Journal of Dermatological Treatment. 2012; 23: 83–89

REVIEW ARTICLE

Mechanisms of action of topical 5-fluorouracil: Review and implicationsfor the treatment of dermatological disorders

ROGER I. CEILLEY

Department of Dermatology, University of Iowa, Iowa City, Iowa, and Dermatology PC, West Des Moines, Iowa, USA

AbstractTopical 5-fluorouracil has proved to be a useful therapy since its discovery nearly 50 years ago for the treatment of a range ofcancers (e.g. skin, colorectal, breast) and dermatological conditions (e.g. cancerous and precancerous conditions such asactinic keratosis, benign tumors, nail psoriasis, mycosis fungoides, and porokeratoses). As a result of the enduring utility inthese conditions, the mechanism of action of 5-fluorouracil has been studied extensively in vivo and in vitro. This reviewprovides an overview of the history and general mechanism of action of 5-fluorouracil and discusses the dermatologicalimplications of the drug, including systemic absorption, selectivity for abnormal skin, targeted delivery, and skin-specific molecular effects. Considerations of 5-fluorouracil treatment in specific dermatological settings are also discussed,as well as recent findings of a role for 5-fluorouracil in the treatment of photoaging.

Key words: actinic keratosis, 5-fluorouracil, keratoacanthoma, mechanisms of action, photoaging, psoriasis, skin cancer, warts

Introduction

5-Fluorouracil (5-FU) was first introduced in 1957 aspart of a new class of antitumor compounds (1). Sincethen, it has been studied extensively and continues tobe clinically useful in a range of cancers, includingskin, colorectal, and breast cancers (2–4). Dermato-logical applications for topical 5-FU include cancer-ous and precancerous conditions, benign tumors, nailpsoriasis, porokeratoses, and skin rejuvenation (5,6).This review discusses the general mechanism ofaction, pharmacokinetics, and rationale for use of5-FU in the context of dermatological conditions,including recently reported findings on the potentialutility of 5-FU in the treatment of photoaging.

Historical overview of 5-FU

Early studies of hepatic tumors in rats demon-strated an increased utilization of exogenous uracil

in malignant tissue compared with normal tissue (7).This led to the hypothesis that uracil analogs mightinterfere with tumorigenesis and/or tumor growth andtherefore might be useful in chemotherapeutics (1).With this knowledge, a drug design strategy wasutilized based on known nucleotide biochemistry tosynthesize novel uracil analogs (8,9). The result was5-FU, which soon showed promise in the treatment ofdermatological malignancies. As early as 1962, topicaluse of 5-FU showed cytotoxic effects in some skincancers and proved to be an effective treatment foractinic keratosis (AK) and keratoacanthoma (10–12).Likewise, early studies of treatment with topical 5-FUdemonstrated common side effects of therapy such asmoderate facial irritation resulting from dryness, ery-thema, and erosion (13). Given the efficacy andtolerability profile, 5-FU (in 1% and 5% formula-tions) was approved for topical use in July 1970; 5-FUcream 0.5% was subsequently approved in August1991. Since this time, topical 5-FU has become animportant component in the treatment of several

Correspondence: Roger I. Ceilley, Clinical Professor of Dermatology, University of Iowa, Dermatology PC, 6000University Avenue, Suite 450,West DesMoines,IA 50266, USA. Fax: +1 515 541 2005. E-mail: Ricakb@aol.com

(Received 14 May 2010; accepted 26 June 2010)

ISSN 0954-6634 print/ISSN 1471-1753 online � 2012 Informa Healthcare USA on behalf of Informa UK Ltd.DOI: 10.3109/09546634.2010.507704

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dermatological conditions. Table I summarizes otherdermatological uses of 5-FU (5).

General mechanism of action

The cytotoxic effect of 5-FU occurs via pathways thatadversely affect the normal synthesis and functioningof RNA and DNA (Figure 1) (3). After entering thecell via the same facilitated transport mechanism asuracil, 5-FU is converted to fluorodeoxyuridinemonophosphate (FdUMP), fluorodeoxyuridine tri-phosphate (FdUTP), and fluorouridine triphosphate(FUTP) by multistep enzymatic reactions (2,3,14).These metabolites of 5-FU then interfere with DNAand RNA.

Interference with DNA. Deoxythymidine monopho-sphate (dTMP) is required for DNA synthesis andrepair, the de novo source of thymidylate synthase(TS) (3). The dTMP synthesis is inhibited after the5-FUmetabolite FdUMP binds to the TS nucleotide-binding site (3). Rapidly dividing cells have intensivedemands for dTMP and other nucleotides. Conse-quently, the inhibition of TS causes depletion ofdTMP and the accumulation of deoxyuridine mono-phosphate (dUMP), creating an imbalance in theproportion of intracellular nucleotides that resultin endonuclease-induced double-strand breaks inDNA (15–17). Furthermore, the accumulation ofdUMP may lead to increased levels of deoxyuridinetriphosphate (dUTP); dUTP and the 5-FU metabo-lite FdUTP may be misincorporated into DNA,requiring excision and repair (3,17). Thus, 5-FUcauses nucleotide pool imbalances and DNA misin-corporation of both naturally occurring nucleotidesand FdUTP. The result is an overwhelming demandon the DNA repair machinery, leading to DNA strandbreaks and ultimately cell death (3).

Interference with RNA. In addition to the DNAeffects of 5-FU, the 5-FU metabolite FUTP is

misincorporated into RNA. Studies have indicatedthat 5-FU interferes with the normal processing andfunction of various RNA species (2,3). 5-FU has beenshown to inhibit pre-rRNA processing and possiblytRNA function (2,18). In addition, 5-FU interfereswith the structure and function of small nuclear RNA-protein complexes, which are responsible for splicingpre-mRNA (19). Incorporation of FUTP into mRNAalso may alter mRNA splicing and has been shown tointerfere with mRNA metabolism and expression(2,20). Thus, 5-FU may interfere with many aspectsof RNA function, possibly leading to disruptive effectson cellular metabolism and cell viability (3).

Other molecular effects. In addition to interfering withnucleic acid processing, 5-FU may also exert effectson p53, the tumor suppressor gene. Known as theguardian of the genome (21), p53 protects against theproliferation of cells with DNA damage by inducingcell-cycle arrest or apoptosis (3). 5-FU has beenshown in vitro to increase p53 expression (22,23),while mutations in p53 may result in 5-FU resis-tance (24). This suggests that p53 is involved incell-cycle arrest and apoptosis in cells treated with5-FU (24). Thus, the DNA damage caused by topicaladministration of 5-FU may result in stimulation ofp53-mediated apoptosis of the rapidly proliferatingcells found in dermatological lesions. Although muta-tions and alterations in p53 expression have beenfound in dermatological conditions, including AK,squamous cell carcinoma, and basal cell carcinoma(25), the potential consequences of 5-FU treatmenthave yet to be elucidated. Further investigation wouldbe required to determine the role of p53 in themechanism of action of 5-FU and the treatment ofdermatological conditions, particularly those in whichthe underlying pathology may be a consequence ofp53 mutation.Although many in vivo and in vitro studies have

examined the general mechanism of action of 5-FU,little is known about molecular changes that occur inthe skin following 5-FU treatment. A recent study

Table I. Reported dermatological uses of 5-FU (5).

Precancerous tumors Actinic keratosis, actinic cheilitis, chronic radiodermatitis, xeroderma pigmentosum,Bowen’s disease, Paget’s disease, lentigo maligna

Malignant tumors Basal cell carcinoma, squamous cell carcinoma, metastatic carcinoma

Benign tumors Keratoacanthoma, seborrheic keratosis, warts (plantar, condylomata, plane, verrucae vulgares)

Dermatoses Psoriasis of the nail, mycosis fungoides, porokeratosis

Others Photoaging

Adapted from ref. (5), J Am Acd Dermatol, Topical Chemotherapy with 5-fluorouracil. A review, 633-649, 1981, with permission fromElsevier.

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examined changes in expression of various molecularmarkers of epidermal injury, inflammation, andextracellular matrix degradation and remodeling inresponse to topical administration of 5-FU (6).Patients with AKs and moderate to severe photo-damage were treated topically with 5% 5-FU creamand then mRNA levels for the molecular markerswere determined from punch biopsies of photoda-maged facial skin. Expression of keratin 16, a markerfor epidermal injury, was significantly upregulatedfollowing topical treatment with 5-FU. It washypothesized that the proinflammatory cytokinesinterleukin 1b and tumor necrosis factor would beinduced following epidermal injury. While tumornecrosis factor mRNA levels did not change,interleukin-1b mRNA levels more than doubled inresponse to topical 5-FU. Matrix metalloproteinase

1 is responsible for the cleavage of fibrillar type I andtype III collagens, which are major structuralproteins of the dermis that can be degraded bymatrix metalloproteinase 3 and matrix metallopro-teinase 9 (6). Matrix metalloproteinase 1 mRNA wasmarkedly induced immediately after 5-FU treat-ment. This initial rise in mRNA levels was followedby marked induction of matrix metalloproteinase3 mRNA; however, no changes were observed formatrix metalloproteinase 9 mRNA levels. Also,levels of procollagen I and III mRNAs and procolla-gen I protein were significantly induced following5-FU treatment (6). These biochemical changeswere typical of a wound-healing response and mayhelp to characterize some of the molecular mechan-isms involved in the response of skin to the effects of5-FU. However, the molecular mechanisms linking

DNA damage

DHFU

FUTP

FdUTP

RNA effects:Expression, splicing, metabolism,

processing, function

Cell death

dTMP

Nucleotide poolimbalances

RNA misincorporation

DNA misincorporation

p53keratin 16IL-1βMMPs 1 and 3Procollagen types I and III

5-FU

FdUMP

DPD

dUMP

AAAAA

TS

HN

NH

O O

F

Figure 1. Molecular mechanisms of 5-fluorouracil (5-FU). (DHFU, dihydrofluorouracil; DPD, dihydropyrimidine dehydrogenase; dTMP,deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeox-yuridine triphosphate; FUTP, fluorouridine triphosphate; MMPs, matrix metalloproteinases; TS, thymidylate synthase.) Reprintedby permission from Macmillan Publishers Ltd: Nat Rev Cancer ref. 3, copyright 2003.

MOAs of 5-fluorouracil in dermatological disorders 85

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the effects of 5-FU to the upregulation and expres-sion of genes involved in wound healing have yet tobe established.

Pharmacokinetic/pharmacodynamicconsiderations

Intravenous formulation

Following intravenous administration, 5-FU is dis-tributed readily to all tissues, including sites of activecell proliferation such as the bone marrow, spleen,and small intestine (9). Given the widespreaddistribution and cytotoxicity of 5-FU for proliferat-ing cells, minimizing systemic exposure is an impor-tant clinical consideration. Therefore, topicaladministration of 5-FU is the standard route ofadministration for the treatment of dermatologicalconditions.

Topical formulations

5-FU is available in topical formulations ranging from0.5% to 5% concentrations in solutions or creams(26,27). Most formulations are indicated for twice-daily application, while a controlled-release 0.5%microsphere formulation is indicated for once-daily use (28–30).

Systemic absorption

Systemic absorption of topically applied 5-FUappears to be minimal but has not been extensivelystudied in humans (9,29). In 1965, it was foundthat <6% of topically applied 5-FU was absorbedsystemically and that, given the dosage, systemicabsorption should be small enough to be inconse-quential (31). However, a later report found thatalthough <2% of topically administered 5-FU wasabsorbed systemically through normal skin, systemicabsorption may have been as much as 75 times greaterwhen administered to diseased skin (32). The clinicalimportance of percutaneous absorption of 5-FU wasemphasized in a case report of a patient who wasseverely deficient in the enzyme dihydropyrimidinedehydrogenase (DPD) (33), which is responsible fordegrading >80% of 5-FU (9). Systemic absorption oftopically administered 5-FU caused life-threateningtoxicity in this patient due to an inability to convert5-FU to biologically inactive metabolites (33). It isimportant to point out, however, that this was anunusual case, and similar adverse events are rarely

reported in DPD-deficient patients who receivetopical 5-FU – approximately one in two millioncases (34).

Retention in skin

An in vitro system was used to investigate the absorp-tion and flux of tritiated 5-FU in human cadaver skin(29). The findings indicated that 86–92% of theapplied dose of a 0.5% microsphere formulationwas retained in the skin compared with 54% usinga 5% standard cream formulation. After accountingfor the difference in 5-FU concentrations, 5-FU fluxthrough the skin was approximately two- to fourfoldhigher for the 5% cream versus the 0.5% microsphereformulation. The 5-FU microsphere formulation pro-vided targeted drug delivery, had greater drug reten-tion in the skin, and had a lower potential for systemictoxicity than the 5% cream.

Dermatological considerations

Selectivity for abnormal skin

Cytotoxicity with 5-FU occurs only in the rapidlyproliferating cells of abnormal skin (9). Typically,inflammation, erosion, and disappearance of theabnormal lesions progress after topical applicationsof 5-FU (12). Early studies noted that actinic skinseemed to be more affected by topical 5-FU treatmentthan normal skin (11,12). In 1963, treatment with20% 5-FU resulted in responsiveness in areas ofkeratosis, while surrounding normal skin appearedto be relatively unaffected (12). To better understandthe mechanism of action of 5-FU in human skin, alocal intradermal injection of tritiated deoxyuridinewas used to monitor TS activity (35). The studyresults showed that topical application of 5-FU couldinhibit TS activity completely in actinic skin, but onlypartially in normal skin (35).

Use in dermatological settings

Topical 5-FU has been shown to be efficacious in theclinical treatment of a variety of dermatologicalconditions that are characterized by hyper-restrained or unrestrained proliferation of epidermalcells, leaving normal skin cells relatively unaffected(11,12). It is approved in the United States for thetopical treatment of AK and superficial basal cellcarcinomas when conventional methods are imprac-tical (26–28). Topical 5-FU offers an alternative to

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ablative and surgical treatments, which may causescarring, may require reconstructive procedures,and may not treat subclinical or multiple diffuselesions (4). A recent review summarized clinicalstudies investigating the use of 5-FU in variousdermatological settings, including AK, basal cellcarcinoma, keratoacanthoma, warts, and psoriasis,highlighting the versatility of topical 5-FU andrecommending additional research to definitivelydetermine its role in treatment (4). While thisrole is defined, the relationship between thepathophysiology of the aforementioned conditionsand the mechanism of action of 5-FU can beexplored.

Actinic keratosis

For more than 40 years, 5-FU has been known as aneffective treatment for AK. A recent systematicreview concluded that a 90% reduction in total lesioncount is likely following a full treatment course of5-FU, with approximately half of all treated patientsachieving complete clearance (36). In addition, theinflammatory response induced by 5-FU treatmenthas been shown to reveal subclinical lesions, whichmay be clinically helpful in the earlier trackingand detection of AKs (31). Combination therapyconsisting of a short course of 5-FU cream 0.5%followed by cryotherapy significantly improved long-term AK outcomes over cryotherapy alone (37).Topical 5-FU also has been used in combinationwith chemical peels and photodynamic therapy.Combination therapy consisting of topical 5-FUand glycolic acid significantly reduced the numberof AKs and improved the cosmesis of photodamagedskin compared with treatment with glycolic acidalone (38). A more recent study suggested thatglycolic acid may increase skin permeability for5-FU while reducing 5-FU inflammation by increas-ing desquamation (39).

Basal cell carcinoma

Topical 5-FU (5% cream) may be useful for thetreatment of multiple or surgically impractical super-ficial basal cell carcinomas (27,40). It should be notedthat topical 5-FU is not recommended for the treat-ment of invasive basal cell carcinoma because inhibi-tion of tumor growth is superficial (41). This mayresult in the misleading appearance of efficacy whiledeeper tumor extensions continue to grow undetected,permitting the cancer to reach an advanced stage (41).

Keratoacanthoma

Keratoacanthomas are rapidly growing lesions thatcan leave cosmetically displeasing scars (42). Becausethese neoplasms are usually benign, patient comfortand cosmetic considerations may be emphasized (42).In certain instances, topical treatment with 5-FU maybe used in place of surgical removal, thereby mini-mizing patient discomfort and scarring (43). Use ofintralesional 5-FU has also been reported as a suc-cessful component of treatment for keratoacanthomas(44). 5-FU, in combination with imiquimod, has alsobeen reported to be effective for squamous cell car-cinoma in situ (45,46).

Warts

Human papillomavirus (HPV) causes hyperprolifera-tion of infected epithelial cells and leads to clinicallyevident warty papules (47). Host DNA and RNA arerequired for both viral replication and proliferation ofhost cells (48). The effects of 5-FU on DNA andRNA may prevent viral replication, host proliferation,and subsequent propagation of the infection (48).However, one systematic review concluded thatdata were insufficient to demonstrate advantages oftopical 5-FU over other simpler treatments for wartsin terms of efficacy (47).

Psoriasis

5-FU has been studied in the treatment of psoriasis ofthe nail, with variable results (4). For example, thecombination of 1% 5-FU with a nail permeationenhancer cream (urea plus propylene glycol) showedimprovements in nail area severity scores for patientswith psoriasis of the fingernails; however, at the end oftreatment, these improvements were not large enoughto be statistically significant compared with the nailenhancer alone (p = 0.063) (49). Further investigationis needed to determine the potential utility of 5-FU forthis condition.

Photoaging

The key risk factor in the development of AK, squa-mous cell carcinoma, and basal cell carcinoma – threeconditions in which 5-FU treatment is indicated – isalso responsible for photodamaged skin and photo-aging, namely, sun exposure. Consequently, theseconditions are highly interrelated, and the potentialeffects of 5-FU treatment on photoaging can bereadily identifiable. In an early study of skin changes

MOAs of 5-fluorouracil in dermatological disorders 87

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in patients treated with systemic 5-FU, softening andsmoothening of senile ichthyosiform roughening ofthe skin was observed (50).Recently, an investigation was conducted into

the molecular role that topical 5-FU may have inrejuvenating photodamaged skin (6). Mean scoresfor wrinkles, tactile roughness, mottled hyperpig-mentation, lentigines, sallowness, and overall sever-ity of photoaging showed statistically significantimprovement following topical 5-FU treatment.Data collected from questionnaires indicated thatthe majority of patients had experienced improve-ment in their skin texture and were willing toundergo treatment again. The study investigatorsnoted a significant increase in AKs immediately after5-FU therapy and argued that these red, scaly areasof confluence may have simply been inflamed areasof photodamaged skin and suggested that 5-FU mayexert effects on photodamaged skin in general, notjust to areas of keratosis. This study also found that5-FU induced an upregulation of mRNA levels ofmolecular markers of wound healing and dermalmatrix remodeling. Taken together, these data sug-gest that wound healing and dermal matrix remodel-ing are responsible for the improved appearance ofphotodamaged skin in patients treated with topical5-FU. Further investigation is necessary to deter-mine the true mechanisms, as well as the clinical andpractical applications for these findings, both from aclinical and cosmetic perspective.

Conclusions

The molecular mechanism of action of 5-FU is mul-tifaceted and includes direct and indirect perturba-tions of DNA and RNA and may involve p53-inducedpathways of cell death. In dermatological settings,hyper-restrained or unrestrained proliferation ofabnormal skin cells requires rapid nucleic acid syn-thesis; thus, the abnormal cells are more sensitive tothe effects of 5-FU. Molecular effects in the skin alsomay indicate that 5-FU induces a wound-healingresponse in photodamaged skin.The clinical utility of topical 5-FU has been well

established in precancerous and cancerous dermato-logical conditions such as AK and superficial basalcell carcinoma. Studies also have described the effi-cacy of 5-FU in treating benign dermatological con-ditions such as warts and keratoacanthoma, andrecent reports have begun to elucidate a role of5-FU in the cosmetic improvement of photodamagedskin. Combination treatment with 5-FU and othertreatments, such as cryotherapy, chemical peels, andphotodynamic therapy, may improve the efficacy and

tolerability of 5-FU. Further investigation of 5-FUdelivery techniques, dosing regimens, combinationswith other therapeutic modalities, and skin-specificmolecular effects may lead to improved – and perhapsbroader – dermatological utility of this well-established therapy.

Acknowledgements

Editorial support for this article, funded by DermikLaboratories, a business of sanofi-aventis U.S. LLC,was provided by Albert Balkiewicz, MSc, of PelotonAdvantage, LLC. The author was fully responsiblefor the content, editorial decisions, and opinionsexpressed in the current article and did not receivean honorarium related to the development of thismanuscript.

Declaration of interest: The author reports noconflicts of interest.

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