5-Fluorouracil (5-FU) is a commonly used antimetabolite in cancer therapy. Patients (25% to 38%) undergoing chronic systemic 5-FU chemotherapy are affected by ocular toxicity and require cessation of therapy to manage ocular complications. However, the mechanism by which 5-FU crosses the blood-tear barrier is not well understood. The current study investigates the role of organic anion transporters (OAT2 and 3) in the blood-tear barrier of the lacrimal gland, in trafficking 5-FU into the ocular surface.
Method:
Computer simulations were performed to determine the substrate specificity of 5-FU for OAT isoforms. Tear pharmacokinetic studies of intravenous 5-FU were conducted in rabbits (n = 3 per group), with and without OAT blockade. The ocular adverse effect of 5-FU was assessed in vitro using human corneal epithelial cells (HCEC). Furthermore, the potential of artificial tears to reduce ocular accumulation of 5-FU was evaluated.
Results:
Computational studies indicated that 5-FU is a substrate for OAT2. 5-FU was detected in the tear from systemic circulation (Cmax = 16.7 µg/mL) within five minutes of administration. The concentration of 5-FU reaching the ocular surface reduced HCEC viability in a concentration-dependent manner. Furthermore, topical pretreatment with OAT2 blockers reduced 5-FU exposure in tears by 1.53 to 2.96-fold, and prophylactic artificial tears containing polyethylene glycol 400 and propylene glycol achieved a 1.68-fold reduction in 5-FU exposure in tears.
Conclusion:
Blocking OAT-2 with eye drops (OAT2 blockers and artificial tears) reduced the tear concentration of 5-FU, suggesting a potential to minimize ocular toxicity of 5-FU in patients undergoing chemotherapy.
LongleyDB, HarkinDP, JohnstonPG. 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer2003;3(5):330–338.
2.
HoffPM, CassidyJ, SchmollH-J. The evolution of fluoropyrimidine therapy: From intravenous to oral. Oncologist2001;6(Suppl 4):3–11.
3.
ZhangN, YinY, XuS-J, et al.5-Fluorouracil: Mechanisms of resistance and reversal strategies. Molecules2008;13(8):1551–1569.
4.
NoordhuisP, HolwerdaU, Van der WiltCL, et al.5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers. Ann Oncol2004;15(7):1025–1032.
5-Fluorouracil and capecitabine: Assessment and treatment of uncommon early-onset severe toxicities associated with administration. Clin J Oncol Nurs Epub ahead of print 2018; doi: 10.1188/18.CJON.627-634
7.
LeoS, TatulliC, TaveriR, et al.Dermatological toxicity from chemotherapy containing 5-fluorouracil. J Chemother1994;6(6):423–426.
8.
GelenV, ŞengülE, YıldırımS, et al.The protective effects of hesperidin and curcumin on 5-fluorouracil–induced nephrotoxicity in mice. Environ Sci Pollut Res Int2021;28(34):47046–47055.
9.
EisemanAS, FlanaganJC, BrooksAB, et al.Ocular surface, ocular adnexal, and lacrimal complications associated with the use of systemic 5-fluorouracil. Ophthalmic Plast Reconstr Surg2003;19(3):216–224.
StevensA, SpoonerD. Lacrimal duct stenosis and other ocular toxicity associated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer. Clin Oncol (R Coll Radiol)2001;13(6):438–440.
12.
LoprinziCL, LoveRR, GarrityJA, et al.Cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-induced ocular toxicity. Cancer Invest1990;8(5):459–465.
13.
ForbesJE, BrazierDJ, SpittleM. 5-Fluorouracil and ocular toxicity. Br J Ophthalmol1993;77(7):465–466.
14.
SinghS, TrakosN, AliMJ. Effect of topical 5-fluorouracil on lacrimal drainage system: Histopathological evidence from animal experiments and potential clinical implications. Ophthalmic Plast Reconstr Surg2023;39(3):288–292.
15.
SchmidKE, KornekGV, ScheithauerW, et al.Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol2006;51(1):19–40.
16.
ChiangJCB, ZahariI, MarkoulliM, et al.The impact of anticancer drugs on the ocular surface. Ocul Surf2020;18(3):403–417.
17.
Cunha-VazJ. The blood-ocular barriers. Surv Ophthalmol1979;23(5):279–296.
18.
SebbagL, AllbaughRA, WeaverA, et al.Histamine-induced conjunctivitis and breakdown of blood–tear barrier in dogs: A model for ocular pharmacology and therapeutics. Front Pharmacol Epub ahead of print 2019;10:752; doi: 10.3389/fphar.2019.00752
19.
ChristophidisN, VajdaFJE, LucasI, et al.Ocular side effects with 5‐fluorouracil. Aust N Z J Med1979;9(2):143–144.
20.
MalaniM, ShahM, VelpandianT, et al.Organic cation transporter 1 in the lacrimal gland facilitates the entry of systemic drugs causing ocular surface toxicity. Exp Eye Res2024;248:110098.
21.
NirmalJ, SirohiwalA, SinghSB, et al.Role of organic cation transporters in the ocular disposition of its intravenously injected substrate in rabbits: Implications for ocular drug therapy. Exp Eye Res2013;116:27–35.
22.
NoguchiS, TakagiA, TanakaT, et al.Fluorouracil uptake in triple‐negative breast cancer cells: Negligible contribution of equilibrative nucleoside transporters 1 and 2. Biopharm Drug Dispos2021;42(2–3):85–93.
23.
WangY, ZhuQ, HuH, et al.Upregulation of histone acetylation reverses organic anion transporter 2 repression and enhances 5-fluorouracil sensitivity in hepatocellular carcinoma. Biochem Pharmacol2021;188:114546.
24.
KobayashiY, OhshiroN, TsuchiyaA, et al.Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOAT3): Further substrate specificity of mOAT3. Drug Metab Dispos2004;32(5):479–483.
25.
SharmaHP, HalderN, SinghSB, et al.Evaluation of the presence and functional importance of nucleoside transporters in lacrimal gland for tear disposition of intravenously injected substrate in rabbits. Curr Eye Res2021;46(11):1659–1665.
26.
MalaniM, HiremathMS, SharmaS, et al.Interaction of systemic drugs causing ocular toxicity with organic cation transporter: An artificial intelligence prediction. J Biomol Struct Dyn2024;42(10):5207–5218.
WielińskaJ, NowackiA, LiberekB. 5-Fluorouracil—complete insight into its neutral and ionised forms. Molecules2019;24(20):3683.
30.
LomizeAL, ToddSC, PogozhevaID. Spatial arrangement of proteins in planar and curved membranes by PPM 3.0. Protein Sci2022;31(1):209–220.
31.
AfinjuomoF, FouladianP, ParikhA, et al.Preparation and characterization of oxidized inulin hydrogel for controlled drug delivery. Pharmaceutics2019;11(7):356.
32.
MalaniM, ThodikayilAT, SahaS, et al.Carboxylated nanofibrillated cellulose empowers moxifloxacin to overcome Staphylococcus aureus biofilm in bacterial keratitis. Carbohydr Polym Epub ahead of print 2024;324:121558; doi: 10.1016/j.carbpol.2023.121558
33.
BrayF, LaversanneM, SungH, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin2024;74(3):229–263.
34.
StoicescuEA, IancuRC, Popa CherecheanuA, et al.Ocular adverse effects of anti-cancer chemotherapy. J Med Life2023;16(6):818–821.
35.
KligmanBE, FrancisJH, AbramsonDH. Ocular Complications Due to Cancer Treatment. Survivors of Childhood and Adolescent Cancer2015, pp. 95–111.
36.
Van DelftJL, MeijerF, Van BestJA, et al.Permeability of blood‐tear barrier to fluorescein and albumin after application of platelet‐activating factor to the eye of the guinea pig. Mediators Inflamm1997;6(5–6):381–383.
37.
KobayashiY, OhshiroN, SakaiR, et al.Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol2005;57(5):573–578.
38.
KamoshidaS. Immunohistochemical analysis of organic anion transporter 2 and reduced folate carrier 1 in colorectal cancer: Significance as a predictor of response to oral uracil/ftorafur plus leucovorin chemotherapy. Mol Clin Onc Epub ahead of print 2013; doi: 10.3892/mco.2013.104
39.
RothM, ObaidatA, HagenbuchB. OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol2012;165(5):1260–1287.
40.
RamachandranGN, SasisekharanV. Conformation of polypeptides and proteins. Adv Protein Chem1968;23:283–438.
41.
KapustaK, KarS, CollinsJT, et al.Protein reliability analysis and virtual screening of natural inhibitors for SARS-CoV-2 main protease (Mpro) through docking, molecular mechanic & dynamic, and ADMET profiling. J Biomol Struct Dyn2021;39(17):6810–6827.
42.
WangY, WangY, FangY, et al.SND1 regulates organic anion transporter 2 protein expression and sensitivity of hepatocellular carcinoma cells to 5-fluorouracil. Drug Metab Dispos2024;52(9):997–1008.
43.
ÖmanM, WettergrenY, OdinE, et al.Pharmacokinetics of preoperative intraperitoneal 5-FU in patients with pancreatic ductal adenocarcinoma. Cancer Chemother Pharmacol2021;88(4):619–631.
44.
AcheampongA, ShackletonM, LamS, et al.Cyclosporine distribution into the conjunctiva, cornea, lacrimal gland, and systemic blood following topical dosing of cyclosporine to rabbit, dog, and human eyes. Adv Exp Med Biol1998;438:1001–1004.
HongS-J, WuW-C, LaiY-H, et al.Mechanism of 5-fluorouracil-induced apoptosis on cultured corneal endothelial cells. OJApo2014;03(02):5–15.
47.
HuhtalaA, TähtiH, SalminenL, et al.Evaluation of adverse ocular effects of 5-fluorouracil by using human corneal epithelial cell cultures. J Toxicol Cutaneous Ocul Toxicol2002;21(4):283–292.
48.
Test No. 491: Short Time Exposure In Vitro Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage. OECD Publishing, 2025. Epub ahead of print. doi: 10.1787/9789264242432-en
49.
SweilehWM. Global research publications on irrational use of antimicrobials: Call for more research to contain antimicrobial resistance. Global Health2021;17(1):94.
50.
LeBlancTW, McNeilMJ, KamalAH, et al.Polypharmacy in patients with advanced cancer and the role of medication discontinuation. Lancet Oncol2015;16(7):e333–e341.
51.
OtterM, OswaldS, SiegmundW, et al.Effects of frequently used pharmaceutical excipients on the organic cation transporters 1–3 and peptide transporters 1/2 stably expressed in MDCKII cells. Eur J Pharm Biopharm2017;112:187–195.
52.
EngelA, OswaldS, SiegmundW, et al.Pharmaceutical excipients influence the function of human uptake transporting proteins. Mol Pharm2012;9(9):2577–2581.
53.
SempDA, BeesonD, SheppardAL, et al.Artificial tears: A systematic review. Clin Optom (Auckl)2023;15:9–27.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
