Johnson TW, Pepose JS. Development of late-onset subepithelial corneal haze after laser-assisted subepithelial keratectomy with prophylactic intraoperative mitomycin-C. Case report and literature review. J Cataract Refract Surg. 2006;32:1573–8.CrossRefPubMed
78.
Kremer I, Ehrenberg M, Levinger S. Delayed epithelial healing following photorefractive keratectomy with mitomycin C treatment. Acta Ophthalmol. 2012;90:271–6.CrossRefPubMed
79.
Mohammadi SF, Ashrafi E, Norouzi N, et al. Effects of mitomycin-C on tear film, corneal biomechanics, and surface irregularity in mild to moderate myopic surface ablation: preliminary results. J Cataract Refract Surg. 2014;40:937–42.CrossRefPubMed
80.
Roh DS, Cook AL, Rhee SS, et al. DNA cross-linking, double-strand breaks, and apoptosis in corneal endothelial cells after a single exposure to mitomycin C. Invest Ophthalmol Vis Sci. 2008;49:4837–43.CrossRefPubMedPubMedCentral
81.
Chang S-W. Early corneal edema following topical application of mitomycin-C. J Cataract Refract Surg. 2004;30:1742–50.CrossRefPubMed
82.
McDermott ML, Wang J, Shin DH. Mitomycin and the human corneal endothelium. Arch Ophthalmol. 1994;112:533–7.CrossRefPubMed
83.
Morales AJ, Zadok D, Mora-Retana R, et al. Intraoperative mitomycin and corneal endothelium after photorefractive keratectomy. Am J Ophthalmol. 2006;142:400–4.CrossRefPubMed
84.
Nassiri N, Farahangiz S, Rahnavardi M, et al. Corneal endothelial cell injury induced by mitomycin-C in photorefractive keratectomy: nonrandomized controlled trial. J Cataract Refract Surg. 2008;34:902–8.CrossRefPubMed
85.
Gharaee H, Zarei-Ghanavati S, Alizadeh R, Abrishami M. Endothelial cell changes after photorefractive keratectomy with graded usage of mitomycin C. Int Ophthalmol. 2018;38:1211–7.CrossRefPubMed
86.
Pfister RR. Permanent corneal edema resulting from the treatment of PTK corneal haze with mitomycin: a case report. Cornea. 2004;23:744–7.CrossRefPubMed
87.
Schraermeyer U, Diestelhorst M, Bieker A, et al. Morphologic proof of the toxicity of mitomycin C on the ciliary body in relation to different application methods. Graefes Arch Clin Exp Ophthalmol. 1999;237:593–600.CrossRefPubMed
88.
Kymionis GD, Diakonis VF, Charisis S, et al. Effects of topical mitomycin C on the ciliary body and intraocular pressure after PRK: an experimental study. J Refract Surg. 2008;24:633–8.CrossRefPubMed
89.
Kim HK, Choi J-Y, Park SM, et al. Tyrosine kinase inhibitor, vatalanib, inhibits proliferation and migration of human pterygial fibroblasts. Cornea. 2017;36:1116–23.CrossRefPubMed
Metadata
Title
A Critical Overview of the Biological Effects of Mitomycin C Application on the Cornea Following Refractive Surgery
Authors
Esther Arranz-Marquez
Andreas Katsanos
Vassilios P. Kozobolis
Anastasios G. P. Konstas
Miguel A. Teus
Publication date
01-04-2019
Publisher
Springer Healthcare
Published in
Advances in Therapy / Issue 4/2019
Print ISSN: 0741-238X
Electronic ISSN: 1865-8652
DOI
https://doi.org/10.1007/s12325-019-00905-w

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