Journal of Dermatological Treatment.

2012; 23: 8389

REVIEW ARTICLE
Mechanisms of action of topical 5-uorouracil: Review and implications
for 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
Abstract
Topical 5-uorouracil has proved to be a useful therapy since its discovery nearly 50 years ago for the treatment of a range of
cancers (e.g. skin, colorectal, breast) and dermatological conditions (e.g. cancerous and precancerous conditions such as
actinic keratosis, benign tumors, nail psoriasis, mycosis fungoides, and porokeratoses). As a result of the enduring utility in
these conditions, the mechanism of action of 5-uorouracil has been studied extensively in vivo and in vitro. This review
provides an overview of the history and general mechanism of action of 5-uorouracil and discusses the dermatological
implications of the drug, including systemic absorption, selectivity for abnormal skin, targeted delivery, and skin-
specic molecular effects. Considerations of 5-uorouracil treatment in specic dermatological settings are also discussed,
as well as recent ndings of a role for 5-uorouracil in the treatment of photoaging.
Key words: actinic keratosis, 5-uorouracil, keratoacanthoma, mechanisms of action, photoaging, psoriasis, skin cancer, warts
Introduction
5-Fluorouracil (5-FU) was rst introduced in 1957 as
part of a new class of antitumor compounds (1). Since
then, it has been studied extensively and continues to
be clinically useful in a range of cancers, including
skin, colorectal, and breast cancers (24). Dermato-
logical applications for topical 5-FU include cancer-
ous and precancerous conditions, benign tumors, nail
psoriasis, porokeratoses, and skin rejuvenation (5,6).
This review discusses the general mechanism of
action, pharmacokinetics, and rationale for use of
5-FU in the context of dermatological conditions,
including recently reported ndings on the potential
utility 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 might
interfere with tumorigenesis and/or tumor growth and
therefore might be useful in chemotherapeutics (1).
With this knowledge, a drug design strategy was
utilized based on known nucleotide biochemistry to
synthesize novel uracil analogs (8,9). The result was
5-FU, which soon showed promise in the treatment of
dermatological malignancies. As early as 1962, topical
use of 5-FU showed cytotoxic effects in some skin
cancers and proved to be an effective treatment for
actinic keratosis (AK) and keratoacanthoma (1012).
Likewise, early studies of treatment with topical 5-FU
demonstrated common side effects of therapy such as
moderate facial irritation resulting from dryness, ery-
thema, and erosion (13). Given the efcacy and
tolerability prole, 5-FU (in 1% and 5% formula-
tions) was approved for topical use in July 1970; 5-FU
cream 0.5% was subsequently approved in August
1991. Since this time, topical 5-FU has become an
important component in the treatment of several
Correspondence: Roger I. Ceilley, Clinical Professor of Dermatology, University of Iowa, Dermatology PC, 6000 University Avenue, Suite 450, West Des Moines,
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 other
dermatological uses of 5-FU (5).
General mechanism of action
The cytotoxic effect of 5-FU occurs via pathways that
adversely affect the normal synthesis and functioning
of RNA and DNA (Figure 1) (3). After entering the
cell via the same facilitated transport mechanism as
uracil, 5-FU is converted to uorodeoxyuridine
monophosphate (FdUMP), uorodeoxyuridine tri-
phosphate (FdUTP), and uorouridine triphosphate
(FUTP) by multistep enzymatic reactions (2,3,14).
These metabolites of 5-FU then interfere with DNA
and RNA.
Interference with DNA. Deoxythymidine monopho-
sphate (dTMP) is required for DNA synthesis and
repair, the de novo source of thymidylate synthase
(TS) (3). The dTMP synthesis is inhibited after the
5-FU metabolite FdUMP binds to the TS nucleotide-
binding site (3). Rapidly dividing cells have intensive
demands for dTMP and other nucleotides. Conse-
quently, the inhibition of TS causes depletion of
dTMP and the accumulation of deoxyuridine mono-
phosphate (dUMP), creating an imbalance in the
proportion of intracellular nucleotides that result
in endonuclease-induced double-strand breaks in
DNA (1517). Furthermore, the accumulation of
dUMP may lead to increased levels of deoxyuridine
triphosphate (dUTP); dUTP and the 5-FU metabo-
lite FdUTP may be misincorporated into DNA,
requiring excision and repair (3,17). Thus, 5-FU
causes nucleotide pool imbalances and DNA misin-
corporation of both naturally occurring nucleotides
and FdUTP. The result is an overwhelming demand
on the DNArepair machinery, leading to DNAstrand
breaks and ultimately cell death (3).
Interference with RNA. In addition to the DNA
effects of 5-FU, the 5-FU metabolite FUTP is
misincorporated into RNA. Studies have indicated
that 5-FU interferes with the normal processing and
function of various RNA species (2,3). 5-FU has been
shown to inhibit pre-rRNA processing and possibly
tRNA function (2,18). In addition, 5-FU interferes
with the structure and function of small nuclear RNA-
protein complexes, which are responsible for splicing
pre-mRNA (19). Incorporation of FUTP into mRNA
also may alter mRNA splicing and has been shown to
interfere with mRNA metabolism and expression
(2,20). Thus, 5-FU may interfere with many aspects
of RNAfunction, possibly leading to disruptive effects
on cellular metabolism and cell viability (3).
Other molecular effects. In addition to interfering with
nucleic acid processing, 5-FU may also exert effects
on p53, the tumor suppressor gene. Known as the
guardian of the genome (21), p53 protects against the
proliferation of cells with DNA damage by inducing
cell-cycle arrest or apoptosis (3). 5-FU has been
shown 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 in
cell-cycle arrest and apoptosis in cells treated with
5-FU (24). Thus, the DNA damage caused by topical
administration of 5-FU may result in stimulation of
p53-mediated apoptosis of the rapidly proliferating
cells found in dermatological lesions. Although muta-
tions and alterations in p53 expression have been
found in dermatological conditions, including AK,
squamous cell carcinoma, and basal cell carcinoma
(25), the potential consequences of 5-FU treatment
have yet to be elucidated. Further investigation would
be required to determine the role of p53 in the
mechanism of action of 5-FU and the treatment of
dermatological conditions, particularly those in which
the underlying pathology may be a consequence of
p53 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 in
the 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,
Bowens disease, Pagets 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-uorouracil. A review, 633-649, 1981, with permission from
Elsevier.
84 R. I. Ceilley
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examined changes in expression of various molecular
markers of epidermal injury, inammation, and
extracellular matrix degradation and remodeling in
response to topical administration of 5-FU (6).
Patients with AKs and moderate to severe photo-
damage were treated topically with 5% 5-FU cream
and then mRNA levels for the molecular markers
were determined from punch biopsies of photoda-
maged facial skin. Expression of keratin 16, a marker
for epidermal injury, was signicantly upregulated
following topical treatment with 5-FU. It was
hypothesized that the proinammatory cytokines
interleukin 1b and tumor necrosis factor would be
induced following epidermal injury. While tumor
necrosis factor mRNA levels did not change,
interleukin-1b mRNA levels more than doubled in
response to topical 5-FU. Matrix metalloproteinase
1 is responsible for the cleavage of brillar type I and
type III collagens, which are major structural
proteins of the dermis that can be degraded by
matrix metalloproteinase 3 and matrix metallopro-
teinase 9 (6). Matrix metalloproteinase 1 mRNA was
markedly induced immediately after 5-FU treat-
ment. This initial rise in mRNA levels was followed
by marked induction of matrix metalloproteinase
3 mRNA; however, no changes were observed for
matrix metalloproteinase 9 mRNA levels. Also,
levels of procollagen I and III mRNAs and procolla-
gen I protein were signicantly induced following
5-FU treatment (6). These biochemical changes
were typical of a wound-healing response and may
help to characterize some of the molecular mechan-
isms involved in the response of skin to the effects of
5-FU. However, the molecular mechanisms linking
DNA damage
DHFU
FUTP
FdUTP
RNA effects:
Expression, splicing, metabolism,
processing, function
Cell death
dTMP
Nucleotide pool
imbalances
RNA misincorporation
DNA misincorporation
p53
keratin 16
IL-1
MMPs 1 and 3
Procollagen types I and III
5-FU
FdUMP
DPD
dUMP
AAAAA
TS
HN
N
H
O O
F
Figure 1. Molecular mechanisms of 5-uorouracil (5-FU). (DHFU, dihydrouorouracil; DPD, dihydropyrimidine dehydrogenase; dTMP,
deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FdUMP, uorodeoxyuridine monophosphate; FdUTP, uorodeox-
yuridine triphosphate; FUTP, uorouridine triphosphate; MMPs, matrix metalloproteinases; TS, thymidylate synthase.) Reprinted
by permission from Macmillan Publishers Ltd: Nat Rev Cancer ref. 3, copyright 2003.
MOAs of 5-uorouracil 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 to
be established.
Pharmacokinetic/pharmacodynamic
considerations
Intravenous formulation
Following intravenous administration, 5-FU is dis-
tributed readily to all tissues, including sites of active
cell proliferation such as the bone marrow, spleen,
and small intestine (9). Given the widespread
distribution and cytotoxicity of 5-FU for proliferat-
ing cells, minimizing systemic exposure is an impor-
tant clinical consideration. Therefore, topical
administration of 5-FU is the standard route of
administration for the treatment of dermatological
conditions.
Topical formulations
5-FU is available in topical formulations ranging from
0.5% 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 (2830).
Systemic absorption
Systemic absorption of topically applied 5-FU
appears to be minimal but has not been extensively
studied in humans (9,29). In 1965, it was found
that <6% of topically applied 5-FU was absorbed
systemically and that, given the dosage, systemic
absorption should be small enough to be inconse-
quential (31). However, a later report found that
although <2% of topically administered 5-FU was
absorbed systemically through normal skin, systemic
absorption may have been as much as 75 times greater
when administered to diseased skin (32). The clinical
importance of percutaneous absorption of 5-FU was
emphasized in a case report of a patient who was
severely decient in the enzyme dihydropyrimidine
dehydrogenase (DPD) (33), which is responsible for
degrading >80% of 5-FU (9). Systemic absorption of
topically administered 5-FU caused life-threatening
toxicity in this patient due to an inability to convert
5-FU to biologically inactive metabolites (33). It is
important to point out, however, that this was an
unusual case, and similar adverse events are rarely
reported in DPD-decient patients who receive
topical 5-FU approximately one in two million
cases (34).
Retention in skin
An in vitro system was used to investigate the absorp-
tion and ux of tritiated 5-FU in human cadaver skin
(29). The ndings indicated that 8692% of the
applied dose of a 0.5% microsphere formulation
was retained in the skin compared with 54% using
a 5% standard cream formulation. After accounting
for the difference in 5-FU concentrations, 5-FU ux
through the skin was approximately two- to fourfold
higher for the 5% cream versus the 0.5% microsphere
formulation. The 5-FU microsphere formulation pro-
vided targeted drug delivery, had greater drug reten-
tion in the skin, and had a lower potential for systemic
toxicity than the 5% cream.
Dermatological considerations
Selectivity for abnormal skin
Cytotoxicity with 5-FU occurs only in the rapidly
proliferating cells of abnormal skin (9). Typically,
inammation, erosion, and disappearance of the
abnormal lesions progress after topical applications
of 5-FU (12). Early studies noted that actinic skin
seemed to be more affected by topical 5-FU treatment
than normal skin (11,12). In 1963, treatment with
20% 5-FU resulted in responsiveness in areas of
keratosis, while surrounding normal skin appeared
to be relatively unaffected (12). To better understand
the mechanism of action of 5-FU in human skin, a
local intradermal injection of tritiated deoxyuridine
was used to monitor TS activity (35). The study
results showed that topical application of 5-FU could
inhibit TS activity completely in actinic skin, but only
partially in normal skin (35).
Use in dermatological settings
Topical 5-FU has been shown to be efcacious in the
clinical treatment of a variety of dermatological
conditions that are characterized by hyper-
restrained or unrestrained proliferation of epidermal
cells, leaving normal skin cells relatively unaffected
(11,12). It is approved in the United States for the
topical treatment of AK and supercial basal cell
carcinomas when conventional methods are imprac-
tical (2628). Topical 5-FU offers an alternative to
86 R. I. Ceilley
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ablative and surgical treatments, which may cause
scarring, may require reconstructive procedures,
and may not treat subclinical or multiple diffuse
lesions (4). A recent review summarized clinical
studies investigating the use of 5-FU in various
dermatological settings, including AK, basal cell
carcinoma, keratoacanthoma, warts, and psoriasis,
highlighting the versatility of topical 5-FU and
recommending additional research to denitively
determine its role in treatment (4). While this
role is dened, the relationship between the
pathophysiology of the aforementioned conditions
and the mechanism of action of 5-FU can be
explored.
Actinic keratosis
For more than 40 years, 5-FU has been known as an
effective treatment for AK. A recent systematic
reviewconcluded that a 90%reduction in total lesion
count is likely following a full treatment course of
5-FU, with approximately half of all treated patients
achieving complete clearance (36). In addition, the
inammatory response induced by 5-FU treatment
has been shown to reveal subclinical lesions, which
may be clinically helpful in the earlier tracking
and detection of AKs (31). Combination therapy
consisting of a short course of 5-FU cream 0.5%
followed by cryotherapy signicantly improved long-
term AK outcomes over cryotherapy alone (37).
Topical 5-FU also has been used in combination
with chemical peels and photodynamic therapy.
Combination therapy consisting of topical 5-FU
and glycolic acid signicantly reduced the number
of AKs and improved the cosmesis of photodamaged
skin compared with treatment with glycolic acid
alone (38). A more recent study suggested that
glycolic acid may increase skin permeability for
5-FU while reducing 5-FU inammation by increas-
ing desquamation (39).
Basal cell carcinoma
Topical 5-FU (5% cream) may be useful for the
treatment of multiple or surgically impractical super-
cial basal cell carcinomas (27,40). It should be noted
that topical 5-FU is not recommended for the treat-
ment of invasive basal cell carcinoma because inhibi-
tion of tumor growth is supercial (41). This may
result in the misleading appearance of efcacy while
deeper tumor extensions continue to growundetected,
permitting the cancer to reach an advanced stage (41).
Keratoacanthoma
Keratoacanthomas are rapidly growing lesions that
can leave cosmetically displeasing scars (42). Because
these neoplasms are usually benign, patient comfort
and cosmetic considerations may be emphasized (42).
In certain instances, topical treatment with 5-FU may
be used in place of surgical removal, thereby mini-
mizing patient discomfort and scarring (43). Use of
intralesional 5-FU has also been reported as a suc-
cessful component of treatment for keratoacanthomas
(44). 5-FU, in combination with imiquimod, has also
been 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 clinically
evident warty papules (47). Host DNA and RNA are
required for both viral replication and proliferation of
host cells (48). The effects of 5-FU on DNA and
RNA may prevent viral replication, host proliferation,
and subsequent propagation of the infection (48).
However, one systematic review concluded that
data were insufcient to demonstrate advantages of
topical 5-FU over other simpler treatments for warts
in terms of efcacy (47).
Psoriasis
5-FU has been studied in the treatment of psoriasis of
the nail, with variable results (4). For example, the
combination of 1% 5-FU with a nail permeation
enhancer cream (urea plus propylene glycol) showed
improvements in nail area severity scores for patients
with psoriasis of the ngernails; however, at the end of
treatment, these improvements were not large enough
to be statistically signicant compared with the nail
enhancer alone (p = 0.063) (49). Further investigation
is needed to determine the potential utility of 5-FUfor
this condition.
Photoaging
The key risk factor in the development of AK, squa-
mous cell carcinoma, and basal cell carcinoma three
conditions in which 5-FU treatment is indicated is
also responsible for photodamaged skin and photo-
aging, namely, sun exposure. Consequently, these
conditions are highly interrelated, and the potential
effects of 5-FU treatment on photoaging can be
readily identiable. In an early study of skin changes
MOAs of 5-uorouracil in dermatological disorders 87
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in patients treated with systemic 5-FU, softening and
smoothening of senile ichthyosiform roughening of
the skin was observed (50).
Recently, an investigation was conducted into
the molecular role that topical 5-FU may have in
rejuvenating photodamaged skin (6). Mean scores
for wrinkles, tactile roughness, mottled hyperpig-
mentation, lentigines, sallowness, and overall sever-
ity of photoaging showed statistically signicant
improvement following topical 5-FU treatment.
Data collected from questionnaires indicated that
the majority of patients had experienced improve-
ment in their skin texture and were willing to
undergo treatment again. The study investigators
noted a signicant increase in AKs immediately after
5-FU therapy and argued that these red, scaly areas
of conuence may have simply been inamed areas
of photodamaged skin and suggested that 5-FU may
exert effects on photodamaged skin in general, not
just to areas of keratosis. This study also found that
5-FU induced an upregulation of mRNA levels of
molecular markers of wound healing and dermal
matrix remodeling. Taken together, these data sug-
gest that wound healing and dermal matrix remodel-
ing are responsible for the improved appearance of
photodamaged skin in patients treated with topical
5-FU. Further investigation is necessary to deter-
mine the true mechanisms, as well as the clinical and
practical applications for these ndings, both from a
clinical 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-induced
pathways of cell death. In dermatological settings,
hyper-restrained or unrestrained proliferation of
abnormal skin cells requires rapid nucleic acid syn-
thesis; thus, the abnormal cells are more sensitive to
the effects of 5-FU. Molecular effects in the skin also
may indicate that 5-FU induces a wound-healing
response 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 supercial basal
cell carcinoma. Studies also have described the ef-
cacy of 5-FU in treating benign dermatological con-
ditions such as warts and keratoacanthoma, and
recent reports have begun to elucidate a role of
5-FU in the cosmetic improvement of photodamaged
skin. Combination treatment with 5-FU and other
treatments, such as cryotherapy, chemical peels, and
photodynamic therapy, may improve the efcacy and
tolerability of 5-FU. Further investigation of 5-FU
delivery techniques, dosing regimens, combinations
with other therapeutic modalities, and skin-specic
molecular effects may lead to improved and perhaps
broader dermatological utility of this well-
established therapy.
Acknowledgements
Editorial support for this article, funded by Dermik
Laboratories, a business of sano-aventis U.S. LLC,
was provided by Albert Balkiewicz, MSc, of Peloton
Advantage, LLC. The author was fully responsible
for the content, editorial decisions, and opinions
expressed in the current article and did not receive
an honorarium related to the development of this
manuscript.
Declaration of interest: The author reports no
conicts of interest.
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