Fluoropyrimidines

Fluorouracil and its prodrug, capecitabine, have been utilized in multiple malignancies
including breast cancer and multiple gastrointestinal tumors. Capecitabine is metabolized via
the liver and within tumor tissue to fluorouracil. Fluorouracil requires multiple conversions to
form active metabolites with the main cytotoxic activity being via inhibition of thymidylate
synthase. Common toxicities with both agents include gastrointestinal effects
(mucositis, nausea, vomiting, etc.), as well as hand foot syndrome in those receiving
continuous infusion fluorouracil and capecitabine. Patients receiving bolus fluorouracil
infusions are at higher risk for myelosuppressive effects. Metabolism to inactive metabolites
occurs via dihydropyrimidine dehydrogenase (DPD) and those with deficiency of DPD are at
increased risk for toxicity with both medications.
Read full chapter
Cancer chemotherapy
Jane M Dobson, ... Anne E Peaston, in Small Animal Clinical Pharmacology (Second
Edition), 2008
5-Fluorouracil
Other names
5-FU, fluorouracil, NSC-19893
Clinical applications
5-Fluorouracil is rarely used in the dog and is not recommended for use in cats due
to neurotoxicity in this species. In humans, 5-fluorouracil with leucovorin rescue is a
mainstay in the treatment of colon cancer. Basal cell carcinoma is treated with topical 5-
fluorouracil. Treatment regimens for human pancreatic, breast and gastric carcinoma may
include 5-fluorouracil. Two case reports of dogs with gastrointestinal
adenocarcinoma showed clinical benefit from a treatment protocol containing 5-fluorouracil
and cisplatin.
Mechanism of action
5-Fluorouracil is a fluorinated pyrimidine. This drug has two primary mechanisms of action
capable of inducing cytotoxicity. First, 5-fluorouracil is phosphorylated to fluorouridine
triphosphate, a fraudulent nucleotide, which is incorporated into RNA by RNA polymerase,
inhibiting RNA synthesis and function. Fluorodeoxyuridine monophosphate
inhibits thymidylate synthetase, depleting intracellular levels of thymidine
monophosphate and thymidine triphosphate, which are essential for DNA synthesis.
Mechanism of drug resistance
Because 5-fluorouracil metabolism is intricate, mechanisms of drug resistance are complex.
Changes in enzyme activity involved in 5-fluorouracil activation or degradation, the presence
of salvage pathways that circumvent normal pyrimidine metabolism and inadequate
intracellular pools of reduced folates all contribute to 5-fluorouracil resistance.
Formulations and dose rates
DOGS
•
2
5 mg/kg IV and 150–200 mg/m IV weekly have been used safely
•
Regional administration of 5-fluorouracil in a gel matrix has proved to be effective for
the control of canine solar-induced squamous cell carcinoma
CATS
•
Neurotoxicity prevents the use of intravenous or topical 5-fluorouracil in the cat
Pharmacokinetics
Some 21% of 5-fluorouracil is protein bound in normal dogs. The majority of 5-fluorouracil
is metabolized to fluorodeoxyridine monophosphate in the liver or intestinal mucosa by
dihydrouracil dehydrogenase. Unmetabolized drug attains high concentrations in the bone
marrow. First half-life following a 10 mg/kg bolus of 5-fluorouracil was 3.4 min, terminal
half-life was 23.5 min and volume of distribution 1.9 L/kg. In another normal dog study,
pharmacokinetic analysis of a 30 mg/kg bolus injection of 5-fluorouracil resulted in a first-
order elimination of drug from all compartments. The best-fit plasma level time area under
the curve was 4024 g/mLxmin.
A proposed model of pharmacokinetics included flow-dependent clearance of 5-fluorouracil
by the liver and linear elimination via the kidney. Total plasma clearance of 5-fluorouracil
exceeds cardiac output and, consequently, extrahepatic pathways of disposition must be
present to account for this phenomenon. Dose-dependent pulmonary extraction and clearance
of 5-flourouracil has been demonstrated in the dog. As the dose of 5-fluorouracil increases,
the percentage of drug cleared by the lung decreases. 5-Fluorouracil enters CSF and attains
concentrations similar to plasma levels.
Adverse effects
•
Some of the best information on 5-fluorouracil toxicity comes from cases of
accidental ingestion in dogs. Accidental ingestion of 5-fluorouracil occurs in dogs
exposed to their owner's topical 5-fluorouracil preparation. Exposure to more than 43
mg/kg resulted in death in all dogs exposed. Clinical signs of toxicosis occurred
within 1 h of ingestion and included seizures, vomiting, tremors, respiratory
distress, hypersalivation, diarrhea, depression, ataxia and cardiac arrhythmias.
•
Temporary hair loss may occur in dogs receiving a nonlethal dose of 5-fluorouracil.
•
Similar clinical signs as described above may occur when topical 5-fluorouracil is
applied to dogs for the treatment of skin tumors.
Known drug interactions
Concurrent administration of cimetidine or α-interferon may decrease 5-
fluorouracil clearance.
Read full chapter
Toxic Encephalopathies I: Cortical and Mixed
Encephalopathies
Tracy J. Eicher, in Clinical Neurotoxicology, 2009
5-Fluorouracil
5-Fluorouracil is an analogue of the pyrimidine uracil. It is used in the treatment of head and
neck cancers and colorectal adenocarcinoma. Neurotoxic effects of 5-fluorouracil include
encephalopathy and cerebellar symptoms of horizontal nystagmusand limb and gait ataxia. In
most cases, these symptoms are fairly mild; however, patients with a deficiency
of dihydropyrimidine dehydrogenase (an enzyme needed to metabolize 5-fluorouracil) may
develop a profound encephalopathy and seizures.58 Treatment regimens for colorectal
adenocarcinoma may employ the combination of 5-fluorouracil and levamisole. This
combination may result in a multifocal inflammatory leukoencephalopathy. The symptoms
tend to respond to steroids and remit after discontinuation of the medications.46,59
Read full chapter
F
Carl P. Weiner MD, MBA, FACOG, Clifford Mason PhD, in Drugs for Pregnant and
Lactating Women (Third Edition), 2019
International Brand Names
Log on to ExpertConsult.com for a list of all international brand names.
Actino-Hermal (Germany); Adrucil (Canada); Efudex (Canada); Efudix (Argentina, Belgium,
Bulgaria, Costa Rica, Czech Republic, Dominican Republic, El Salvador, England, France,
Germany, Ghana, Guatemala, Honduras, Hong Kong, Ireland, Italy, Japan, Kenya, Mexico,
Netherlands, Nicaragua, Panama, Peru, Poland, Puerto Rico, Singapore, South Africa, Spain,
Switzerland, Taiwan, Tanzania, Uganda, Uruguay, Zambia); Efurix (Brazil); Fivoflu
(Philippines); Fluoxan (Philippines); Fluracedyl (Malaysia); Flurox (Thailand); Ifacil
(Mexico); Oncofu (Argentina); Uflahex (Philippines); Utoral (Philippines)
Drug Class Antimetabolites; Antineoplastics
Malignancies including breast, colon, basal cell, and gestational
Indications
trophoblast
Mechanism Pyrimidine analog that inhibits both DNA and RNA synthesis

Malignancy—Depends on tumor and protocol

NOTE: Available in a topical preparation for the treatment of basal
cell carcinoma.
Dosage With
Qualifiers
•
Contraindications—hypersensitivity to drug or class,
myelosuppression, serious infection, recent surgery
 •
Caution—hepatic or renal dysfunction, prior use of
alkylating agents, CAD
There are no adequate reports or well-controlled studies
of fluorouracil in pregnant women. Fluorouracil is most commonly
used during pregnancy in the second and third trimesters for the
treatment of metastatic breast cancer, where it is often combined
with doxorubicin and cyclophosphamide (FAC). Although it should
be used only when there is significant risk for the mother’s survival,
Maternal breast cancer can be treated with FAC chemotherapy during the
Considerations second and third trimesters without significant short-term
complications for the majority of children exposed to
chemotherapy in utero.
Side effects include leukopenia, thrombocytopenia, agranulocytosis,
GI bleeding, N/V, diarrhea, anorexia, enteritis, alopecia, dermatitis,
photosensitivity, erythema, ulceration, stomatitis, lethargy, malaise,
headache, and confusion.
There are no adequate reports or well-controlled studies in human
fetuses. Fluorouracilapparently crosses the human placenta, because
maternal administration is associated with fetal immunosuppression.
The few published epidemiologic studies support multiple case
reports of normal pregnancy outcome after early exposure. There is
no evidence of teratogenicity in humans due to fluorouracil, but
other DNA synthesis inhibitors
(e.g., methotrexate and aminopterin) have been associated with
Fetal
teratogenic effects in humans. Little is known about the long-term
Considerations
effects of intrauterine exposure to fluorouracil. Fluorouracil crosses
the rodent placenta and produces a variety of defects involving the
skeleton and palate. It is embryotoxic to the rodent. The
malformations associated with in utero exposure to FAC are highly
variable, but growth deficiency and anomalies of the craniofacial
region and limbs are most common. The pattern appears to be
directly related to the age at and duration of exposure rather than to
the specific drug itself.
There is no published experience in nursing women. It is unknown
whether fluorouracilenters human breast milk. One case report notes
Breastfeeding that fluorouracil was undetectable at any time during and following
Safety chemoradiotherapy, despite maternal plasma concentrations that
exhibited normal pharmacokinetics. Recommend not breastfeeding
for 24–48 h after exposure.
Drug
Leucovorin may enhance the toxicity of fluorouracil.
Interactions
Gwyn KM, Theriault RL. Curr Treat Options Oncol 2000; 3:239-43.
References Hahn KM, Johnson PH, Gordon N, et al. Cancer 2006; 107:1219-26.
Inoue T, Horii I. J Toxicol Sci 2002; 27:79-86.
 Murthy RK, Theriault RL, Barnett CM, et al. Breast Cancer Res
2014; 16:500.

Pregnancy Category: D
Lactation Category: U

•
Summary Fluorouracil should be used during pregnancy and lactation
only if the benefit justifies the potential perinatal risk.
•
Based on animal studies, fluorouracil should not be
administered in the first trimester.
Read full chapter
Therapeutic Drug Monitoring of Selected Anticancer Drugs
Michael C. Milone, in Therapeutic Drug Monitoring, 2012
5-Fluorouracil
5-Fluorouracil exhibits limited effectiveness as a single agent anticancer drug, but it is the
most widely use anticancer agent worldwide, with incorporation into combination
therapies for a range of malignancies of the gastrointestinal tract, the breast and the head and
neck. Following conversion to a pyrimidine nucleotide, 5-fluorouracil exerts its cytotoxic
activity through several mechanisms, including inhibition of thymidylate synthase and
incorporation into DNA and RNA. The effects of 5-fluorouracil can be further enhanced by
administration of leucovorin, which also inhibits thymidylate synthase, and this combination
is frequently used. Numerous administration schemes are currently employed for 5-
fluorouracil and leucovorin with some variation in timing, but there are two general
approaches: continuous intravenous infusion of 5-fluorouracil, or bolus administration
performed over repeated treatment cycles spaced by 1 to several weeks apart. The optimal
administration of 5-fluorouracil that maximizes efficacy with minimized toxicity appears to
depend upon the cancer and the co-administered chemotherapeutic drugs. A thorough
discussion of the various 5-fluorouracil regimens can be found in Chabner and Longo [30].
5-Fluorouracil has been shown to display significant pharmacokineticvariability (%CV of
~ 35% for clearance with 24-hour constant infusion) [61]. Based upon this PK variability,
dose adaptation based upon concentration monitoring has been advocated. In a randomized
concentration-controlled trial of 5-fluorouracil that compared fixed dose to concentration-
adapted dosing, patients who underwent pharmacokinetic-guided (PK-guided) dose
adjustment experienced a statistically significant improvement in their objective response rate
(33.7% in the adjusted-dose group versus 18.3% in the fixed-dose control group).
Although toxicity was primarily grade I/II diarrhea and hand–foot syndrome, there was also a
significant reduction in overall adverse events in the dose-adjusted group [62]. This study
suggests that many patients receiving 5-fluorouracil at tolerable dosing determined by
population-level studies may be receiving too little or too much of the drug. Unfortunately,
this trial used a somewhat unconventional 5-fluorouracil regimen, so the transferability of
their results to other regimens is less clear. Nevertheless, it does support the notion that we
may be able to do better with more individualized dosing of anticancer drugs, including a
drug like 5-fluorouracil that has been in use for over 40 years.
While active concentration monitoring is one potential method of individualization of 5-
fluorouracil therapy, understanding the factors that affect 5-fluorouracil metabolism may be
useful in predicting 5-fluorouracil pharmacokinetic and pharmacodynamic behavior. More
than 80% of a single 5-fluorouracil dose is metabolized rapidly to inactive metabolites, with
only 1–3% converted to active, cytotoxic metabolites through the cells’ normal nucleotide
synthetic pathways (see Fig. 14.2). The rate-limiting enzyme in 5-fluorouracil metabolism is
the enzyme dihydropyrimidine dehydrogenase. Several studies have demonstrated that
dihydropyrimidine dehydrogenase activity is highly variable in the general population, and
3–5% of Caucasians exhibit low dihydropyrimidine dehydrogenase activity. A single
nucleotide polymorphism (SNP) at the splice site between exons 13 and 14 that leads to
skipping of the 14th exon and a non-functional enzyme (known as c.1905+G>A,
IVS14+G>A or DPD∗2A) has been consistently demonstrated to be associated
with dihydropyrimidine dehydrogenase deficiency in Caucasians and severe 5-FU toxicity;
however, dihydropyrimidine dehydrogenase is a large gene with 23 exons and over 7000
SNPs. An association between a number of additional SNPs (e.g., 1679T>9 and 2846A>T)
and dihydropyrimidine dehydrogenase and/or 5-fluorouracil toxicity has been reported
(extensively reviewed in [63]). Of course, additional polymorphisms in genes involved in 5-
fluorouracil action have also been shown to impact 5-fluorouracil efficacy and toxicity, either
directly (thymidylate synthase) or indirectly (methylene-tetrahydrofolate reductase) [64]. It is
clear that an individual’s genetics impacts 5-fluorouracil therapy. The challenge of using this
genetic information prospectively in routine clinical care remains, especially for 5-
fluorouracil with such varied dosing schemes and combinations with other chemotherapeutic
agents.
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FIGURE 14.2. 5-FU metabolism.
5-Fluorouracil enters the pathways of normal pyrimidine nucleotide synthesis leading to the formation of 5-fluoro-
deoxyuridine monophosphate (5-dUMP), which is a potent inhibitor of thymidylate synthase (TYMS). The inhibition
of de novodeoxythymidine monophosphate (dTMP) synthesis from deoxyuridine monophosphate (dUMP) by TYMS
leads to cellular deficiency of dTTP affecting DNA synthesis. Incorporation of 5-fluoro-uridine triphosphate (5-
FUTP) and 5-fluoro-deoxyuridine triphosphate (5-FdUTP) from 5-FU precursor further affects RNA and DNA
synthesis. More than 80% of 5-FU is eliminated by dihydropyrimidine dehydrogenase (DPYD), which is the rate-
limiting enzyme in the metabolism of 5-FU.
Read full chapter
Drug‐Induced and Iatrogenic Neurological Disorders
Katie Kompoliti, Stacy S. Horn, in Textbook of Clinical Neurology (Third Edition), 2007
5‐Fluorouracil
5‐Fluorouracil is a fluorine‐substituted analogue of the pyrimidineuracil. It inhibits the
enzyme thymidylate synthetase, blocking DNA synthesis by
reducing thymidine monophosphate formation. It is associated with a characteristic cerebellar
syndrome in 1% of patients when the recommended doses are used. When doses exceed the
usual recommendations, the incidence of this cerebellar syndrome may be as high as 3% to
7%. The mechanism of 5‐fluorouracilneurotoxicity is unknown, but its conversion to
fluocitrate and fluoacetate in the CNS with subsequent inhibition of the Krebs cyclehas been
postulated.90,103,106 Concomitant administration of α‐interferon, cisplatin, leucovorin, or
thymidine potentiates the toxic effects.90
Clinically, 5‐fluorouracil induces pancerebeller dysfunction, characterized by the acute or
subacute onset of gait ataxia, limb incoordination, dysarthria, nystagmus, and,
sometimes, diplopia(Video 214, Stance Ataxia; Video 228, Saccadic Dysmetria). The
symptoms are usually controlled by dose reduction or increase in intervals between
treatments. Although the syndrome is reversible, cases of re‐emergence after subsequent
treatment have been reported.90,103,106
Other neurotoxic reactions associated with 5‐fluorouracil include encephalopathy, seizures,
as well as a parkinsonian syndrome in 40% of patients.106,107 The encephalopathy is usually
mild to moderate but can range from lethargy to coma with high‐dose infusions. All
the neurological symptoms associated with 5‐fluorouracil are usually reversible on cessation
of the drug, and no pathological changes have been noted in the brain at postmortem
examination.106
Cerebral demyelination has been described with 5‐fluorouracil monotherapy. In a patient who
completed chemotherapy with 5‐fluorouracil, an MRI showed areas of demyelination that
enhanced with contrast. A repeat MRI of the brain was completed in 2 months and showed a
decreased number of demyelinating lesions. The demyelination was felt to be causally related
to partial dihydropyrimidine dehydrogenase deficiency in combination with 5‐fluorouracil
administration.108,109 Ischemic strokes following administration of 5‐fluorouracil and cisplatin
have occurred in five patients. In each, no other cause for stroke could be identified in spite
of an extensive workup. Each patient developed ischemic stroke in the second or third
treatment cycle with development of symptoms in close relation to medication
administration.110Peripheral neuropathy associated with 5‐FU is rare but has been reported
with both 5‐FU and capecitabine, a pro‐drug of 5‐FU, which is rapidly metabolized to 5‐FU
in patients with normal liver function. The neuropathy is reversible upon discontinuation of
the drug but can recur with re‐initiation.111,112
Read full chapter
A worldwide yearly survey of new data in adverse drug
reactions and interactions
Felicity Murphy, Mark Middleton, in Side Effects of Drugs Annual, 2012
Fluorouracil [SED-15, 1407]
5-Fluorouracil (5-FU) is a fluoropyrimidine analogue that was developed more than 50 years
ago and continues to be widely used in the treatment of cancer. Fluorouracil often forms the
backbone of combination chemotherapy regimens and is used in the management
of colorectal cancer and cancers of the breast and respiratory and digestive tracts. In
colorectal cancer, higher response rates and better tolerability are seen from infusions than
bolus regimens and with the addition of leucovorin (folinic acid) [70R]. Fluorouracil is also
used topically to treat basal cell carcinoma.
Mechanism of action Fluorouracil is an analogue of uracil. After entry into cells it
undergoes conversion to active metabolites: fluorodeoxyuridine monophosphate (FdUMP),
fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). FdUMP
directly inhibits thymidylate synthetase, reducing the availability of thymidine nucleotides,
which are required for DNA synthesis, until new enzyme can be synthesized. FUTP is
incorporated into RNA and causes impaired RNA processing and functioning, which disrupts
cellular metabolism and viability [71R].
The rate-limiting step in fluorouracil metabolism is mediated by dihydropyrimidine
dehydrogenase (DPD) which degrades fluorouracil to dihydrofluorouracil (DHFU) in the
liver [2R,70R].
Pharmacokinetics The pharmacokinetics of fluorouracil are non-linear and there is marked
inter- and intra-patient variability. Oral absorption is erratic, with systemic availability of 40–
70%. The primary plasma half-life is 8–14 minutes after a standard bolus dose of 370–
720 mg/m2 but is dose related. As catabolism of fluorouracil by dihydropyrimidine
dehydrogenase is saturable, its clearance decreases with higher doses and with bolus doses
compared with infusions.
The apparent volume of distribution is 8–11 l/m2. Fluorouracil readily penetrates the
extracellular space, including the cerebrospinal fluid and third spaces, such
as ascites and pleural effusions. More than 80% of the dose is broken down by
dihydropyrimidine dehydrogenase in the liver and less than 10% is excreted unchanged in the
urine [72R,73R].
General adverse effects and adverse reactions The main adverse effects of fluorouracil are
hematologic and gastrointestinal. They are generally less common with infusions than bolus
doses [74C]. Dihydropyrimidine dehydrogenase deficiency affects about 5% of patients and is
associated with severe adverse reactions, including grade 3 or 4 mucositis, diarrhea,
and neutropenia. In patients with severe toxicity, further treatment with fluorouracil should
be withheld and testing for dihydropyrimidine dehydrogenase deficiency, an autosomal
recessive condition, performed before considering further dosing [70R].
Cardiovascular Adverse cardiac events occur in 3–8% of patients treated with fluorouracil.
However, up to 50% of patients may have non-specific cardiographic changes, including T
wave changes that can mimic those of myocardial infarction [75A]. Chest pain, with or
without accompanying cardiographic changes, is common, but cardiac enzyme rises are
infrequent. Acute cardiac toxicity presenting with myocardial infarction, left ventricular
dysfunction, tachydysrhythmias and sudden cardiac death has been reported. As symptoms
usually develop during or shortly after intravenous infusion, one postulated mechanism
is coronary vasospasm. Autopsy studies have raised the possibility of myocarditis or
myocardiomyopathy as other potential precipitants.
Cardiac toxicity is most commonly observed during second and subsequent cycles of
treatment. The risk appears to be greater in patients with known ischemic heart disease.
Fluorouracil infusion should be discontinued and treatment includes nitrates or calcium
channel blockers [13R,76R].
Nervous system Fluorouracil can cause acute nervous system toxicity. Acute cerebellar
syndrome affects up to 5% of patients and is usually self-limiting after withdrawal. It can
occur within weeks to months of starting fluorouracil and presents with ataxia, nystagmus,
and dysarthria [77A,78A]. An encephalopathy can occur rarely and is often associated with
markedly raised ammonia concentrations in the absence of underlying liver disease. Ischemic
stroke has also been reported and the risk appears to be increased when fluorouracil is
combined with cisplatin [60R,79c]. Other rare adverse reactions include oculomotor
disturbances, focal dystonia, parkinsonian syndrome, peripheral neuropathy, and seizures
[80R]. Dihydropyrimidine dehydrogenase deficiency also increases the risk of nervous system
toxicity [81A].
Sensory systems Excessive lacrimation is common with fluorouracil and affects 30% of
patients [82A]. Other ocular adverse reactions include blurred vision, ocular irritation and
pain, photophobia, conjunctivitis, circumorbital edema, ectropion, keratitis, and tear
duct stenosis. Most patients can be managed symptomatically
with methylcellulose or dexamethasone eye drops. Occasionally fluorouracil may need to be
withdrawn and the symptoms usually resolve in 1–2 weeks [18R]. Optic neuropathy is rare
[79R].
Hematologic Myelosuppression is dose and schedule related and is more common with bolus
doses than infusions. Leukopenia is more common than thrombocytopenia and the nadir in
the neutrophil count typically occurs at 9–12 days after treatment [72R].
Gastrointestinal Oral mucositis is a dose-limiting adverse reaction to fluorouracil. It affects
40% of patients overall and is grade 3/4 in about 15% [83M,84R]. Prophylactic use of
a chlorhexidine mouthwashor topical cooling with crushed ice can reduce the severity of
symptoms [85c]. Diarrhea is also common and affects up to 40–50% of patients, particularly
with bolus regimens with leucovorin and in combination therapy with oxaliplatin [86C]. In
one phase III trial, the associated death rate was 5%, predominantly in elderly patients with
concomitant leukopenia and bacteremia [87C]. Among patients with colorectal cancer, the
presence of the primary tumor and previous episodes of chemotherapy-related diarrhea are
susceptibility factors for fluorouracil-associated diarrhea [88c]. Algorithms have been
proposed for assessing and managing treatment-induced diarrhea [70R].
Skin Cutaneous reactions to fluorouracil include photosensitivity, erythema, maculopapular
rashes, and hyperpigmentation [89R]. Alopecia is uncommon. Hand–foot syndrome affects
about 50% of patients but it is usually mild. It occurs after a median of nine cycles of
treatment and necessitates dosage reduction or delay in 15% of patients [90r]. It is less
frequent with bolus doses than infusions [83M].
Susceptibility factors Women and patients over 70 years of age are more likely to have more
severe adverse reactions to fluorouracil-based therapy [91c,92R].
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Surgical Management
Antoine Labbé, Christophe Baudouin, in Glaucoma (Second Edition), 2015
Introduction
5-fluorouracil (5-FU) was the first antimetabolite used to increase the success of filtering
surgery by reducing scarring.4 Since this first publication in 1984, and despite numerous
variations in total doses, mean doses and modes of application, the efficacy of 5-FU as
an antifibrotic agent has been clearly demonstrated.3 Originally, in the prospective
randomized multi-center Fluorouracil Filtering Surgery Study (FFSS), 5-FU (10 mg/mL) was
injected subconjunctivally at a dose of 5 mg twice a day during the first 7 postoperative days
and once a day over the next 7 days, for a total dose of 105 mg.5 This regimen has been
progressively modified, and today, in most cases, 5-FU is applied intraoperatively (50 mg/mL
for 5 min) with additional postoperative subconjunctival injections if necessary in case of
excessive scarring.6 In case of failure involving excessive bleb scarring, revision of the bleb
by needling using 5-FU is also possible sometime after filtration surgery.
Read full chapter
Neurologic Complications of Oncologic Therapy
Isabel Arrillaga-Romany, ... Patrick Y. Wen, in Handbook of Neuro-Oncology Neuroimaging
(Second Edition), 2016
5-Fluorouracil
5-Fluorouracil (5-FU) is a fluorinated pyrimidine that disrupts DNA synthesis and is used in
treatment of many cancers, including colon and breast cancers. 5-FU crosses the blood–brain
barrier and the highest concentration is found in the cerebellum, where it is toxic to Purkinje
and granule cells.153 An acute cerebellar syndrome can occur and is characterized by acute
onset of ataxia, dysmetria, dysarthria, and nystagmus.154 Onset begins weeks to months after
initiation of treatment154 and the drug should be discontinued when symptoms emerge.
Complete recovery is the rule. Patients with decreased dihydropyrimidine
dehydrogenase activity are at an increased risk for developing severe neurologic toxicity
following 5-FU chemotherapy.155,156 Other toxicities of 5-FU include
encephalopathy,157,158 optic neuropathy,159 focal dystonia,160Parkinsonian syndromes, eye
movement abnormalities, and cerebrovascular disorders.161 Peripheral neuropathy has also
been reported.162 The mechanism of toxicity might involve damage to myelinated tracts and
altered translational regulation of oligodendrocytes.163 The combination of 5-
fluorouracil and levamisole used to treat colon cancer has been rarely associated with the
development of a multifocal leukoencephalopathy.164Capecitabine, a prodrug that is
metabolized to 5-FU by the enzyme thymidine phosphorylase, is used to treat breast and
gastrointestinal malignancies. Neurologic complications are uncommon, but some patients
experience paresthesias, headaches, and cerebellar symptoms. Several cases of
neuropathies165,166 and multifocal leukoencephalopathy have also been described.167
Read full chapter
Immunomodulating Pharmaceuticals
Gideon P. Smith, Edwin S.L. Chan, in Clinical Immunology (Fifth Edition), 2019
5-Fluorouracil
5-Fluorouracil is a uracil analogue that has two modes of action. First, it inhibits cell
proliferation via direct incorporation into RNA causing abnormal base pairing. Second, it
binds thymidylate synthetase, blocking the conversion of deoxyuridine
monophosphateto deoxythymidine monophosphate, which is essential to DNA synthesis. It
may also increase expression of p53, a frequently mutated gene in nonmelanoma skin
cancers.28 It can be administered topically, intramuscularly, or intravenously. In topical form,
its main uses are to treat actinic keratosis, superficial basal cellcarcinoma, Bowen
disease, keratoacanthoma, porokeratosis, and verruca vulgaris. However, intravenous
treatment of recalcitrant psoriasis, mycosis fungoides, and scleroderma has also been
reported.
Adverse Effects
Topical application is associated with an irritant dermatitis, but this is also seen as a marker
of clinical efficacy. Parenteral administration for inflammatory conditions is not widespread;
adverse effects from parenteral administration are more severe and include clinically
significant bone marrow suppression, GI toxicity, and cutaneous reactions.
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