Curr. Med. Chem.

- Anti-Cancer Agents, 2002, 2, 267-310 267

The Prodrugs of 5-Fluorouracil

M. Malet-Martino*, P. Jolimaitre and R. Martino

Groupe de RMN Biomédicale, Laboratoire des IMRCP (UMR CNRS 5623), Université Paul Sabatier, 118, route de
Narbonne, 31062 Toulouse Cédex, France

Abstract: Although 5-fluorouracil (FU) was first introduced in 1957, it remains an essential part of the treatment of
a wide range of solid tumors. FU has antitumor activity against epithelial malignancies arising in the
gastrointestinal tract, breast as well as the head and neck, with single-agent response rates of only 10-30%.
Although FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than a third of
patients achieve objective responses. Recent research has focused on the biomodulation of FU to improve the
cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer
agents, FU leads to several toxicities. The toxicity profile of FU is schedule dependent. Myelotoxicity is the major
toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis,
neuro- and cardiotoxicity are associated with continuous infusions. Other adverse effects associated with both
bolus-dose and continuous infusion regimens include nausea and vomiting, diarrhea, alopecia and dermatitis. All
these reasons explain the need of more effective and less toxic fluoropyrimidines.
In the first part of the review, we briefly present the metabolic pathways of FU responsible for the efficacy and
toxicity of the drug. This knowledge is also necessary to understand the target(s) of the biomodulation.
The second part is devoted to a review of the literature on the various prodrugs of FU, including 5’-deoxy-5-
fluorouridine, capecitabine, BOF-A2, ftorafur, UFT, and S-1. The promising approach of gene directed enzyme-
prodrug therapy is also presented. A brief survey of antibody directed enzyme-prodrug therapy and some new FU
prodrugs concludes the paper. The pharmacological principles that have influenced the development of these new
drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity
and toxicity, are presented.

5-FLUOROURACIL
5-fluorouracil (FU) (Fig. (1)) is an example of a
rationally designed anticancer agent. The observation that rat
hepatomas utilize radiolabelled uracil more avidly than
nonmalignant tissues implied that the enzymatic pathways
for utilization of uracil differ between malignant and normal
cells [1]. Heidelberger et al. [2] thus synthesized FU in 1957
as an antimetabolite agent. In this molecule, the hydrogen
atom in position 5 of uracil is replaced by the similar sized
atom of fluorine, and was designed to occupy the active sites
of enzyme targets thereby blocking metabolism in malignant
cells. Although this antimetabolite is toxic, its efficacy
makes it one of the most widely used agents against solid
tumors. As several reviews have been devoted to FU [3-13],
we present briefly the main features of its metabolism,
mechanism of action, and clinical uses.
1. Metabolism of FU
After penetration into the cell, FU is metabolized via two
routes in competition with each other: the anabolic route,
*Address correspondence to this author at the Groupe de RMN
Biomédicale, Laboratoire des IMRCP (UMR CNRS 5623), Université Paul
Sabatier, 118, route de Narbonne, 31062 Toulouse Cédex, France; Tel:
(33) 561-55-6271; Fax: (33) 561-55-7625; E-mail: martino@chimie.ups-
tlse.fr
which gives rise to the active metabolites, and the catabolic
route, which inactivates FU and leads to elimination of the
drug from the organism.
1.1. The Anabolic Route
The anabolism of FU is rather complex (Fig. (2)) with
various parallel reactions, identical to the de novo pathways
followed by uracil.
Initially, FU can react in the following three ways. The
first, that is quantitatively the least significant, leads in two
stages to the formation of 5-fluoro-2'-deoxyuridine-5'-
monophosphate (FdUMP). First, addition of deoxyribose-1-
phosphate onto FU under the action of thymidine
phosphorylase (TP) leads to 5-fluoro-2'-deoxyuridine
(FdUrd). It is followed by phosphorylation by thymidine
kinase giving rise to FdUMP, a recognized inhibitor of
thymidylate synthase (TS).
The other two routes both form 5-fluorouridine-5'-
monophosphate (FUMP). In one, it is produced directly in a
single stage; under the action of orotate phosphoribosyl
transferase (OPRT), a ribose 5’-monophosphate from 5’-
phosphoribosyl-1-pyrophosphate (PRPP) is transferred to the
N1 of FU to give FUMP. The second occurs in two stages;
in a first step, a ribose is grafted onto FU under the action of
uridine phosphorylase to give 5-fluorouridine (FUrd), which
is then phosphorylated into FUMP by uridine kinase.

1568-0118/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd.

268 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

O
H C
N O
O O
F F F
O NH NH NH
F
4 3 NH
5 HOH2 C N O N O N O
H3 C H3 C
6 1 2 O O O
N O
H
OH HO OH HO OH
FU FdUrd 5'dFUrd CAP

O O O O O
NC
F C F F
N NH NH NH
O
C O N O C
N O N O N O N O
O O
O H
O

BOF-A2 FTO U
FTO

UFT

O
F OH O NH 2
NH
Cl F
N NH NH
N O
O
N OH N O N O
-OOC H H

FTO CDHP OXO FC

S-1

Fig. (1). Structures of 5-fluorouracil and its prodrugs.

FUMP can then undergo two successive phosph- 1.2. The Catabolic Route
orylations. Under the action of pyrimidine monophosphate
After administration of FU, more than 80% of the
kinase, 5-fluorouridine-5'-diphosphate (FUDP) is formed,
injected dose are degraded according to the scheme shown in
which via the action of pyrimidine diphosphate kinase leads
Fig. (3). The catabolism of FU is identical to the natural
to 5-fluorouridine-5'-triphosphate (FUTP) that can be
reduction route of the pyrimidines, uracil and thymine.
incorporated into RNA instead of uridine-5’-triphosphate
(UTP). FUTP can be conjugated to sugars giving FU- The first stage of this degradation occurs very rapidly;
nucleotide sugars (FUDP-sugars) under the action of UDP under the action of dihydropyrimidine dehydrogenase (DPD)
glucose (or N-acetylglucosamine) pyrophosphorylase. and in the presence of the reduced form of nicotinamide
adenine dinucleotide phosphate (NADPH), FU is reduced to
After the first phosphorylation of FUMP into FUDP,
5,6-dihydro-5-fluorouracil (FUH2). This first stage effectively
ribonucleotide reductase dehydroxylates the ribose of FUDP
governs the rate at which FU is available for anabolism. The
in position 2' to give 5-fluoro-2'-deoxyuridine-5'-diphosphate
pyrimidine ring of FUH2 is then cleaved between positions 3
(FdUDP). FdUDP is also formed by phosphorylation of
and 4 to give α-fluoro-β-ureidopropionic acid (FUPA). A
FdUMP. FdUDP is then dephosphorylated to FdUMP or
third stage leads to the formation of α-fluoro- β-alanine
phosphorylated to 5-fluoro-2'-deoxyuridine-5'-triphosphate
(FBAL), the major catabolite of FU, by the concomitant
(FdUTP) via pyrimidine monophosphate kinase and
release of ammonia from nitrogen 3 and carbon dioxode from
pyrimidine diphosphate kinase respectively. FdUTP acts as a
carbon 2 of the former pyrimidine ring. Urea is formed in the
substrate for DNA polymerases and can thus be incorporated
urea cycle from ammonium ion (NH4+) and carbon dioxide
into DNA.
(CO2).
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 269

O O
F F
NH NH
uridine
HO N O H N O
O phosphorylase H
FU
OH OH orotate
FUrd phosphoribosyl thymidine
uridine transferase (+ PRPP) phosphorylase
O O
kinase
F F
NH NH
OH
HO P O N O HO N O
O O
O

OH OH OH
FUMP FdUrd
pyrimidine thymidine
monophosphate kinase
kinase
O O O
F F F
NH NH NH
OH OH OH OH OH
HO P O P O N O HO P O P O N O HO P O N O
O O O
O O O O O
ribonucleotide pyrimidine
reductase monophosphate
OH OH OH kinase OH
FUDP FdUDP FdUMP
pyrimidine pyrimidine
diphosphate diphosphate
kinase kinase
O O ternary complex
F F FdUMP-thymidylate
NH NH
OH OH OH OH OH OH synthase-folate
HO P O P O P O N O HO P O P O P O N O
O O
O O O O O O

OH OH OH
FUTP FdUTP

RNA polymerase UDP glucose DNA polymerase

phosphorylase

THYMIDYLATE SYNTHASE
RNA INCORPORATION DNA INCORPORATION
INHIBITION

O dUMP X dTMP
F
NH
OH OH
Sugar P O P O N O
O
O O

FUDP-sugar OH OH

Fig. (2). Intracellular anabolism of 5-fluorouracil. All the compounds are represented in neutral form.

Most of the catabolic schemes of FU stop at these - fluoride ion (F -), that stems from enzymatic cleavage of the
metabolites, although recent studies using more C-F bond of FBAL [14, 15];
sophisticated analytic methods have identified other
catabolites of FU including:
270 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

O O H2O
O OH
NADPH NADP+ F F
F C
NH NH NH 2
H H
H H
H N O N O N O
H H H H H
NADPH NADP+
FU FUH2 H2O FUPA
dihydropyrimidine
dehydrogenase dihydropyrimidinase

b-ureido-
propionase H2O

H2O HCO3-

-O C HN CH2 CH C OH H2N CH2 CH C OH + NH 3 + CO2

O F O F O
H+
CFBAL H2O HCO3- FBAL

H2N C NH 2
O
urea
alanine-
N-acylCoA
glyoxylate
transferase alanine
transferase
transaminase (?)

F-
FBAL conjugates with bile acids

NADH NAD+ CO2

HO C CH2 H C CH2 H C CH C OH
O F O F O F O
NADH NAD+
FAC Facet FMASAld

NADH NADH

NAD+ NAD+

HO CH2 CH C OH
F O
FHPA

Fig. (3). Catabolic pathway of 5-fluorouracil. All the compounds (except CFBAL) are represented in neutral form. FMASAld,
fluoromalonic acid semi-aldehyde; Facet, fluoroacetaldehyde.

- N-carboxy-α-fluoro-β-alanine (CFBAL) derived from the 2. Mechanism of Action of FU

N-carboxylation of FBAL in the presence of bicarbonate ions
(HCO3). This reaction is an equilibrium [16];
- three conjugates of FBAL with bile acids [17, 18];
- two metabolites of FBAL by transamination: 2-fluoro-3-
hydroxypropanoic acid (FHPA) and fluoroacetate (FAC) [19,
20].
As seen above, one of the routes of metabolism of FU
gives rise to FUTP. The atom of fluorine replacing the
hydrogen on position 5 of uracil is of comparable size, and
during transcription, this fluoronucleotide thus mimics UTP
and is recognized by RNA-polymerases. This leads to the
incorporation of FU in all classes of RNA. It is thought that
the full cytotoxicity stems from a combination of the
numerous modifications of RNA due to incorporation of FU
rather than alteration of a single function.
The Prodrugs of 5-Fluorouracil
The second way of activation of FU by the formation of
FdUMP could be the most significant. Indeed, this
fluoronucleotide is an inhibitor of TS, which is involved in
the synthesis of DNA. TS is an obvious target for cytotoxic
agents since thymidine is the only nucleotide precursor
specific to DNA. In the presence of the cofactor 5,10-
methylene tetrahydrofolate (MeTHF) serving as the methyl
donor, TS and 2’-deoxyuridine-5’-monophosphate (dUMP)
form a ternary complex, that enables transfer of a methyl
group on carbon 5 of dUMP to form thymidine-5'-
monophosphate (dTMP). Following FU exposure and
adequate FdUMP formation, the methyl transfer does not
take place because the fluorine atom in the C5 position of
FdUMP is much more tightly bound than hydrogen. The
enzyme is then trapped in a slowly reversible ternary
complex. The presence of MeTHF (or its polyglutamates) is
essential for tight binding of FdUMP to TS. The formation
of dTMP is therefore blocked, thereby decreasing the
availability of thymidine-5'-triphosphate (dTTP) for DNA
replication and repair. The “genotoxic stress” resulting from
TS inhibition may activate programmed cell death pathways.
Throughout the seventies, it was believed that the
anticancer effect of FU was the result of the two previous
mechanisms. Later, it has been reported that two other
mechanisms can be partly responsible for the cytotoxic effect
of FU. The first one is the incorporation of FU into DNA.
Uracil is not a normal constituent of DNA, and various
enzymes protect DNA from incorporating this pyrimidine :
- deoxyuridine triphosphate pyrophosphorylase that hydro-
lyses 2’-deoxyuridine-5’-triphosphate (dUTP) into dUMP;
- uracil-DNA-glycosylase that recognizes and excises uracil
from DNA.
However, FdUTP is not thought to be recognized by the
first enzyme, and is thus not dephosphorylated and can be
incorporated into DNA; the second enzyme is not thought to
recognize FU and will thus not excise it from DNA strands.
The second mechanism is the alteration of the membrane
function of FU-treated cells. This is related to a decrease in
glycoprotein synthesis that is suggested to be due to the
formation of FUDP-sugars and their incorporation into
membranes.
The extent to which any of these pathways predominates
in human tumors is unknown and is likely to vary across
tumor types and with different modes and doses of drug
administration. Recent studies suggest that more prolonged
exposure to low doses of FU leads to cell death primarily via
the TS-directed mechanism, whereas bolus administration of
FU results primarily in an RNA-mediated process of cell
death [21-23].
3. Limitations of the Activity of FU
The activity of FU is markedly limited by its rapid
degradation into FUH2 via the action of the cytosolic enzyme
DPD, the first enzyme in the catabolic cycle of FU (Fig.
(3)). It has been demonstrated that this enzyme deactivates
more than 85% of the injected dose of FU. Little drug is
Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 271
thus left for anabolism. Moreover, there is considerable
variability in the activity of this enzyme between both
normal and tumor tissues within a patient and between
different patients [24, 25]. The bioavailability of FU,
especially after oral administration, is thus unpredictable. In
some cases, DPD possesses strong activity, little FU will be
available and its efficiency will be consequently low. On the
other hand, if DPD possesses weak activity, levels of FU
will be elevated, which may lead to toxicity from overdose.
There are also several other determinants of cellular
sensitivity to FU. Among these, the activity of enzymes
involved in FU anabolism, the availability of cofactors
necessary for FU activation (e.g. PRPP), the level of TS
activity or expression, the size of intracellular reduced folate
and endogenous dUMP pools, the extent of FUTP
incorporation into RNA and FdUTP into DNA, and the
intratumor activity of DPD have been identified as important
in determining response to FU chemotherapy in patients
with solid tumors [26].
4. FU in Chemotherapy
Since its introduction more than 40 years ago, FU has
become a component of the standard therapy for a variety of
malignancies, including gastrointestinal cancers, head and
neck cancer, and breast cancer.
FU is a small molecule with a pK A (8.0) that should
predict excellent absorption and bioavailability. However,
the use of oral FU was abandoned decades ago because of its
irregular absorption. Plasma levels of FU are quite
unpredictable after oral administration with marked intra- and
inter-individual differences due to the variable activity of
DPD, especially in the gastrointestinal mucosa [27, 28].
This effectively rules out oral treatment with FU.
Until recently, the standard regimen for treatment with
FU was 400-600 mg/m2 administered by intravenous (i.v.)
bolus once a week for six weeks, or for five consecutive days
every 4 or 5 weeks. However, since the t1/2 of FU is low (5
to 20 min) [29], tumor cells are only exposed to the active
principle for a short time. The development of permanent
venous access devices and portable infusion pumps has
allowed continuous infusion of FU over prolonged periods,
designed to prolong exposure of cells to the drug and so
confer higher activity [30, 31]. Indeed, the initial clinical
results bore out this assumption and showed a two-fold
increase in response rate for continuous infusion compared to
treatment by bolus, with a comparable survival [32]. In
1998, a meta-analysis of six randomized trials on 1219
patients with colorectal cancers treated by continuous i.v.
infusion of FU over 120 h or i.v. bolus was published [33].
The response rate was clearly higher for the first than for the
second regimen (22% vs 14%). Median survival time (MST)
was comparable for the two treatments (12.1 months with
bolus treatment vs 11.3 months with infusional therapy).
The toxicity profile of FU is schedule dependent. For the
bolus regimen, toxicity included myelosuppression, oral
mucositis, and gastrointestinal disturbances (diarrhea,
nausea, vomiting) due to phosphorylation of FU into FUMP
272 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2
by OPRT in the digestive tract [34]. For the continuous
regimen, toxic reactions included the hand-foot syndrome
(HFS; i.e. dermal pain in hands and feet) observed in many
cases, but less hematologic and gastrointestinal toxicity.
Cardiotoxicity and neurotoxicity may be observed during
treatment with FU (2 to 5% of cases), but symptoms
disappear on stopping the treatment, and resumption of
treatment with a lower dose is generally well tolerated.
The treatment by continuous i.v. infusion thus presents
advantages compared to the treatment by bolus i.v., with
respect to both rate of response and toxicity, although mean
survival is no better. Despite these benefits, the complex
nature of the treatment (requirement for continuous infusion
pumps), its high cost and the added risks mean that it is
relatively little used and the conventional treatment is still
by i.v. bolus.
To increase the activity of FU, various authors have
proposed utilization of biochemical modulators. A
biochemical modulator is a pharmacological agent designed
to enhance the biological effect of the chemotherapy either by
selectively increasing the antitumor action or by selectively
protecting the host. A FU modulator can act at two levels,
(i) on the anabolic pathways, which will increase selectively
the antitumor activity, or (ii) on catabolism to enhance
bioavailability of the active principle as well as minimize
toxic effects.
Several agents modulating the metabolism of FU have
been tested. The most efficient during treatment with FU is
the calcium salt of folinic acid, also called leucovorin (LV).
LV is an intracellular source of reduced folates, which
stabilize the ternary complex that they form with TS and
FdUMP, and thus increase and prolong the inhibition of TS
and so enhance the efficacy of the drug. This modulator thus
acts on the anabolism of FU.
The modulation of FU by LV has been extensively
developed and a meta-analysis of 1381 patients in nine
randomized clinical trials has clearly demonstrated its
superiority over bolus FU with a response rate of 23% vs
11%. However, this improvement in response rates failed to
convey a significant survival advantage; MST in patients
treated with FU alone was 11 months, compared with 11.5
months in those given FU plus LV [35].
At the present time, the combination FU/LV is
considered the standard chemotherapy for colon cancer in
both advanced disease and in the adjuvant setting. The two
common regimens, which often serve as the control arms for
phase III trials evaluating new agents in colorectal cancer, are
(i) FU (370-425 mg/m2/d) + LV (low dose 20 mg/m 2/d or
high dose 200 mg/m2/d) administered by i.v. bolus during 5
consecutive days every 4 to 5 weeks [36], and (ii) FU (600
mg/m 2/week) + LV (500 mg/m2/week) administered by i.v.
bolus during 6 consecutive weeks and repeated every 8 weeks
[37].
Although these two regimens are associated with similar
response rates and survival, the toxicities observed with each
regimen differ. Dose-limiting toxicity associated with the
daily administration is primarily mucositis and neutropenia
Malet-Martino, et al.
(affecting 24 and 29% of patients, respectively), whereas the
predominant toxicity seen in patients on the weekly regimen
is diarrhea (32% of patients) [38]. 20-30% of the patients on
these FU/LV regimens require hospitalization for toxicity-
related events.
5. Conclusion
As discussed above, FU is relatively efficient, but has
numerous drawbacks. First of all, it is relatively toxic,
causing myelosuppression and gastrointestinal disorders, due
mainly to phosphorylation of FU in the digestive tract.
Toxicity also derives from the lack of selectivity of the drug
towards tumors. Its efficiency is limited by the short t1/2 of
FU in plasma, by its low bioavailability due to the activity
of DPD and by the resistance to FU of some tumors with
strong expression of TS, or low reserves of reduced folates.
Its mode of administration is also a problem. Any i.v.
administration, whether by bolus or continuous infusion,
requires the presence of the patient in hospital, whereas oral
treatment can be taken at home with a corresponding
reduction in stress. Furthermore, i.v. administration is not
without risk of complications (venous thrombosis or
infection round the catheter).
For these reasons, one of the challenges of cancer research
is the development of prodrugs of FU that diminish or
circumvent some of these disadvantages: reduction in
toxicity by avoiding certain routes of degradation (prodrug
not being a substrate for the enzymes of degradation) or by
targeting the tumor site (prodrugs that liberate the active
principle selectively in tumor cells); enhancement of activity
by reducing catabolism (use of DPD inhibitors) or by
increasing anabolism; improvement in quality of life of the
patient by developing oral prodrugs.
PRODRUGS OF FU
1. What is a Prodrug?
A prodrug is defined as a pharmacologically inactive
compound that is converted into an active agent by a
metabolic biotransformation. The objective is a chemical
modification of the antitumor agent to render it temporarily
inactive. In vivo, via the action of enzyme(s), this prodrug
decomposes liberating the active principle. In most cases, a
judiciously selected chemical group is bound covalently to
the active principle. This group must be non-toxic,
biologically inactive and labile in vivo. This group will often
govern the solubility of the prodrug, its stability, the rate at
which it liberates the active principle and the particular
enzyme(s) required for its transformation.
The prodrugs of FU are characterized by a pyrimidine
ring with a fluorine atom in position 5. They differ from FU
in a variety of chemical alterations. Their main benefit is that
of oral administration. They are designed to be well absorbed
intact from the gastrointestinal tract and subsequently
enzymatically converted into FU in the liver or within the
tumor itself in order to expose the tumor to FU for a longer
time but at lower concentrations than those observed after an
The Prodrugs of 5-Fluorouracil
i.v. bolus, hence minimizing toxicity. New orally
administered fluoropyrimidines thus provide protracted FU
delivery, which offers advantages that include schedule
flexibility and a reduction in professional health care resource
requirements, administration costs, and toxicity-related
hospitalization. These advantages may reduce the overall cost
of treatment [39].
In a study of 103 patients, 89% stated a preference for
oral therapy. Reasons for this choice included convenience
and fewer problems with venous access. Nevertheless, 70%
of survey respondents were unwilling to accept a lower
response rate with oral therapy [40]. Thus, although
convenience is an important potential advantage, therapeutic
equivalence or superiority is required for oral agents.
Each agent has been developed according to a
specification with a well-defined mechanism for liberation of
the active principle. Some are designed to function alone and
others require coadministration of a modulator. The aim is to
mimic the pharmacokinetics of FU administered by
continuous i.v. infusion, not only by virtue of their chemical
structure but also by careful choice of dosage.
2. Prodrugs in Clinical Trials or Already Used in Clinic
Over the years many attempts have been made to
synthesize more effective fluoropyrimidine drugs. FdUrd
(Floxuridine® ; Fig (1)) represents the first generation. It is
much more efficiently metabolized by the liver than FU,
which explains why its major clinical use is hepatic arterial
administration for liver metastases of colorectal cancer [41].
Even if severely compromised by the FdUrd induced
hepatoxicity, it has been demonstrated in a meta-analysis of
randomized trials that hepatic arterial administration of
FdUrd is superior in terms of response rate and survival to
i.v. treatment [42]. Recently, a high response rate (74%) was
observed when colorectal cancer patients with unresectable
hepatic metastases were treated with concurrent systemic
CPT-11 and hepatic arterial infusion of FdUrd and
dexamethasone [43].
Ftorafur and 5’-deoxy-5-fluorouridine, the second
generation, were developed with the hope of permitting oral
administration. The third-generation compounds include the
enzymatically activated prodrug capecitabine and the DPD
inhibitory compounds (UFT, eniluracil, S-1, and BOF-A2).
The industrial sponsor of eniluracil having discontinued
development of the drug in 2000, further clinical trials of the
FU/eniluracil have been abandoned [44, 45]. The studies
conducted with this drug will not be reviewed. Several
reviews on the new fluoropyrimidine agents have been
recently published; only some of the most recent are cited
[44-56].
2.1. 5’-Deoxy-5-Fluorouridine
5'-deoxy-5-fluorouridine (5'dFUrd) was synthesized in
1979 by Cook et al. [57]. It is commonly called
doxifluridine or Furtulon ® and has a molecular structure
consisting of a molecule of FU to which a pseudopentose is
Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 273
bonded in position 1 (Fig. (1)). This compound cannot be
phosphorylated and cannot, therefore, be incorporated into
nucleic acids without prior metabolic transformation into
FU. The rationale for its development has been the need of
the enzyme TP, a tumor-associated angiogenesis factor [58],
for cleavage into FU, and thus activation. The high level of
this enzyme in tumors and in the intestinal tract compared
with normal proliferating tissues [59, 60] left hope for an
enhanced selectivity. However, very high activity of TP is
found in normal human liver. Moreover, high levels of this
enzyme also predict for resistance to FU, the active
metabolite of 5’dFUrd, making the rationale a bit shaky. It
has been shown recently that the human concentrative
nucleoside transporter (hCNT1) is involved in 5’dFUrd
uptake, and that its expression may increase cell sensitivity
to 5’dFUrd treatment [61].
The first clinical trials of 5’dFUrd with an i.v.
administration has indicated good activity for colorectal
cancers, but at the expense of marked neurological and
cardiac toxicity. Its development has been discontinued until
it can be made available in an oral formulation, which
appears to avoid the neurological and cardiac complications.
The phase II trials conducted with this drug are listed in
Table 1. The toxicity from an oral regimen is essentially
gastrointestinal (nausea, diarrhea) due to the formation of FU
in the gastrointestinal tract rich in TP. Nevertheless, the
lower toxicity after oral administration has rekindled interest
in this prodrug of FU. Even if 5’dFUrd is no more
employed in Europe and USA, numerous clinical studies are
still underway in Japan.
To determine if the expression of TP might be used to
predict the response to 5’dFUrd chemotherapy, endoscopic
biopsies were performed in 41 patients with inoperable
advanced gastric carcinoma. The response rate among
patients whose tumors were positive for TP expression
(57%) was higher than that among patients whose tumors
were negative for TP expression (0%) [80].
5’dFUrd has been the object of two recent Japanese phase
III trials in gastric cancer patients. A phase III randomized
study investigated effects of supportive chemotherapy with
oral 5’dFUrd (800 mg/body/day, 75 patients, group A) or
oral FU (200 mg/body/day, 75 patients, group B) in
advanced gastric cancer when intensive chemotherapy was
not an option. Group A patients with prior chemotherapy
tended to have longer survival and hospital-free survival and
significantly longer time to progression [81].
These results were supported in a larger randomized phase
III study comparing oral 5’dFUrd and oral FU in gastric
cancer patients as postoperative adjuvant chemotherapy.
Patients (245) from group A were treated with daily 5’dFUrd
at a dose of 460 mg/m 2/day for two years. Patients (237)
from group B received daily FU at a dose of 115 mg/m2/day
for two years. 5’dFUrd was more effective in reducing
peritoneal recurrence than FU. Moreover, patients from
Group A with Stage III or IIIb had more favorable disease-
free survival curves and survival curves than those from
Group B with similar stages [82].
274 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

Table 1. Phase II Trials on Patients Treated with Oral 5'dFUrd

Other(s) Median duration of

Response rate
Number of evaluable compound(s) and/or response (MDR)
Studies 5’dFUrd dose (95% confidence Main side-effects
patients, disease treatment Median survival
limit interval)
administered time (MST)

anorexia
Shimizu et al . (1984) 15 non-small-cell 0.8 g/m 2 /d (>4
0% diarrhea
[62] lung cancer weeks)
nausea

140 gastric cancer 14%

Niitani et al . (1985)
76 colorectal cancer 0.8-1.2 g/m 2 /d 9% diarrhea
[63]
103 breast cancer 36%

2.25 g/d in 3 doses

Falcone et al . (1994) 36 (>69 y) 14% MDR 37 w diarrhea
for 4 consecutive
[64] colorectal cancer a
(5%-29%) MST 40 w nausea, vomiting
days every week

1.2 g/m 2 /d LV 25 mg/dose

Colleoni et al . (1995) 32 16% MDR 2 m
for 5 consecutive 2h before 5’dFUrd diarrhea
[65] biliary tract cancer b
(5%-33%) MST 8 m
days every 10 days (levo-LV)

108 (U) 32% (U) MDR 4 m

1.2 g/m 2 /d LV 25 mg/dose
Bajetta et al . (1995) colorectal cancer (21%-45%) MST 14 m
for 5 consecutive 2h before 5’dFUrd diarrhea
[66] (62 untreated (U), (P) 13% (P) MDR 4 m
days every 10 days (levo-LV)
46 pretreated (P)) (5%-26%) MST 12 m

31 ( ≥70 y) 2.25 g/d in 3 doses

Baldini et al . (1996) 13%
non-small-cell lung for 4 consecutive MDR 55.5 w diarrhea
[67] (4%-30%)
cancer days every weekc

0.75 g/m 2 twice daily LV 25 mg/dose

Bajetta et al . (1996) 60 17% MDR 5 m
for 4 consecutive 2h before 5’dFUrd diarrhea
[68] colorectal cancer (8%-28%) MST 11 m
days every 12 days d (levo-LV)

1.2 g/m 2 /d
34 for 5 consecutive LV 25 mg/dose
Bajetta et al . (1997) 12%
colorectal cancer FU days followed by 5 2h before 5’dFUrd MDR 6 m diarrhea
[69] (1%-23%)
resistant days off (levo-LV)
5 cycles

1 g/m 2 /d in 2 doses MST

34 LV 20 mg/dose
Neri et al. (1998) [70] every 2 days for 6 35% responders 17.1 m
colorectal cancer 2h before 5’dFUrd
months non-responders 6.5 m

0.6 g/m 2 twice daily LV 25 mg/dose

Bajetta et al . (1998) 73 (>70 y) 26% MDR 7 m diarrhea
for 4 consecutive 2h before 5’dFUrd
[71] breast cancer e
(17%-45%) MST 24 m nausea, vomiting
days every 12 days (levo-LV)

1.2 g/m 2
Ahn et al . (1998) 19 28%
d 1-4 and d 15-18 cisplatin 70 mg/m2 MST 25 w
[72] gastric cancer (10%-54%)
every 4 weeks

24 2.25 g/d in 3 doses

Lencioni et al . (2000) 17% diarrhea
hepatocellular for 4 consecutive MST 7 m
[73] f
(5%-37%) nausea, vomiting
carcinoma days every week

0.8-1.2 g/m 2 /d every

Takahashi et al. 140
day for at least 4 14% MST 12.4 m
(2000) [74] gastric cancer
weeks

57 MITg 8 mg/m 2 iv
Iino et al. (2000) [75] anthracycline-resistant 0.6 g/d every 4 weeks 26% MDR 32+ w leukopenia
breast cancer MPAg 0.6 g/d
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 275

(Table 1) contd….

Other(s) Median duration of

Response rate
Number of evaluable compound(s) and/or response (MDR)
Studies 5’dFUrd dose (95% confidence Main side-effects
patients, disease treatment Median survival
limit interval)
administered time (MST)

mitomycin
6 mg/m 2 iv d1
54 leukopenia
0.6 g/m 2 VP 16 75 mg/m2 oral
Kim et al. (2001) [76] anthracycline-resistant 41% MDR 15.6 m thrombocytopenia
d 1-21 d 2, 4, 6
breast cancer gastrointestinal
MPAg 400 mg/m2
oral d 1-21

Group A: 84%
sizofilan 40 mg/w in diarrhea
Yamamoto et al. 37 (19 + 18) Group A: 0.6 g/d (60%-97%)
1 or 2 im injections nausea, vomiting
(2001) [77] uterine cervix cancer Group B: 0.8 g/d Group B: 100%
radiotherapy leukopenia
(82%-100%)

cisplatin
Tong et al. (2001) 13 1.2 g/d diarrhea
3.5 mg/m2 /d iv 46% MST 320 d
[78] gastrointestinal cancer d 1-10 every 2 weeks nausea, vomiting
d 1-5 every 4 weeks

LV 30 mg/d
Seong et al. (2001) 21 0.9 g/d every 8 h every 8 h, d 1-35
86% diarrhea
[79] rectal cancer d 1-35 radiotherapy
(45 Gy) over 5 w

a
median duration of treatment, 9 weeks (range 0-53)
b
median duration of treatment, 10 cycles per patient
c
median duration of treatment, 15 weeks (range 3-80)
d
median duration of treatment, 7 courses (range 1-15)
e
median duration of treatment, 10 cycles (range 1-15); response assessed after 5 cycles
f
median duration of treatment, 10 cycles (range 2-72); response assessed after 8 weeks
g
MIT : mitoxantrone; MPA: medroxyprogesterone acetate

Another recent Japanese trial reported a randomized
controlled study comparing 5’dFUrd combined with
cyclophosphamide (CP) and medroxyprogesterone acetate
(MPA) to a standard regimen of CP, adriamycin, FU and
MPA as first-line chemotherapy for advanced/recurrent breast
cancer. Response rates (RR) and MST were comparable in
both arms, but the incidence of adverse reactions was lower
in the therapy with 5’dFUrd [83].
28 patients with advanced rectal cancer were randomized
to i.v. FU/LV (450 and 20 mg/m2 respectively, administered
for 5 consecutive days during the first and fifth weeks of
radiation therapy; 14 patients) or oral 5’dFUrd/LV (700 and
20 mg/m2 respectively, given daily with radiation treatment;
14 patients). Tumor responses were 71% in the i.v. arm and
57% in the oral arm. Gastrointestinal toxicity was 14% in
the i.v. arm vs 36% in the oral arm. Stomatitis was only
observed in the i.v. arm. Hematological toxicity was 21% in
the i.v. arm and 29% in the oral arm. Therefore, oral
5’dFUrd-based chemotherapy as preoperative chemoradiation
for advanced rectal cancer did not show any significant
advantages over i.v. infusion of FU [84].
2.2. Capecitabine
N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine, more
commonly called capecitabine (CAP) (Fig. (1)) or Xeloda® ,
is a cytotoxic agent that is administered orally and should be
activated preferentially in tumors. This carbamate of
fluoropyrimidine was synthesized in the 1990s by Japanese
researchers [85] as an oral formulation designed to
circumvent the unacceptable toxicity of 5'dFUrd. As
mentioned above, the main limitation of 5'dFUrd derives
from its gastrointestinal toxicity, attributed to liberation of
FU in the small intestine under the action of TP [86]. CAP
was thus designed as a prodrug of 5'dFUrd that could not be
metabolized by TP in the intestine.
Indeed, after oral administration, CAP crosses the
gastrointestinal barrier intact and is rapidly and almost
completely absorbed [87, 88]; diarrhea should not thus occur
with its use. It is subsequently converted into FU in a three-
stage mechanism involving several enzymes (Fig. (4)). In a
first step, it is metabolized into 5'-deoxy-5-fluorocytidine
(5'dFCR) by hepatic carboxylesterase. 5'dFCR is then
deaminated into 5'dFUrd by cytidine deaminase mainly
localized in liver and tumor tissues. Finally, 5'dFUrd is
transformed into FU under the action of TP, an enzyme with
higher activity in tumor that in normal tissues. Higher levels
of FU are thus produced within tumors with minimal
exposure of healthy tissue to FU [89]. It must be underlined
that a high phosphorylase activity is good for activation of
CAP to FU, but bad for activation of FU nucleoside
derivatives up to the fluoronucleotides level (Fig. (2)). This
reaction is in fact bi-directional, but the main direction is
toward breakdown of the nucleosides to the bases [90].
276 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

O
H C
N O NH 2

F F
NH NH

N O carboxylesterase N O
H3 C H3 C
O O
liver

HO OH HO OH

CAP 5'dFCR

cytidine deaminase
liver, tumors

O O
F F
NH thymidine phosphorylase NH

liver, tumors
N O N O
H3 C
H O

HO OH

FU 5'dFUrd

Fig. (4). Metabolic pathway of capecitabine.

In theory, this prodrug of FU should have two main
advantages, which may translate into an improved
therapeutic index. First, it should increase the concentration
of the active principle at the tumor site and so should have
greater activity; second, it should decrease the concentration
in drug in healthy tissues with a consequent reduction in
systemic toxicity.
A pharmacokinetic study was carried out to verify these
expectations [91]. Nineteen patients with colorectal cancers
who were undergoing elective resection of either a primary
lesion or liver metastases were treated prior to surgery with
1255 mg/m2 of CAP administered twice daily over 5 to 7
days. Analysis of samples removed on operation showed a
higher concentration of FU in the tumors than in adjacent
healthy tissues. FU concentrations in the colorectal
resections were on average 3.2 times greater than in the
normal bowel, and 21 times greater than in plasma. In liver
metastases, the ratio of FU concentrations was 1.4 when
metastases were compared with normal liver (not statistically
significant) and 9.9 when compared with plasma. These data
are explained by the fact that the activity of TP is four times
higher in colorectal tumor tissue than in healthy colorectal
tissue, whereas it is similar in liver metastasis and healthy
liver.
These encouraging findings have prompted a number of
phase I trials of this drug (Table 2). As LV is frequently
used during treatment with FU to enhance inhibition of TS,
Cao et al. [97] proposed using LV to increase the efficacy of
CAP. Their preclinical study confirmed this hypothesis and
has led to a phase I clinical trial with LV. Initial clinical
studies showed that the maximum tolerated doses (MTD) of
CAP were schedule dependent, with higher doses possible
by employing breaks of 1-2 weeks after 2 weeks of
continuous therapy. The dose-limiting toxicities (DLT) in
phase I trials were similar to those observed with continuous
infusion of FU, i.e. mainly diarrhea and the HFS, but also
nausea, vomiting, mucositis, leukopenia, and abdominal
pain. The occurrence of bowel toxicity was disappointing as
in theory it should have been avoided as CAP is not
metabolized in the intestinal mucosa. In a recent study on 41
patients with metastatic colorectal cancer treated with the
intermittent regimen of CAP at a dose of 2500 mg/m2/day,
HFS developed in 28 patients (68%; 95% confidence interval
(CI) 52-82%), with 5 patients (18%) having grade 1, 20
(71%) grade 2, and 3 (11%) grade 3. HFS starts within the
first two cycles of therapy. Dose reduction leads to complete
resolution in all cases [98].
Phase II trials have evaluated both continuous and
intermittent schedules, mainly in breast cancer (Table 3). The
addition of LV increased toxicity, in particular diarrhea and
the HFS, without any perceptible increase in antitumor
efficacy. Monotherapy with CAP given in the intermittent
schedule was thus chosen for further development.
Two large randomized Phase III trials enrolling patients
with advanced colorectal carcinoma were recently conducted.
Both trials had similar study rationale, objectives and
The Prodrugs of 5-Fluorouracil
Table 2. Phase I Trials on Patients Treated with CAP
Studies Number of patients
Taguchi et al. (1996)
12
[92]
Hughes et al. (1996)
24
[93]
Budman et al. (1998)
33
[94]
Mackean et al. (1998)
34
[95]
Cassidy et al. (1998)
31
[96]
a
administered orally in two daily doses every day for 6 weeks (continuous regimen)
b
administered orally in two daily doses for 14 days every 21 days for 12 weeks (intermittent regimen)
design. The primary end-point evaluated was RR, and it was
hoped that at least equivalent RR would be seen in the two
treatment arms. Secondary end-points included efficacy and
safety profile, quality of life and medical care utilization.
Twelves et al. [112] compared CAP administered at 2500
mg/m 2/d in two divided doses for 2 weeks every 3 weeks
with FU 425 mg/m 2 plus LV 20 mg/m 2 administered daily
by i.v. infusion for 5 days every 28 days. It enrolled 602
patients divided equally between the two treatment arms and
was conducted in Western Europe, Russia, Israel, Australia,
New Zealand and Taiwan. The overall RR was significantly
higher for patients treated with CAP (26.6% (95% CI
21.6%-31.6%)) than those receiving FU/LV (17.9% (13.6%-
22.2%)). However, when these responses were reviewed by
an independent committee, statistical significance was absent
as the RR for the CAP arm was 18.9% and 15% for the
FU/LV arm [113]. Median progression-free survival (5.2 for
the CAP group vs 4.7 months for the FU/LV group) and
overall survival (13.2 months for the CAP group vs 12.1
months for the FU/LV) group were equivalent for both
groups [112]. The frequency of grade 3-4 diarrhea was
similar in both arms but the FU/LV regimen was associated
with considerably more grade 3-4 stomatitis and neutropenia,
and dose reductions were required in 35% of patients. HFS
was rare among the FU/LV patients but necessitated dose
reduction in 27% of the CAP patients. CAP patients
required substantially fewer hospital visits for drug
administration and spent fewer days in hospital for the
management of treatment related adverse events. In addition,
CAP reduced the requirement for expensive drugs, in
particular antimicrobial fluconazole and 5-HT3-antagonists to
manage adverse events. Globally, the CAP treatment of
colorectal cancer patients resulted in a substantial resource
use saving relative to the regimen of FU/LV [114].
Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 277
Recommended dose
MTD of CAP Dose of LV Main side-effects
for phase II
hand-foot syndrome
2510 mg/m2 /da
myelosuppression
3514 mg/m2 /db diarrhea 2510 mg/m2 /db
diarrhea
1657 mg/m2 /da nausea 1331 mg/m2 /da
hand-foot syndrome
nausea
2 b fatigue
3000 mg/m /d 2510 mg/m2 /db
anorexia
diarrhea
nausea, vomiting
2 b b stomatitis 1650 mg/m2 /db of CAP
2000 mg/m /d 60 mg/d
diarrhea + 60 mg/db of LV
hand-foot syndrome
Hoff et al. [115] conducted a similar study. CAP was
administered orally at 2500 mg/m 2/day twice daily for 2
weeks every 3 weeks. FU/LV was administered according to
the Mayo Clinic regimen, consisting of a rapid i.v. injection
of 20 mg/m2 LV followed by an i.v. bolus injection of 425
mg/m 2 FU daily, days 1 to 5 every 4 weeks. It enrolled 605
patients with 302 patients randomized to the CAP arm and
303 patients randomized to the FU/LV arm and was
conducted in the US, Canada, Mexico and Brazil. They
found a significant difference in the RR (24.8% for CAP vs
15.5% for FU/LV). When these results were reviewed by the
independent review committee, statistical significance was
maintained and, in fact, improved with a RR of 25.8% for
the CAP arm and 11.6% for the FU/LV arm. However,
duration of response (9.1 vs 9.5 months), median time to
disease progression (4.3 vs 4.7 months), and median overall
survival time (12.5 months vs 13.3 months) were not
significant. Again, the safety profile significantly favored
CAP (Fig. (5)). Similar rates of grade 3-4 diarrhea were
observed in both arms, but increased neutropenia and
stomatitis were reported in the FU/LV arm. However, grade
3 HFS occurred in 18% of the CAP patients vs 1% for the
FU/LV group. Fewer patients in the CAP group required
hospitalization for adverse reactions than in the FU/LV
group (11.4% vs 20.4%). Dose reduction for adverse
reactions was required in 40.5% of patients in the CAP
group (most commonly for HFS or diarrhea) and in 49.3%
of patients in the FU/LV group (most commonly for
stomatitis or diarrhea).
When data from the two clinical trials were pooled and
analyzed, a statistically significant improvement in the
overall RR was observed (25.7% for the CAP patients vs
16.7% for the FU/LV group) and the safety profile was in
278 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

Table 3. Phase II Trials on Patients Treated with CAP

Median duration of
Number of Response rate
response (MDR)
Studies evaluable patients, CAP dose LV dose (95% confidence Main side-effects
Median survival
disease limit interval)
time (MST)

O’Shaughnessy et
61 ( ≥55 y)
al. (1998) [99] 30% hand-foot
untreated breast 2510 mg/m2 /da MST 21.6 m
Leonard (2001) (19%-43%) syndrome diarrhea
cancer
[100]

22
O’Reilly et al. anthracycline- 36%
2510 mg/m2 /da
(1998) [101] resistant breast (17-59%)
cancer

162 diarrhea
Blum et al. (1999) 20% MDR 8.1 m
paclitaxel-resistant 2510 mg/m2 /da hand-foot
[102] (14%-28%) MST 12.8 m
breast cancer syndrome

32
Cervantes et al.
taxanes-resistant 2500 mg/m2 /da 16%
(2000) [103]
breast cancer

7
Sundaram et al. breast cancer hand-foot
2500 mg/m2 /da 71%
(2000) [104] progressing after syndrome
HDC-ASCSb

22
Wong et al. (2000) hand-foot
refractory breast 2500 mg/m2 /da 27%
[105] syndrome
cancer

Vasey et al. (2000) 15 hand-foot

2500 mg/m2 /da 7%
[106] ovarian cancer syndrome diarrhea

hand-foot
Wenzel et al. 12
2500 mg/m2 /da 8% syndrome nausea,
(2000) [107] renal cell cancer
vomiting

55 MST not reached hand-foot

Lozano et al. 16%
hepatobiliary 2000 mg/m2 /da 1-year survival rate syndrome
(2000) [108] (8%-24%)
carcinoma 70% thrombocytopenia

hand-foot
Cartwright (2000) 38
2500 mg/m2 /da 8% MST 214 d syndrome diarrhea
[109] pancreatic cancer
nausea

19 nausea, vomiting
Hoff et al.
FU-resistant 2500 mg/m2 /da 0% diarrhea
(2000) [110]
colorectal cancer abdominal pain

arm A: 39 1331 mg/m2 /dc,d 21% (9%-36%)

109
diarrhea,
Van Cutsem et al. colore
arm B: 35 2510 mg/m2 /da,d 24% (11%-41%) hand-foot
(2000) [111] ctal
syndrome
cancer
arm C: 35 1657 mg/m2 /da,d 60 mg/da 23% (10%-40%)

a
administered orally in two daily doses for 14 days every 21 days (intermittent regimen)
b
HDC-ASCS: high-dose chemotherapy with autologous stem cell support
c
administered orally in two daily doses every day for 12 weeks (continuous regimen)
d
median duration of treatment: 109 d in arm A, 145 d in arm B, and 130 d in arm C; response assessed after 6 and
12 weeks of treatment
The Prodrugs of 5-Fluorouracil
Fig. (5). Adverse reactions of any grade in ≥ 20% of patients treated with capecitabine or the combination 5-fluorouracil/leucovorin
(adapted from ref [115]). *Statistically significant difference (p < .0002).
favor of CAP. However, there was no survival benefit (12.9
months in each group) [116].
The same regimen of CAP is being evaluated in a large-
scale adjuvant trial, which is expected to recruit
approximately 1700 Duke’s C colon cancer patients (X-ACT
study, Roche). Two large randomized phase III trials have
also been designed to evaluate CAP as first-line therapy in
patients with previously untreated metastatic breast cancer
[117].
Since the conversion of CAP to FU is mediated by TP,
the combination of CAP with agents that upregulate TP
concentrations in human cancer xenograft models such as
paclitaxel and docetaxel [118], CP [119], X-ray irradiation
[120] offers the potential to improve efficacy further.
Moreover, a study on breast cancer models reported that the
most potent and synergistic activity was observed when
docetaxel was given on day 8 [121]. Numerous trials with
combinations containing CAP and other anticancer agents
have been recently investigated (Tables 4 and 5).
In a phase III study, patients with metastatic breast cancer
who had failed anthracycline therapy were randomized to
receive either docetaxel 100 mg/m2 every 3 weeks or the
intermittent regimen of CAP (2500 mg/m 2/day) plus 75
mg/m 2 docetaxel. Preliminary data indicated that the
combination is superior to docetaxel monotherapy in terms
of RR, time to progression, and survival [100].
Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 279
In summary, orally administered CAP mimics
continuous infusion FU, is well tolerated with palmar-
plantar erythrodysesthesia and diarrhea the most common
toxicities reported, and is more convenient for patients. It
has also been shown that CAP reduced treatment costs in
patients with metastatic colon cancer (381 US$ per cycle vs
517 US$ for the classical FU/LV regimen, in Uruguay)
[136]. CAP has been approved by the US Food and Drug
Administration for use in patients with metastatic breast
cancer resistant to both paclitaxel and an anthracycline-
containing chemotherapy regimen or resistant to paclitaxel
and for whom further anthracycline therapy is not indicated.
CAP is now commercialized in Europe as a monotherapy for
first-line treatment of metastatic colorectal cancer.
2
The approved dose (2500 mg/m /day as intermittent
regimen) leads to unacceptable toxicity in many patients
with metastatic breast cancer. A recent retrospective analysis
suggests a standard starting dose of 2000 mg/m 2/day. If
patients still have toxicity, individualization of dosing is
necessary [137]. Moreover, the dose of CAP can be reduced
to minimize toxicity without compromising efficacy. The
impact of dose reduction was evaluated retrospectively from
four phase II trials (2510 mg/m2/day, intermittent regimen)
including 321 patients with advanced or metastatic breast
cancer. 131 patients with dose reductions were compared to
190 patients with no dose reductions. There was little
difference in duration of response (220 vs 211 days), time to
treatment failure (234 vs 218 days), and survival time (350
vs 243 days) [138].
280 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

Table 4. Phase I Trials Conducted on Patients Treated with CAP Combined with other Anticancer Agents

Number of evaluable
Main side-effects or patients
Recommended dose
Studies MTD or escalating doses dose-limiting toxicities Response rate
for further studies
(DLT) Median duration of
response (MDR)

HD c hand-foot syndrome
CAP 1650 or 2000 mg/m2 /da 10 CAP 1650 mg/m2 /da
Khoury et al. (1998) [122] febrile neutropenia
paclitaxel 175 mg/m2 b 50% paclitaxel 175 mg/m2 b
LD c no DLT

CAP 1004-1657 mg/m2 /dd

paclitaxel 135 mg/m2 b neutropenia 17
Villalona-Calero et al. CAP 1331 mg/m2 /dd
OR CAP 1331 or 1657 hyperbilirubinemia (15 FU-resistant)
(1999) [123] paclitaxel 175 mg/m2 b
mg/m2 /dd diarrhea 0%
paclitaxel 175 mg/m2 b

diarrhea
CAPa/paclitaxel e
Elza-Brown et al. (2000) asthenia
2500/30, 2500/45, 2500/60 10
[124] hand-foot syndrome
or 2000/60 mg/m2 /d
stomatitis

CAP 1650 mg/m2 /da

asthenia docetaxel 100 mg/m 2 f
CAP 2000 mg/m2 /da 33
Pronk et al. (2000) [125] neutropenia OR
docetaxel 100 mg/m 2 f
15%
alopecia CAP 2500 mg/m2 /da
docetaxel 75 mg/m 2 f

CAP 1530-2120 mg/m2 a

CAP 1970 mg/m2 a
23
docetaxel 75 mg/m 2 f docetaxel 75 mg/m 2 f
Venturini et al. (2000) [126] neutropenia
74%
epirubicin 75 mg/m2 f epirubicin 75 mg/m2 f

Diaz-Rubio et al. (2000) CAP 1000, 1650, 2000 or no DLT at 1000-1650 mg/m 2 18
CAP 2000 mg/m2 /da
[127] 2500 mg/m2 /da diarrhea at 2000-2500 28%
oxaliplatin 130 mg/m2 g

Evans et al. (2000) [128] oxaliplatin 130 mg/m2 g mg/m2 MDR 149 d

CAP 500-1650 mg/m2 /dh leukopenia CAP 1300 mg/m2 /dh

Dunst et al. (2000) [129] 20
radiotherapy (50.4 Gy) skin reactions Radiotherapy (50.4 Gy)

Vanhoefer et al. (2000) CAP 2500 mg/m2 /di diarrhea 11 CAP 2500 mg/m2 /di
[130] CPT-11 80 mg/m2 j neutropenia 36% CPT-11 70 mg/m2 j

Arm A: CAP 2500 mg/m2 /dk

Arm A: hand-foot syndrome
CPT-11 300 mg/m2 l 17
Cassata et al. (2000) [131] Arm B: nausea
Arm B: CAP 2500 mg/m2 /dk 76%
neutropenia
CPT-11 150 mg/m2 m

CAP 1000-2250 mg/m2 /da

22
Nole et al. (2000) [132] vinorelbine 12.5-20 neutropenia
36%
mg/m2 /dn

CAP 1000, 1300 or 1600

Herrmann et al. (2000) myelotoxicity 18 CAP 1300 mg/m2 /da
mg/m2 /da
[133] stomatitis 33% gemcitabine 1 g/m 2 m
gemcitabine 1 g/m 2 m
a
administered orally in two daily doses for 14 days every 21 days (intermittent regimen)
b
i.v. infusion over 3 hours every 21 days
c
HD: high dose; LD, low dose
d
administered orally in two daily doses every day (continuous regimen) from day 3
e
administered every week
f
i.v. infusion on day 1 every 21 days
g
i.v. infusion over 2 hours every 21 days
h
administered orally in two daily doses every day (continuous regimen)
i
administered orally in two daily doses on days 1-14 and 22-35
j
i.v. infusion over 30 min every week for 6 weeks
k
administered orally from day 2 for 14 days every 21 days
l
administered on day 1 every 21 days
m
administered on days 1 and 8 every 21 days
n
i.v. infusion on days 1 and 3 every 21 days
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 281

Table 5. Phase II Trials Conducted on Patients Treated with CAP Combined with other Anticancer Agents

Number of Response rate Median duration

Other compound
Studies evaluable patients, CAP dose (95% confidence of response Main side-effects
administered
disease limit interval) (MDR)

paclitaxel 175 neutropenia

Batista et al. (2000) 64 63%
2000 mg/m2 /da mg/m2 hand-foot
[134] breast cancer (50%-74%)
d1 every 3 weeks syndrome

13
Bangemann et al. HER2- trastuzumab b
2250 mg/m2 /da 62% MDR 315 d
(2000) [135] overexpressing 2 mg/kg/w
breast cancer
a
administered orally in two daily doses for 14 days every 21 days (intermittent regimen)
b
Trastuzumab (Herceptin ®)is the first humanized antibody against HER2

In breast cancer patients with brain metastases, a drug response (38.1% (95% CI 17.3-58.9%)) was reported for 24
interaction between CAP and the anticonvulsant phenytoin patients with advanced gastric cancer treated with 200 mg of
led to cerebellar symptoms indicative of phenytoin BOF-A2 twice daily for 2 weeks followed by a withdrawal
intoxication. CAP downregulates the isoenzyme P4502C9, period of 2 weeks [146]. This RR was superior to those
which plays a major role in the hepatic degradation of obtained with cisplatin, irinotecan and docetaxel. The main
phenytoin. A frequent monitoring of the phenytoin level is toxicities were gastrointestinal. A multicenter phase II study
thus imperative [139]. of BOF-A2 was carried out in 71 patients with non-small
cell lung cancer treated with the same regimen [147]. The
2.3. BOF-A2 overall RR was 17.7% (95% CI 8.2-27.3%). Anorexia,
nausea/vomiting, and stomatitis were the DLT.
Emitefur, more commonly called BOF-A2, is an oral
fluoropyrimidine intended to act as an orally administered 2.4. Ftorafur
source of prolonged systemic FU exposure, similar to that
attained by FU infusion. It was also designed to overcome Ftorafur (FTO) or 1-(2-tetrahydrofuryl)-5-fluorouracil
DPD-dependent circadian rhythm variability. Tatsumi et al. (Fig. (1)) also referred to as Tegafur or Futraful, the first
[140, 141] found that 3-cyano-2,6-dihydroxypyridine prodrug of FU, was developed by a group of researchers in
(CNDP) is a competitive inhibitor of DPD with a potency of
2000 times that of uracil in vitro. Therefore, a compound O O
NC
containing both 1-ethoxymethyl-5-fluorouracil (EMFU), a
F C
prodrug of FU, and CNDP was synthesized in 1989 by Fujii N O
et al. [142] (Fig. (1)). In vivo, BOF-A2 is degraded into
C O N O C
CNDP and EMFU, which is slowly metabolized into FU by N O
hepatic microsomal enzymes (Fig. (6)). Levels of FU remain O
high, since its degradation into FUH2 by DPD is inhibited. O
Emitefur is thus a typical prodrug/modulator combination.
BOF-A2
Clinical studies were initiated in Japan. A phase I study
demonstrated the MTD to be 400 mg/m2 orally for 4 weeks O
and also showed the DLT to include anorexia, diarrhea, NC
F H
stomatitis, leukopenia, and thrombocytopenia [143]. More N
recently, Nemunaitis et al. [144] showed that a dose of 200
mg/m 2/day administered in two divided doses for 14 days N O HO N OH
followed by 7 days of rest is well tolerated in patients with
nonresectable solid tumors. The most frequent adverse events O
observed at this dose level were grade 1-2 nausea, diarrhea,
EMFU CNDP
asthenia, stomatitis, and anorexia, all of which are consistent
with FU-related toxicity. Neutropenia and myelosuppression Liver
complications were remarkably infrequent. microsomal
enzymes
In an early phase II study, a therapeutic response was
FU X FUH2
noted in patients with gastric, colorectal, pancreatic, breast
and non-small cell lung cancers [145]. In subjects with
gastric cancer, a response was observed in 6 of 40 patients
(15.0%) treated with 250 mg/m 2 of BOF-A2. A better Fig. (6). Metabolic pathway of BOF-A2.
282 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2
the former Soviet Union at the end of the 1960s [148]. It
was tested in the USA as a drug for i.v. administration, but
it was soon found to be effective via the oral route [149].
After oral administration, FTO is rapidly absorbed intact
by the organism and then hydroxylated and converted into
FU mainly by microsomal P450 enzymes in the liver and to
some extent by TP [150-152]. The level of FU obtained
from metabolism of FTO is lower than that of the parent
compound (1/50 to 1/400 of the initial concentration of
FTO) [153]. However, FU plasma level decays slowly
indicating that the pharmacokinetics of FTO is comparable
to that of FU by continuous i.v. infusion [153, 154]. One
would therefore expect comparable side effects to those
observed after continuous i.v. infusion of FU, but with the
advantage of oral administration with its reduced cost, better
patient comfort and lower risk of complications.
Unfortunately, clinical trials [149] have not demonstrated
a superior efficiency of FTO administered by the oral route
compared to FU administered by continuous i.v. infusion.
Moreover, FTO frequently leads to severe gastrointestinal
disturbances. Furthermore, the lipophilicity of FTO gives
rise to high concentrations of the drug in the cerebrospinal
fluid leading to severe neurotoxicity. This side-effect has
reduced enthusiasm for this agent, and the advent of new
more efficient and less toxic prodrugs has put an end to its
development in Europe and the USA.
Nevertheless, a significant RR (38.5%) was recently
reported in a phase II study on patients with advanced
colorectal carcinoma treated by a protracted oral
administration of FTO (750 mg/m 2/day for 21 days)
combined to oral LV (45 mg/day) [155].
A RR of 50% was obtained from 14 evaluable patients
treated for untreated advanced gastric cancer with epirubicin
(60 mg/m 2) and cisplatin (70 mg/m2) i.v. on day 1, and oral
FTO (700 mg/m2/d on days 1-14) and levoLV (25 mg/day
for 21 days). Major toxicities were neutropenia and
nausea/vomiting [156].
A RR of 63% with a median duration of response (MDR)
of 10 months were observed in a phase II trial of oral FTO
(750 mg/m 2/day for 21 days) combined to oral LV (45
mg/day) and mitoxantrone (12 mg/m2 i.v. on day 1) as first-
line regimen in 32 patients with metastatic breast cancer.
Diarrhea, stomatitis and nausea/vomiting were the main
toxicities [157].
When patients with advanced breast carcinoma were
treated with CP (600 mg/m 2) and methotrexate (MTX; 40
mg/m 2), both given i.v. on day 1, and FTO (750 mg/m 2)
with LV (45 mg/day), both given orally on days 2-14, a RR
of 46% was reported and toxicities were mild [158].
The 5-year relapse-free survival rate was significantly
higher for patients with stage II oestrogen receptor-positive
breast cancers receiving, as postoperative adjuvant therapy,
oral tamoxifen (30 mg/day) plus oral FTO (600 mg/day)
than for patients receiving tamoxifen only (94% and 87%,
respectively) [159].
Malet-Martino, et al.
2.5. UFTTM and Orzel®
In an effort to improve the therapeutic index of FTO,
Japanese researchers [160] prepared a special formulation of
FTO, called UFTTM (Fig. (1)), a mixture of FTO and uracil
(U) in molar proportions of 1:4. This ratio was chosen based
on preclinical models that suggested maximal tumor
selectivity with these relative concentrations. U acts as a
modulator on the catabolism of FU. Being a natural
substrate for DPD, it competes with FU. Since its molar
concentration is much higher than that of FU (in the form of
FTO), little FU will be degraded by DPD and will thus be
more available to the anabolic route of activation. The
coadministration of FTO (slow liberation of FU in the
organism) and U (reduced degradation of FU) was designed
to produce a constant reserve of FU and its active
metabolites, and minimize production of inactive and
potentially toxic metabolites [161]. In ten patients receiving
equimolar dosages of FU by continuous infusion (250
mg/m 2/day over 5 days) or oral UFT (370 mg/m2/day over
28 days), similar systemic FU exposure (measured by the
area under the curve (AUC)) was obtained [162]. This study
also demonstrated a prolonged elimination half-life of FU
after oral UFT administration.
It has been reported recently that UFT, partly by
maintaining a high and long-lasting blood level of FU, and
partly through its metabolites (γ -hydroxybutyric acid and γ -
butyrolactone) has a stronger angiogenesis inhibitory effect
in murine renal carcinoma cell line than FU or 5’dFUrd
[163]. While the clinical relevance of this observation
remains to be determined, it might be another mechanism of
action of this compound.
Of the newer oral fluoropyrimidines, UFT has been
studied the most extensively. Japanese investigators studied
UFT about 20 years ago, but interpretation of the data was
difficult because dissimilar methodologies, criteria, and
evaluation standards were used [56]. Results of these studies
indicated that UFT was well tolerated and had significant
activity in patients with colon, stomach, and breast cancers
[164]. Since the initial studies using UFT alone have
produced encouraging results, researchers have proposed
using an additional modulator such as LV to act on the
anabolism of FU by increasing available reduced folates and
thereby stabilizing the binding of FdUMP to TS. LV has
been shown to enhance the inhibition of TS in gastric cancer
patients [161, 165]. Orzel® is the trade name for the
combination UFT/LV. It is composed of UFT capsules co-
packaged with LV tablets.
The phase I trials (Table 6) have established that the
maximal dosage of UFT administered concomitantly with
LV over 14 to 28 days in divided doses ranges from 350 to
400 mg/m2/day, which will thus be employed in the phase II
trials. The main toxic reactions at the MTD were
gastrointestinal (diarrhea, nausea, vomiting). The occurrence
of these toxic effects correlated significantly with the
maximum plasma concentration and AUC0-6h of FU [173].
The HFS, characteristic to continuous i.v. infusion of FU,
was not observed.
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 283

Table 6. Phase I Trials Conducted on Patients Treated with UFT

Number of evaluable Recommended dose

Studies MTD of UFT LV dose Main side-effects
patients for phase II

fatigue
Muggia et al. (1996)
26 400 mg/m2 /da diarrhea 400 mg/m2 /da
[166]
nausea

Pazdur et al. (1996) 19 800 mg/m2 /db granulocytopenia 800 mg/m2 /db
[167] 23 400 mg/m2 /dc diarrhea 360 mg/m2 /dc

vomiting
20 mg/m2 iv
Spicer et al. (1991) 2 d stomatitis
14 300 mg/m /d on days 1, 8, 15, 22
[168] diarrhea
from cycle 2
leukopenia

stomatitis
Gonzalez-Baron et al. d1: 500 mg/m2 iv
24 390 ± 10 mg/m2 /de diarrhea 390 mg/m2 /de
(1993) [169] d2-d14: 30 mg/d oral
epigastralgia

diarrhea
Meropol et al. (1996) 60+45+45 mg/d
26 350 mg/m2 /dc nausea, vomiting 350 mg/m2 /dc
[170] in 3 oral doses
fatigue

Pazdur et al. (1997) 150 mg/d

14 350 mg/m2 /df diarrhea 350 mg/m2 /df
[171] in 3 oral doses

Pazdur et al. (1998) 150 mg/d

18 350 mg/m2 /dc diarrhea 300 mg/m2 /dc
[172] in 3 oral doses
a
administered orally for 28 days in three daily doses every 6 weeks
b
administered orally during 5 days in three daily doses every 3 weeks
c
administered orally during 28 days in three daily doses every 5 weeks
d
administered orally during 28 days every 5 weeks
e
administered orally during 14 days in two daily doses every 4 weeks
f
administered orally during 14 days in three daily doses every 4 weeks

2.5.1. UFT/LV in Colorectal and Rectal Cancers
Phase II Trials in Colorectal Cancer
The phase II trials in advanced colorectal cancer have
shown that an oral regimen of UFT/LV is well tolerated and
is at least as efficient as treatment by FU administered by
continuous i.v. infusion with or without LV (Table 7). The
objective RR ranged from 20% to 40%, and median overall
survival was around 13 months. The most frequent severe
toxicities were diarrhea and nausea/vomiting. The absence of
objective responses in patients refractory to previous i.v.
bolus FU suggests that UFT is cross-resistant with bolus FU
[171, 180]. For elderly patients, the RR were lower than in
the general population [178, 179].
Phase III Trials in Colorectal Cancer
These results have led to two randomized phase III trials
comparing oral treatment of UFT/LV (300 mg/m 2/day in
three daily doses for 28 days every 5 weeks in combination
with 75 or 90 mg/day of oral LV, the doses found to lead to
maximum LV bioavailability) with i.v. administration of
FU/LV (425 mg/m 2/day of FU + 20 mg/m 2/day of LV
administered by bolus i.v. during 5 days every 4 or 5 weeks)
in patients with metastatic colorectal cancer [185, 186]. The
overall RR were not significantly different in both studies.
In the study of Pazdur et al., which enrolled 816 patients, it
was 12% in the Orzel arm and 15% in the FU/LV arm. For
the 380 patients evaluated in the study of Carmichael et al.,
it was 11% in the Orzel arm and 9% in the FU/LV arm. In
the last study, the median time to progression was 3.4 and
3.3 months in the Orzel arm and the FU/LV arm,
respectively. The MST were 12.2 (Orzel arm) vs 11.9
months (FU/LV arm) in the Carmichael study, and 12.4
(Orzel arm) vs 13.2 months ( FU/LV arm) in the Pazdur
study. However, Orzel was associated with significant
improvements in safety compared with the FU/LV regimen.
Orzel treatment resulted in fewer episodes of febrile
neutropenia and documented infection. Significant HFS was
not observed with Orzel, whereas bilirubin was increased
more often in the Orzel-treated patients. Both studies
concluded that the oral treatment is accompanied by lower
toxicity and is thus an acceptable alternative to the treatment
by i.v. FU/LV. In a randomized crossover trial comparing
oral Orzel and i.v. FU/LV, 27 out of 32 patients (84%)
preferred oral UFT to i.v. FU because they experienced less
stomatitis and diarrhea and they could take their medication
at home [187].
Adjuvant Therapy in Colorectal Cancer
Oral UFT or UFT/LV were also explored in the adjuvant
setting of colon cancer. 476 patients were given either i.v.
mitomycin C (MMC; 6 g/m 2 on the day and the day after
284 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

Table 7. Phase II Clinical Studies Conducted on Patients Treated with UFT for Colorectal Cancer

Median duration of
Number of Response rate
response (MDR)
Studies evaluable UFT dose LV dose (95% confidence Main side-effects
Median survival time
patients limit interval)
(MST)

17%
Malik et al. (1990) [174] 36 600 mg/da MST 34 w cutaneous eruption
(6%-33%)

350 then 300 150 mg/d in 3 oral 42%

Pazdur et al. (1994) [175] 45 MST 15.8 mc diarrhea
mg/m2/db doses (28%-58%)

15 mg/d in 3 oral 25% MDR 7 m diarrhea

Saltz et al. (1995) [176] 20 350 mg/m2/db
doses (6%-44%) MST 12+ m mucositis

diarrhea
mucositis
nausea, vomiting
Abad et al. (1997) [178]77 (≥72
y) 400 mg/d 45 mg/d 17%
d1: 500 mg/m2 iv (9%-27%) MST 14.4 m nausea,
Gonzalez-Baron et al. 39% MDR 10 m
75 390 mg/m2/dd d2-d14: 30 mg/d vomiting diarrhea
(1995) [177] (28%-50%) MST 13.5 m
oral Feliu et al. (1997) [179] 38 ( >70
y) 390 mg/m2 /dd d1: 500 mg/m2 iv
d2-d14: 30 mg/d oral 29%
(15%-46%) MDR 9 m
MST 12.5 m diarrhea
mucositis nausea, vomiting

18
diarrhea
colorectal
90 mg/d in 3 oral pancreatitis
Meropol et al. (1999) [180] cancer 300 mg/m2 /db 0%
doses nausea, vomiting
resistant to
hyperbilirubinemia
bolus FU

150 mg/d in 3 oral 21% diarrhea

Aranda et al. (1999) [181] 111 300 mg/m2 /db MST 13 m
doses (14%-30%) nausea, vomiting

30 + 15 + 15 mg/d 33%
Lin et al. (2000) [182] 40 300 mg/m2 /db MST not reached nausea, vomiting diarrhea
in 3 oral doses (18%-47%)

Ichikawa et al. (2000) 15 mg/d in 3 oral 35% MDR 95 d diarrhea

20 400 mg/m2 /de
[183] doses (14%-56%) MST 228+ d mucositis
a
administered orally in three daily doses; median duration of treatment: 10 weeks
b
administered orally for 28 days in three daily doses every 5 weeks
c
reference [184]
d
administered orally for 14 days in two daily doses every 4 weeks
e
administered orally in two daily doses for 5 days, followed by a two-day rest period, every 4 weeks

surgery) or the same dose of MMC plus oral UFT (400
mg/day for one year). The disease-free survival rate of the
UFT group was significantly higher than that of the control,
though no significant difference in the overall survival rate
was observed [188].
A clinical trial of oral UFT (600 mg/day for 5 days
followed by 2 drug-free days for a year) as adjuvant
chemotherapy for resected colorectal cancer was conducted on
87 patients. This schedule was well tolerated and was
favorable in terms of compliance [189].
Espinosa et al. [190] evaluated 269 patients with operated
Dukes’ stage B2-C colon cancer. The UFT/LV regimen was
390 mg/m 2 for 14 days every 4 weeks and i.v. LV (500
mg/m 2) on day 1 followed by oral LV (24 mg/day) on days
2-14. Diarrhea was the primary side-effect. After a median
follow-up of 36 months, the disease-free survival was 83%
for stage B2 and 62% for stage C. The overall survival rates
were 94% and 87%, respectively.
The National Surgical Adjuvant Breast and Bowel
Project Protocol C-06 is a randomized comparison of the
relative efficacies of i.v. FU/LV vs oral UFT/LV. The
FU/LV regimen was given for 3 cycles and consisted of a 2-
hour infusion of LV (500 mg/m 2), and 1 hour after
beginning LV, an i.v. bolus of FU (500 mg/m2), both given
weekly for 6 weeks. The oral UFT/LV regimen consisted of
five cycles of UFT (300 mg/m2/day) in three daily doses and
LV (90 mg/day) for 28 days every 5 weeks. An interim
analysis on 473 patients indicated that both regimens were
well tolerated and had similar toxicity profiles [191].
A randomized prospective trial was performed to
determine the efficacy of preoperative and postoperative
adjuvant oral UFT, administered with MMC after resection
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 285

for advanced colorectal cancer. The patients received oral The Future in Colorectal Cancer
UFT (400 mg/day) for 7 days prior to surgery and, after
Phase I-II trials are being conducted in which UFT alone
surgery, were randomly assigned to group A receiving MMC
or Orzel is combined with other agents to find more effective
or group B receiving MMC and oral UFT (400 mg/day) for
regimens for advanced metastatic colorectal cancer that
one year. The survival results revealed no significant
incorporate both i.v. and oral drugs (Table 8).
difference between groups A and B. However, in patients
with nuclear DNA aneuploid tumors, the hematogenous Another promising approach is the use of
recurrence rate after curative surgery was lower in group B pharmacokinetic modulating chemotherapy (PMC), which is
than in group A [192]. based on the concept that the benefit of a continuous i.v. FU
infusion can be potentiated by low-dose oral UFT. Fifty-six
A recent study on 55 patients compared the effects of
patients with unresectable colorectal carcinoma received UFT
sequential MTX (100 mg/m2) and FU (600 mg/m2) followed
(200-400 mg/day) 5-7 days per week and FU (600
by LV rescue (treatment MFL), as an adjuvant
mg/m 2/day) once a week. PMC markedly improved the MST
chemotherapy, vs a combination of MMC (12 mg/m 2
(26.6 months vs 9.2 months in the non-PMC group). This
intraoperatively, then 6 mg/m2 every other week after surgery
significant improvement is observed in unresectable primary
for 2 months) and oral UFT (375 mg/m2/day) for at least 3
colorectal carcinoma, recurrent tumors, local extension, lung
years. The overall survival and disease-free survival rates
metastases, liver metastases, and peritoneal seedings. PMC
were significantly higher and the recurrence rate significantly
resulted in a good quality of life as only one patient required
lower in the MFL group, demonstrating the superiority of
toxicity-related hospitalization. The authors recommended
MFL therapy for improving postsurgical survival [193].
the use of PMC for more than 6 months [201]. This efficacy

Table 8. Recent Results of Phase I/II and II Trials Conducted on Patients Treated with UFT Combined with other Anticancer
Agents for Colorectal Carcinoma

Number of evaluable
patients
MTD or escalating Dose-limiting Recommended doses
Studies LV dose Response rate
doses toxicities for phase II
Median survival time
(MST)

16 (UFT 250 mg/m2 /da UFT 250 mg/m2 /da

UFT 250 mg/m2 /da a neutropenic fever
Hill et al. (2000) [194] 90 mg/d oral CPT-11 250 mg/m2 b ) LV 90 mg/d oral a
CPT-11 300 mg/m2 b diarrhea
25% CPT-11 250 mg/m2 b

Escudero et al. (2000) UFT 250 mg/m2 /dc diarrhea 18 UFT 250 mg/m2 /dc
[195] CPT-11 120 mg/m2 d fatigue 0% CPT-11 110 mg/m2 d

Gravalos et al. (2000) UFT 300 mg/m2 /de 13

45 mg/de diarrhea
[196] CPT-11 300 mg/m2 f 54%

Mel et al. (2000) [197]

UFT 200-350 mg/m2 /dg 28
Vazquez Estevez et al. diarrhea
raltitrexed 2-3 mg/m 2 h 21%
(2000) [198]

UFT 300 mg/m2 /di

2
d1: 250 mg/m LV d1: 250 mg/m2
Dorta et al. (2000) UFT 390 mg/m2 /di diarrhea 34
2h iv infusion 2h iv infusion
oxaliplatin 85 mg/m2 j
[199] nausea, vomiting 35%
d2-d14: 15 mg/d oral d2-d14: 15 mg/d oral
oxaliplatin 85 mg/m2 j

63
Jakobsen et al. (2001) UFT 300 mg/m2 /dk
levoLV 22.5 mg/dk gastrointestinal 22%
[200] hydroxyurea 0.5 g/dk
MST 11 m
a
administered orally during 14 days every 3 weeks
b
administered i.v. on day 1 every 3 weeks
c
administered orally for 21 days in divided daily doses every 4 weeks
d
administered over a 60 min i.v. infusion on days 1, 8 and 15 every 4 weeks
e
administered orally during 14 days in three daily doses every 3 weeks
f
administered over a 90 min i.v. infusion on day 1 every 3 weeks
g
administered orally during 28 days in three daily doses every 6 weeks
h
administered over a 15 min i.v. infusion on days 1 and 21 every 6 weeks
i
administered orally during 14 days in two daily doses every 4 weeks
j
administered on days 1 and 14 every 4 weeks
k
administered orally during 28 days every 5 weeks
286 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

is based on the fact that PMC targets at least two different
phases of the cell cycle [202].
Rectal Cancer
Preoperative protracted i.v. infusions of FU with
concurrent pelvic radiotherapy (RT) are commonly used to
treat rectal carcinoma [203]. Preliminary results suggest that
Orzel combined to RT has similar efficacy, improved
tolerability, and enhanced quality of life in comparison with
continuous FU (Table 9).
2.5.2. UFT in Gastric Tumors
Several phase II trials were conducted to evaluate UFT
alone or in combination with other agents in gastric cancer
(Table 10).
Gastric cancer being the most frequently occurring
malignant tumor in Japan, a cooperative randomized trial
involving 169 patients from 13 institutions compared the
efficacy of oral FTO (500 mg/m2/day for 28 days) plus i.v.
MMC (5 mg/m2/week) and oral UFT (375 mg/m2/day for 28
days) plus MMC (same schedule) [218]. A superior RR was
observed in the UFT arm (25.3% vs 7.8%) as well as a
survival advantage. No significant difference in toxicity was
noted.
In another small randomized trial, UFT/MMC was
compared to FU/MMC. RR were 23% for the first regimen
and 7% for the second [219].
UFT has also been used in the adjuvant therapy after
resection for gastric cancer. A slight difference in five-year
survival was reported when patients were treated for two
years with oral FTO or UFT at a dose of 600 mg/day (52.1%
vs 68.7% (p = 0.04)) [220].
1410 patients from 180 Japanese institutions were
allocated into a low-dose group receiving MMC (8 mg/m2
on the day of surgery) and 3 capsules of UFT (300 mg in
FTO) daily for 6 months, and a high-dose group receiving
MMC (8 mg/m2 on the day of surgery, and in weeks 4, 10,
16, and 22 after surgery) and 6 capsules of UFT (600 mg in
FTO) daily for 6 months. Although the number of adverse
events increases, a better prognosis can be expected with the
high-dose regimen [221].
2.5.3. UFT in Non-Small Cell Lung Cancer
UFT has been used in patients with advanced disease and
in the adjuvant setting. Several phase II studies (Table 11)
showed that the combination UFT/cisplatin is comparable
with other currently used regimens for this disease. Three

Table 9. Phase I and II Trials Conducted on Patients with Rectal Carcinoma Treated with UFT Combined with LV or LV and
Radiotherapy

Number of evaluable
Other compound patients
Dose-limiting Recommended dose
Studies UFT dose and/or treatment Response rate
toxicities for phase II
administered (95% confidence limit
interval)

Sanchiz & Milla (1994) 52

600 mg/m2 a LV 90 mg/m2 /da leukopenia
[204] 40%

LV 30 mg/d oral
de la Torre et al. 300 mg/m2 /d 32
d8-d35 diarrhea
(1999) [205] d8-d35 82%
radiotherapy 45 Gy

UFT 300 mg/m2 /db

LV d1: 500 mg/m2
diarrhea 28 LV d1: 500 mg/m2
Feliu et al. (1999) iv infusion
300 or 350 mg/m2 /db vomiting 71% iv infusion
[206] d2-d14: 30 mg/d oral
mucositis (54%-86%) d2-d14: 30 mg/d oral
radiotherapy 45 Gy
radiotherapy 45 Gy

18
Pfeiffer et al. (2000) levoLV 22.5 mg/dc
150-300 mg/m2 /dc diarrhea 89% patients alive
[207] radiotherapy 60 Gy
after median 45 w

preoperatively
preoperatively diarrhea 14
Hoff et al. (2000) preoperatively UFT 350 mg/m2 /dd
LV 90 mg/dd anorexia 21% (complete
[208] 250-400 mg/m2 /dd LV 90 mg/dd
radiotherapy 45 Gy nausea response)e
radiotherapy 45 Gy
a
administered orally for 14 days in three daily doses every 4 weeks
b
administered orally during 14 days in two daily doses every 4 weeks, 3 courses
c
administered orally in three daily doses for 5 days (same days as radiotherapy) followed by a 2 day rest
d
administered orally in three daily doses for 5 days (same days as radiotherapy) followed by a 2 day rest for 5
consecutive weeks
e
pathologic evaluation of the surgical specimens
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 287

Table 10. Phase II Clinical Studies Conducted on Patients with Gastric Cancer Treated with UFT and other Anticancer Agents

Median duration
Other(s) Response rate of response
Number of
Studies UFT dose compound(s) (95% confidence (MDR) Main side-effects
evaluable patients
administered limit interval) Median survival
time (MST)

Malik et al. (1990) 6%

18 600 mg/da MST 12 w cutaneous eruption
[174] (0.3%-30%)

cisplatin 50 mg/d
continuous infusion
anorexia
Hashimoto et al. 400 mg/d d 1-2
13 31% nausea, vomiting
(1993) [209] d 8-28 FU 500-750 mg/d
leukocytopenia
continuous infusion
d 2-7

mitomycin C
Jin et al. (1994) weakness
93 450 mg/d 20 mg iv once a 60%
[210] leukopenia
week

anorexia
cisplatin
Sato et al. (1995) 2 b diarrhea
14 400 mg/m /d 30 mg/m2 iv for 3 43% MST 11.4 m
[211] nausea, vomiting
days every 4 weeks
leukocytopenia

VP16 d1: 100

mg/m2 iv
d2,d3: 200 mg/m2
diarrhea
Feliu et al. (1996) oral 35% MDR 10 m
46 390 mg/m2 /dc anemia
[212] LV d1: 500 mg/m2 (22%-51%) MST 9 m
nausea, vomiting
iv
d2-d14: 30 mg/d
oral

diarrhea
Kim et al. (1996) 29%
14 480 mg/m2 /dd LV 25 mg/m2 /d oral MST 25 w mucositis
[213] (5%-52%)
nausea, vomiting

diarrhea
Kim et al. (1997) 27% MDR 30 w
37 360 mg/m2 /dd LV 25 mg/m2 /d oral mucositis
[214] (15%-43%) MST 30 w
nausea, vomiting

d1 epirubicin 50
leukopenia
mg/m2 and cisplatin
Kim et al. (2000) 2 d 54% nausea, vomiting
46 360 mg/m /d 60 mg/m2 iv MST 10 m
[215] (40%-69%) mucositis
d1-d21 LV 45 mg/d
diarrhea
oral

d1 epirubicin 50 neutropenia
Chaves et al. (2000)
16 300 mg/d mg/m2 and cisplatin 19% MST 10 m nausea, vomiting
[216]
60 mg/m2 iv alopecia

Sato et al. (2000) d8 cisplatin 51% MDR 85 d

41 400 mg/m2 /de neutropenia
[217] 80 mg/m2 iv (35%-67%) MST 8.3 m
a
administered orally in three daily doses; median duration of treatment: 6 weeks
b
administered orally for 28 days
c
administered orally for 14 days every 4 weeks
d
administered orally for 21 days in divided daily doses every 4 weeks
e
administered orally for 21 days in two daily doses every 4 weeks

trials have been conducted in the adjuvant setting [228-230]. cisplatin (50 mg/m2), vindesine (2-3 mg/kg b.w.) for three
In the study of Wada et al. [229], 323 patients were courses and one year of oral UFT (400 mg/kg b.w.), or one
randomized to one of three arms. They were treated with year of oral UFT at the same dose, or randomized to receive
288 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

Table 11. Phase II Clinical Studies Conducted on Patients Treated with UFT and other Compounds for Non-Small Cell Lung
Cancer

Median duration
Other(s)
Response rate of response
Number of compound(s)
Studies UFT dose (95% confidence (MDR) Main side-effects
evaluable patients and/or treatment
limit interval) Median survival
administered
time (MST)

MDR 6 m
Ichinose et al. 2 a d8: cisplatin 35% MST 11 m (stage leukopenia
31 400 mg/m /d
(1995) [222] 80 mg/m2 iv (19%-52%) III) thrombocytopenia
8 m (stage IV)

anorexia
Gemma et al. d4, 8: cisplatin 47%
17 400 mg/m2 /db nausea, vomiting
(1995) [223] 60 mg/m2 /d iv (23%-71%)
leukocytopenia

cisplatin
d1: 90 mg/m2 iv
d2,d3: 200 mg/m2 nausea, vomiting
Feliu et al. (1996) 2 c oral 12% leukopenia
25 390 mg/m /d
[224] LV d1: 500 mg/m2 (3%-32%) diarrhea
iv epigastralgia
d2-d14: 30 mg/d
oral

Ichinose et al. d8: cisplatin 29% vomiting

103 400 mg/m2 /dd MST 40 w
(2000) [225] 80 mg/m2 iv (20%-38%) hyperbilirubinemia

d8, 29, 50: cisplatin

Yoshino et al. 400 mg/m2 /d 80 mg/m2 iv
23 91% MST 16 m leukopenia
(2000) [226] d1-d52 radiotherapy 60.8
Gy

anorexia
Saito et al. (2001) 2 e d8-12: cisplatin 38% MDR 113 d nausea
47 400 mg/m /d
[227] 20 mg/m2 iv (24%-52%) MST 12.8 m neutropenia
thrombocytopenia
a
administered orally for 21 days every 4 weeks
b
administered orally for 14 days
c
administered orally for 14 days in two daily doses every 4 weeks
d
administered orally for 14 days in two daily doses every 3 or 4 weeks
e
administered orally for 21 days in two daily doses every 4 weeks

no postsurgical therapy. A benefit was reported in overall
five-year survival rates for the first two groups. Side-effects
were significantly lower in the group treated with UFT alone
compared to the first group. These results were considered
promising and deserving of further study. Ito et al. [230]
evaluated a regimen consisting of low dose cisplatin (6-10
mg/m 2/day) and oral UFT (600 mg/day) on days 1-5, 15-19,
and 29-33 at 4 weeks after operation. Concurrent RT (50 Gy)
was given, followed by the administration of UFT (400
mg/day) for 2 years. The regimen was well tolerated and
effective, with a disease-free survival rate of 90% at one year
and 78 % at two years.
To examine whether the efficacy of postoperative oral
administration of UFT may be influenced by incidence of
apoptosis or apoptosis-related gene status (p53 and bcl-2), 44
patients were treated with UFT (300-400 mg/day) one month
after surgery, whereas 118 were not. For patients with higher
apoptotic index (≥10.9), 5-year survival rate of the UFT
group was significantly higher than that of the control group
(83% and 68%, respectively), whereas there was no difference
for patients with lower apoptotic index (<10.9). Similarly,
UFT was effective for patients without p53 aberrant
expression (5-year survival rate of the UFT group was 95%
vs 74% for the control group), but not for patients with p53
aberrant expression. Bcl-2 status did not influence the
efficacy of UFT [231].
2.5.4. UFT in Breast Cancer
Several phase I and phase II studies were conducted with
UFT alone or in combination with other anticancer drugs
(Tables 12 and 13).
One Japanese study compared the efficacy of oral UFT
(400 mg/day) with that of oral FTO (800 mg/day) in 56
patients (28 in each arm) with advanced breast cancer. The
RR was 39% in the UFT arm and 21% in the FTO arm,
without statistical significance. No significant differences
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 289

Table 12. Phase I and I/II Trials Conducted on Patients with Breast Cancer Treated with UFT and other Anticancer Agents

Number of evaluable
patients
Other(s) compound(s) Recommended dose
Studies MTD of UFT Main side-effects Response rate
administered for phase II
(95% confidence limit
interval)

LV 90 mg/d in 3 oral
Dickson et al. (1999) 200-400 mg/m2 /da dosesa neutropenia 13
[232] MTD not reached paclitaxel 135 or 175 diarrhea 31%
mg/m2 3h infusion d1

UFT 600 mg/db

LV 90 mg/d in 3 oral
neutropenia 26 LV 90 mg/d in 3 oral
Klaasen et al. (1999) dosesb
700 mg/db diarrhea 31% dosesb
[233] paclitaxel 175 mg/m2
nausea, vomiting (14%-52%) paclitaxel 175 mg/m2
3h infusion d1
3h infusion d1

LV 90 mg/d oral c
Lebedinsky et al. 150-350 mg/m2 /dc
paclitaxel 80 mg/m2 nausea 17
(2000) [234] MTD not reached
1h infusion weekly

LV 90 mg/d in 2 oral
dosesd neutropenia
Herrero et al. (2000) 2 d paclitaxel 200 mg/m2 alopecia 9
200-350 mg/m /d
[235] 3h infusion every 21 d diarrhea 100%
doxorubicin 60 mg/m2 vomiting
iv bolus every 21 d

UFT 400 mg/de

LV 90 mg/d in 3 oral
LV 90 mg/d in 3 oral
Fumoleau et al. (2000) dosese neutropenia 25
500 mg/de dosese
[236] vinorelbine 25 mg/m2 anemia 20%
vinorelbine 25 mg/m2
on d 1 and 8
on d 1 and 8

UFT 250 mg/m2 /db

LV dose not reported
LV
epirubicin 60 mg/m2
epirubicin 60 mg/m2
Gregory et al. (2000) d1 every 3 w neutropenia 25
350 mg/m2 /db d1 every 3 w
[237] cyclophosphamide diarrhea 56%
cyclophosphamide
600 mg/m2 d 1 every 3
600 mg/m2 d 1 every 3
w
w
a
administered orally for 21 days from day 2 in three daily doses every 4 weeks
b
administered orally during 14 days in three daily doses every 3 weeks
c
administered orally during 21 days every 4 weeks
d
administered orally continuously in two daily doses
e
administered orally during 21 days in three daily doses every 4 weeks

were demonstrated in time to relapse and overall survival. Anemia and stomatitis were significantly more common in
The adverse effects were similar in both arms [242]. the FU arm [243].

More recently, a randomized trial compared the efficacy
of oral UFT (350 mg/m2/day for 14 days; 31 patients) vs i.v.
FU (500 mg/m 2/day on days 1 and 8; 31 patients), both
treatments being combined to doxorubicin (50 mg/m2 i.v. on
day 1) and CP (500 mg/m 2 i.v. on day 1). No statistical
difference in overall RR was seen (48% in the UFT arm and
35% in the FU arm). The median response duration was 16
weeks for both arms. The median overall survival was 12
months for the UFT arm and 11 months for the FU arm. The
toxicity profile (alopecia, anemia, leukopenia,
thrombocytopenia, and diarrhea) was similar in both groups.
In the adjuvant setting, Spanish investigators have
conducted two trials [244]. In the first one, 187
premenopausal women were randomly assigned to either oral
UFT (400 mg/day for 6 months) and oral prednimustine (60
mg/m 2 for 7 consecutive days, every 28 days in 6 cycles), or
6 cycles of the standard therapy CMF (CP 600 mg/m2, MTX
40 mg/m 2, FU 600 mg/m 2, every 4 weeks). Disease-free
survival and overall survival were similar in both arms. The
toxicity was mild (nausea/vomiting, alopecia) and slightly
worse in the CMF arm. In the second trial, 222
postmenopausal patients received 20 mg/day of tamoxifen
290 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

Table 13. Phase II Clinical Studies Conducted on Patients Treated with UFT and other Agents for Breast Cancer

Median
Number of Response rate
Other(s) compound(s) and/or duration of Main side-
Studies evaluable UFT dose (95% confidence
treatment administered response effects
patients limit interval)
(MDR)

Daniels et al. 10 mg/kg/d for at nausea, vomiting

70 18.5% 9m
(1993) [238] least 2 months diarrhea

Pr: oophorectomy then

9
iv cyclophosphamide (300 mg/d)
6 premenopausal leukopenia
Kiman et al. 300 mg/d every and doxorubicin (30 mg/d) every Pr 50%
(Pr) anorexia
(1994) [239] day 2 weeks Po 33%
3 postmeno- malaise
Po: same drugs + oral tamoxifen
pausal (Po)
(30 mg/d) every d

Richardet et al.
24 300 mg/m2 /da LV 45 mg/da 25% diarrhea
(1999) [240]

doxorubicin 30 mg/m2 iv d1
Fukuda et al. cyclophosphamide 65 mg/m 2 oral 58% leukopenia
19 300 mg/m2 /db
(1999) [241] on d 1-14 (29%-87%) alopecia
tamoxifen 20 mg/d oral d 1-21
a
administered orally for 28 days in two daily doses every 5 weeks
b
administered orally for 14 days every 3 weeks

for 1 year, or the same dose of tamoxifen plus UFT at 400
mg/day for 6 months. The disease-free survival and overall
survival rates were equal in both arms, but were longer in
patients with five or more axillary-involved nodes treated
with tamoxifen plus UFT. The toxicity was negligible in
both arms.
A large Japanese trial [245] evaluated the combination of
UFT, MMC and tamoxifen as postoperative adjuvant therapy
in the treatment of patients with stage II, estrogen receptor
(ER)-positive primary breast cancer. All patients received 13
mg/m 2 of i.v. MMC on the day of surgery. Patients were
then randomly allocated to either oral tamoxifen (20 mg/day,
14 days after surgery for 2 years; 213 evaluable patients;
group A) or oral UFT plus tamoxifen (400 mg/day and 20
mg/day, respectively; 223 evaluable patients; group B).
There was no difference in the 5-year survival rate (93% for
group A and 91% for group B). However, there was a
significant advantage for the UFT plus tamoxifen group in
the 5-year relapse-free survival rate (83% for group A and
91% for group B). In another large Japanese trial, a benefit
was also observed in premonopausal ER-positive patients
receiving a similar regimen (30 mg/day of tamoxifen, 300
mg/day of UFT) [246].
2.5.5. UFT in Head and Neck Cancer
The results of the phase II studies are shown in Table 14.
398 patients had a standard surgical therapy for stage III-IV
head and neck cancer with or without adjuvant oral UFT
(300 mg/day for one year). There was no significant
difference in overall survival or relapse-free survival between
arms. However, the addition of UFT improved distant
metastasis of disease [252].
More recently, a randomized trial compared the classical
combination cisplatin/FU with cisplatin/UFT in the
neoadjuvant treatment of locally advanced stage III or IV
head and neck cancer. Sixty-seven patients received cisplatin
(100 mg/m 2) on day 1 followed by either a continuous
infusion of FU (1 g/m2) on days 2-6, or oral administration
of UFT (300 mg/m 2/day) on days 2-20. Both treatments
were repeated every 21 days for four cycles. Responding
patients received locoregional standard RT (50 to 70 Gy)
after chemotherapy. At a median follow-up of 84 months,
RR (73% vs 79%) and disease-free survival rates were
comparable in both arms. However, a lower incidence of
phlebitis was observed in patients treated with UFT (71% vs
9%) [253].
One study compared the combination UFT/RT vs RT
alone and showed a significant improvement in disease-free
survival and overall survival for the group of patients treated
concomitantly with UFT and RT [254]. More recently,
patients with unresectable stage III-IV head and neck
carcinoma received two cycles of neoadjuvant chemotherapy
(cisplatin (25 mg/m2 for 5 days), LV (500 mg/m 2 for 5
days), and FU (800 mg/m 2) for 4 days every 3 weeks)
followed by radiochemotherapy (carboplatin (300 mg/m 2
every 3 weeks), UFT (600 mg/day), and radiotherapy (65-72
Gy)). Higher complete and partial RR were obtained after
both steps of treatment (complete RR 69%, partial RR 10%)
than after neoadjuvant chemotherapy alone (29%, 56%)
[255].
2.5.6. UFT in other Tumors
Pancreatic Cancer
A retrospective analysis of postoperative chemotherapy
with UFT in 78 patients showed a significant difference in
the MST between UFT group (204 days) and non-UFT
group (123 days) [256]. Recently, a phase I trial examined
the use of UFT/LV with conventional RT (45 Gy) in 12
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 291

Table 14. Phase II Clinical Studies Conducted on Patients Treated with UFT for Head and Neck, Pancreatic or Prostate Cancer

Other(s) Response rate Median duration

Number of
Studies UFT dose compound(s) (95% confidence of response Main side-effects
evaluable patients
administered limit interval) (MDR)

anorexia
Tanaka et al. 43
600 mg/d 37% nausea
(1985) [247] head and neck
stomatitis

inductiona
vinorelbine 25
mg/m2 iv d 1 and 8
inductiona neutropenia
Rivera et al. 47 cisplatin 100 mg/m2
6 mg/kg/d d1-d21 93% nausea, vomiting
(1997) [248] head and neck iv d 1
then 5 mg/kg/d stomatitis
then carboplatin
100 mg/m2 /w iv and
radiotherapy

Read et al. (2000) 29

300 mg/m2 /db LV 90 mg/db 28% diarrhea
[249] head and neck

gemcitabine 1 g/m 2
d1, 8 and 15
de Castro et al. 38 LV d1: 250 mg/m2 16%
390 mg/m2 /dc diarrhea
(2000) [250] pancreas iv (6%-31%)
d2-d14: 15 mg/d
oral

cyclophosphamide
Nishimura et al. 21 100 mg/d oral 57%
400 mg/d 7m diarrhea
(2001) [251] prostate estramustine PSA decline ≥50%
560 mg/d oral
a
combination repeated every 21 days for 4 courses
b
administered orally for 28 days in three daily doses every 5 weeks
c
administered orally for 14 days in two daily doses every 4 weeks

patients. MST was 8 months showing that this treatment is
a viable option and compares favorably with continuous
infusion regimens [257]. The combination gemcitabine/
UFT/LV (Table 14) is an adequate palliative therapy for this
disease as it is moderately active and its toxicity is
acceptable [250].
carcinomas in comparison with the standard therapies.
However, its advantages may be in ease of administration
and absence of infusion-related side effects, including
infection and bleeding. Two phase I trials combining Orzel
and paclitaxel in patients with advanced solid tumors have
been recently published [260, 261].

Prostate Cancer
A phase II trial of UFT/LV in 28 patients with hormone-
refractory prostate cancer demonstrated a level of activity
similar to that obtained with i.v. FU [258]. The combination
of UFT, CP, and estramustine was reported as an active and
well-tolerated regimen (Table 14).
Bladder Cancer
A randomized, prospective trial of prophylactic oral UFT
(300-400 mg/day for 2 years) for patients with superficial
bladder cancer indicated that the recurrence rate was
significantly lower in the UFT group (26% vs 43% for
control). In particular, UFT was effective in preventing
recurrence in patients with single tumors or small lesions.
Gastrointestinal toxicities occurred in less than 10% of
patients [259].
In conclusion, UFT combined to LV or other cytotoxic
agents had shown equivalent efficacy for several advanced
Of note, UFT should not be given with food, which
decreases the systemic exposure to FU [262] and has a lethal
interaction with sorivudine, a new antiviral drug for herpes
zoster. A major metabolite of sorivudine, (E)-5-(2-
bromovinyl)-uracil, formed by gut flora, is absorbed through
the intestinal membrane, reduced in the liver by DPD giving
a reactive intermediate which is a suicide inhibitor of the
enzyme. The DPD inactivation leads to extremely high
concentrations of FU, resulting in severe gastrointestinal and
myelo- toxicity then death [263].
Orzel has been submitted to the US Food and Drug
Administration for approval as a first-line treatment of
advanced colorectal cancer. As of this writing, approval by
the FDA is still pending because the overall role of Orzel
alone remains to be established since the first-line therapy of
advanced colorectal cancer is changing to the combination of
FU/LV/CPT-11 [264]. In Europe, Orzel has been approved
as a first-line treatment of metastatic colorectal cancer.
292 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2
2.6. S-1
Further refinement of the strategy that led to UFT has
resulted in a new mixture called S-1 or TS-1 (Fig. (1)). S-1
is a combination of a prodrug of FU, FTO and two
compounds, 5-chloro-2,4-dihydroxypyridine (CDHP;
gimestat) and potassium oxonate (OXO; otastat). It was
developed in 1996 by Japanese workers in an attempt to
circumvent the adverse reactions of FTO, but without
compromising efficacy [265].
In this combination, FTO provides stable and prolonged
liberation of FU, equivalent to a continuous i.v. infusion of
this drug. Neither CDHP nor OXO has any antitumor
activity itself, and they act solely as modulators of FU
designed to act at different steps in the metabolism of FU.
CDHP is a potent and reversible inhibitor of DPD, thereby
prolonging high FU concentration in the circulation. In
vitro, CDHP is 180 times more potent than U, another
reversible inhibitor of DPD [266]. Animal studies have
demonstrated an elevation and a stability over 12 h in levels
of FU in plasma and tumors after coadministration of FTO
and CDHP, or S-1 [265, 267, 268]. OXO is employed to
limit the gastrointestinal toxicity of FTO. It has already been
pointed out that this toxicity stems from the
phosphorylation of FU within the digestive tract by OPRT.
OXO accumulates in gastrointestinal tissues more than in
other tissues or the blood of normal or tumor-bearing rats
[269, 270]. OXO competitively inhibits this enzyme, which
converts FU to FUMP. The levels of FUMP are decreased
by 69% in the small intestine, 2% in Yoshida sarcoma and
0% in bone marrow. The levels of FU incorporated into
RNA are thus decreased by 71% in the small intestine, 22%
in Yoshida sarcoma and 0% in bone marrow [269]. OXO
also protects the activity of TS by decreasing FdUMP via
FUMP in gastrointestinal tissue, which leads to a reduction
in gastrointestinal toxicity [271].
The optimal molar ratio of the three constituents
(FTO/CDHP/OXO) of this combination is 1:0.4:1. With
this formulation, an optimal inhibition of the transformation
of FU in the intestine is obtained without affecting its
activation in the tumor [265]. Researchers in Japan
conducted preclinical evaluation of S-1 and demonstrated its
Table 15. Phase I Trials on Patients Treated with S-1
Studies Number of patients
Taguchi et al. (1997) [278]
Hoff et al. (1999) [279] 16
Van Groeningen et al.
28
(2000) [280]
a
administered orally during 28 days in one daily dose every 6 weeks
b
administered orally during 28 days in two daily doses every 6 weeks
c
administered orally during 28 days in two daily doses every 5 weeks
d
heavily pretreated patients
e
chemotherapy-naive or minimally chemotherapy-exposed patients
Malet-Martino, et al.
antitumor activity in experimental models of rodent tumors
and human xenografts [267, 268, 272-276]. S-1 significantly
inhibited tumor growth in rats with subcutaneous Yoshida
sarcoma, and in nude rats and mice implanted with human
colon, stomach, head and neck, and breast cancer cell lines.
S-1 achieved induction of high and sustained apoptosis. S-1
also showed a significant anti-metastatic effect on liver
metastasis. The animal studies also confirmed that the
gastrointestinal toxicity of S-1 is low because of the
protection afforded by OXO [273]. Recently, a potentiated
antitumor effect in Yoshida sarcoma-bearing rats has been
demonstrated when S-1 was combined to cisplatin [277].
Phase I studies of S-1 have been conducted in Japan,
Europe, and the United States, and Phase II trials in Japan
(Tables 15 and 16). S-1 achieves similar responses to those
of conventional treatments, with a lower incidence of grade 3
or 4 toxicities. The DLT of S-1 was myelosuppression in
Japan and diarrhea in Western countries. This difference
remains unexplained although it seems that the conversion of
FTO to FU occurs more slowly in Asians than in other
ethnic groups [279, 280, 294, 295].
Based on the good results observed in patients with
gastric cancer, S-1 was given a manufacturing approval from
the Ministry of Health and Welfare of Japan in January 1999,
with indications for advanced and recurrent gastric cancers
[296]. Recently, the relationship between immunoreactivity
of TS and DPD in biopsy specimens and the effects of
chemotherapy was investigated in 41 patients treated with S-
1 for advanced gastric cancer. There were no significant
differences in RR and MST (Table 16), indicating that S-1 is
effective in the treatment of gastric cancer patients, regardless
of intratumoral TS and DPD immunoreactivity status [293].
3. Prodrugs of FU in Gene Therapy: Gene Directed
Enzyme-Prodrug Therapy (GDEPT)
This rapidly expanding therapeutic approach utilizes
vectors to deliver genes encoding prodrug-activating enzymes
to malignant cells; the gene delivered to the target encodes
an enzyme which is not toxic per se, but is able to convert a
Recommended dose for
MTD of S-1 Main side-effects
phase II
myelosuppression
150-200 mg/da,b rash 150 mg/dayb
vomiting
60 mg/m2 /dc diarrhea
90 mg/m2 /dc,d diarrhea 70 mg/m2 /dc,d
80 mg/m2 /dc,e leukopenia 80 mg/m2 /dc,e
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 293

Table 16. Phase II Trials on Patients Treated with S-1

Median duration of
Response rate
Number of evaluable response (MDR)
Studies S-1 dose (95% confidence limit Main side-effects
patients, disease Median survival time
interval)
(MST)

gastric cancer
Horikoshi et al. MDR 84 d
58 leukopenia
(1996)[281] gastric cancer 54% MST 298 d
28 gastric cancer 150-200 mg/da anemia
Sugimashi et al. (1999) colorectal cancer 17% colorectal cancer
30 colorectal cancer diarrhea
[282] MDR 109 d
MST 358 d

leukopenia
neutropenia
Taguchi et al. (1996 anemia
27
and 1998) 100-150 mg/da 41% hemoglobinemia â
breast cancer
[283, 284] anorexia
nausea, vomiting
fatigue

hemoglobinemia â
26 a stomatitis
Fujii et al. (1996) [285] 100-150 mg/d 46%
head and neck cancer neutropenia
anorexia

BSAb <1.25 m 2
Kurihara et al. (1998) hemoglobinemia â
80 mg/da
[286] 50 44% MDR 135 d leukopenia
1.25<BSAb <1.5
Koizumi et al. (2000) gastric cancer (30%-59%) MST 207 d neutropenia
100 mg/da
[287] diarrhea
BSA ≥1.5 120 mg/da
b

BSAb <1.25 m 2 hemoglobinemia â

80 mg/da granulocytopenia
Sakata et al. (1998) 51 49% MDR 68 d
1.25<BSAb <1.5 leukopenia
[288] gastric cancer (36%-62%) MST 250 d
100 mg/da diarrhea
BSA ≥1.5 120 mg/da
b
malaise

BSAb <1.25 m 2 neutropenia

Baba et al. (1998)
80 mg/da thrombocytopenia
[289] 62 35% MDR 171 d
1.25<BSAb <1.5 anemia
Ohtsu et al. (2000) colorectal cancer (25%-48%) MST 12 m
100 mg/da leukopenia
[290]
BSA ≥1.5 120 mg/da
b
anorexia

neutropenia
anorexia
Sano et al. (2000) 81 42% fatigue
80 mg/m2 a
MST 910 d
[291] breast cancer (31%-54%) nausea, vomiting
diarrhea
stomatitis

anorexia
59
Niitani et al. (2000) 2 a 22% diarrhea
non-small-cell lung 80 mg/m MST 309 d
[292] (12%-35%) fatigue
cancer
neutropenia

MST
TSd + 54%
TSd + 284 d
Miyamoto et al. (2000) 41 TSd - 53%
80 mg/m2 c
TSd - 189 d
[293] gastric cancer DPDd + 61%
DPDd + 338 d
DPDd - 48%
DPDd - 207 d
a
administered orally during 28 days in two daily doses every 6 weeks
b
BSA: body surface area
c
administered orally during 28 days every 6 weeks
d
TS: thymidylate synthase; DPD: dihydropyrimidine dehydrogenase
294 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2
Fig. (7). Schematic diagram of gene directed enzyme-prodrug therapy (GDEPT) (adapted from ref [297]). s, enzyme; l, activated drug.
non-toxic compound (prodrug) into a potent cytotoxic drug
(Fig. (7)). The main advantage of this strategy is that the
prodrug is delivered directly to the tumor site, thus
minimizing side effects such as gastrointestinal toxicity, a
consistent reaction to FU. Although this strategy for
treatment of cancer is still in the experimental stage, it
shows considerable promise due to its ability to target
tumors.
3.1. Cytosine Deaminase/5-Fluorocytosine (CD/FC)
FC (Fig. (1)) is an antifungal agent. It is not active
against cancer cells and is non-toxic. CD, found in certain
bacteria and fungi but not in mammalian cells, catalyzes the
deamination of cytosine to uracil. It therefore converts FC
into FU that will be metabolized as already described.
The CD gene used for GDEPT has been cloned from
Escherichia coli [298, 299]. It has been tested in several
cancer cell lines and shown to enhance mammalian cell
sensitivity to FC by up to 50-2000-fold [299-314]. In vivo
antitumor activity of the CD/FC combination has been
demonstrated in several animal models [300, 302, 305, 307,
308, 311, 312, 314-324]. Improved antitumor activity has
been recently achieved by using the catalytically superior
Saccharomyces cerevisiae CD [325-327].
The CD/FC system has one of the strongest bystander
effects demonstrated. The bystander effect is an extension of
the killing effects of the active drug to untransfected
Malet-Martino, et al.
neighboring cells; it is crucial for a successful GDEPT
strategy. Two major categories of bystander effect have been
identified, local or immune-mediated. The local bystander
effect is due to the transfer of toxic metabolites by diffusion
or through gap junctions, and/or to the transfer of apoptotic
factors. A systemic immune response plays an important role
in the distant bystander effect [297]. The CD/FC bystander
effect was observed in vitro and in vivo. It does not require
cell-to-cell contact. It is due to FU that can diffuse easily
into and out of cells by non-facilitated diffusion [302-306,
308, 311, 313, 315, 318, 324, 327-330]. However, the
diffusion of FU can also increase toxicity to surrounding
normal tissues [307]. This bystander effect is not only local
but also distant, i.e. immune-mediated. The immune
component of the CD/FC therapy was first demonstrated by
Mullen et al. [316], who also showed that CD protein itself
is immunogenic. Later on, several authors observed that
lymphocyte T-mediated immune responses play a substantial
role in antitumor effects [317, 329, 331-334].
To enhance the antitumor activity without increasing
systemic toxicity, combinations of treatment modalities or
several genes were investigated. FU being a radiosensitizer,
CD/FC GDEPT with ionizing radiation was tested in tumor
cell lines and in vivo in xenografts. This combined strategy
is synergistic and produced a measurable antitumor effect
[327, 335-344]. The use of CD/FC GDEPT with interferons
increased DNA damage and further inhibited TS activity in
glioma cells [345].
The Prodrugs of 5-Fluorouracil
To enhance the immunological response and so improve
the bystander effect, some strategies combined tumor
immunization with CD/FC GDEPT. Cotransfection of the
suicide gene CD with the cytokine interleukin 6 or 2 gene or
with the granulocyte-macrophage colony-stimulating factor
(GM-CSF) gene or with the GM-CSF and stem cell factor
genes inhibited the growth of tumors in mice and induced
antitumor immunity [346-349].
Combined GDEPT systems were also tested. The most
studied enzyme-prodrug strategy in cancer GDEPT is herpes
simplex virus thymidine kinase (HSV TK) coupled to the
antiherpetic drug ganciclovir (GCV). TK converts the
inactive prodrug GCV to its monophosphate derivative
subsequently transformed into GCV triphosphate, the
cytotoxic agent. Delivery of CD/HSV TK fusion genes
(called double suicide gene therapy) followed by FC and
GCV treatment has a synergistic antitumor effect both in
vitro on gliosarcoma, mammary, renal and prostate
carcinoma cells, and in vivo [331, 350-352]. Improved
antitumor activity was also obtained by cotransfecting cells
with the genes for (i) CD and uracil phosphoribosyl-
transferase (UPRT), a bacterial enzyme absent from
mammalian cells that can directly convert FU to FUMP, and
then treating the cells with FC [353-355], or (ii) CD and
cytochrome P450 2B1 with a subsequent treatment by FC
and ifosfamide [356], or (iii) CD and interferon gamma
[357]. The double suicide gene therapy CD/HSV TK coupled
with RT and a treatment with FC and GCV potentiated the
antitumor effects in vitro in gliosarcoma and prostate
carcinoma cells, and in vivo in gliomas [358-361]. A
bimodal approach combining viral therapy and double
suicide gene therapy (CD/HSV TK), or a trimodal approach
(viral therapy + CD/HSV TK therapy + RT) demonstrated
high antitumor efficacy [362-364].
Monitoring of CD/FC gene therapy in vivo is possible
with fluorine-19 magnetic resonance spectroscopy (19F
MRS), which showed the transformation of FC into FU and
its subsequent anabolites and catabolites in nude mice
bearing subcutaneous human colorectal carcinoma [365].
Diffusion magnetic resonance imaging, a technique
producing quantitative and noninvasive images of the
apparent mobility of water within a tissue, detected early
changes associated with a CD/FC gene therapy in gliomas
[366].
To our knowledge, two clinical trials involved the
CD/FC therapy. In an ongoing phase I clinical study, a CD-
containing adenovirus is intratumorally administered to
eighteen patients with metastatic liver disease associated
with colorectal carcinoma, followed by oral administration of
FC [367]. In a phase I study, twelve breast cancer patients
received an intratumoral injection of a plasmid containing
the CD gene driven by the tumor-specific erbB-2 promoter,
and systemic FC (200 mg/kg/day). The approach was shown
to be safe and selective as significant levels of expression of
the suicide gene were specifically restricted to erbB-2-
positive tumor cells. In four patients, there was evidence of
tumor regression, even though two of them did not receive
the prodrug, which may be due to the immunogenicity of
CD [368].
Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 295
3.2. UPRT/FU
UPRT is a pyrimidine salvage enzyme (corresponding to
OPRT in mammalian cells) that catalyzes the synthesis of
UMP from uracil and PRPP. Adenoviral-mediated
transduction of Escherichia coli UPRT gene resulted in
marked sensitization of colon, gastric, liver, and pancreas
cancer cell lines to low concentration of FU, and also
increased antitumor effects in vivo [369, 370]. This is
provoked by increased incorporation of FU into RNA and
marked inhibition of TS due to enhanced level of FdUMP
[370]. A diffusible bystander effect was observed when
hepatoma Hep 3B cells were infected with UPRT-expressing
adenovirus and in rat gliosarcoma cells [369, 371]. On the
other hand, the bystander effect was marginal in Colon
26/UPRT cells and in mice inoculated with these cells [372].
This is explained by the fact that the expression level of
connexin 43, a protein that constitutes gap junctions, is high
in gliosarcoma cells but low in Colon 26 cells [371].
3.3. Gamma Herpes Virus 72 Thymidine Kinase (MHV
72 TK)/ FdUrd
The efficiency of MHV 72 TK as a suicide gene when
FdUrd is used as a prodrug has been recently demonstrated
on rat fibroblastoid cells deficient in the cellular TK gene. A
bystander effect was also observed [373].
3.4. TP/5’dFUrd
Unlike the prodrug FC that needs activation by an
enzyme not normally expressed in mammalian cells, other
strategies use agents activated by enzymes endogenously
expressed in tumors. The sensitivity of tumors to these
drugs can thus be enhanced by using gene delivery to
increase levels of these activating enzymes [374].
Transfection of a human breast cancer cell line with the
human TP cDNA yielded cells with 165-fold increased
sensitivity to 5’dFUrd over the parental line. A strong
bystander effect was also demonstrated due to diffusible FU
as already described for the CD/FC system [375, 376].
Recently, an enhancement of the sensitivity to 5’dFUrd and
CAP with a bystander effect was observed when human renal
carcinoma cells were transfected with TP cDNA [377].
4. Antibody Directed Enzyme-Prodrug Therapy
(ADEPT)
ADEPT is another approach to target cytotoxic drugs to
neoplastic tissue. It has long been known that certain types
of tumor cells present characteristic tumor-associated
antigens on their surface. In the first step of this method, an
enzyme-monoclonal antibody is administered and allowed
sufficient time to localize to the tumor and clear from
circulation. Following this, the tethered enzyme catalytically
metabolizes a separately-given prodrug, releasing an effector
able to diffuse to and enter surrounding tumor cells (Fig. (8))
[378]. The applicability of ADEPT is limited by the paucity
of tumor-specific antigens.
296 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2
Fig. (8). Schematic diagram of antibody directed enzyme-prodrug therapy (ADEPT) (adapted from ref [378]).
4.1. Fluorocytosine for Cytosine Deaminase
In a first paper, Senter et al. [379] covalently attached to
CD the antibody L6, which binds to an antigen on human
carcinomas, and 1F5, which binds to the CD20 antigen on
normal and neoplastic B-cells. The combination of L6-CD
and FC was equivalent in cytotoxic activity to FU when
tested against the H2981 human lung adenocarcinoma cell
line L6 positive and 1F5 negative. In a second paper [380],
the same group showed that the L6-CD/13B/FC
combination can be used to deliver substantially higher
levels of FU to H2981 tumor-bearing mice than can be
achieved via systemic administration. The first step of the
experiment was the injection of the conjugate L6-CD. 24
hours later, the antiidiotypic antibody 13B chosen as it
could bind to circulating L6-CD but not to L6-CD bound to
H2981 cells was injected to accelerate the clearance of
circulating conjugate. As a result it was possible to
administer in excess of 800 mg/kg of FC with no toxicity,
compared to only 90 mg/kg of FU alone. The L6-
CD/13B/FC combination resulted in 17 times more
intratumoral FU compared to systemic FU administration.
The conversion of FC into FU was low in blood, kidneys
and liver. The activation of FC to FU was monitored in
H2981 cells after L6-CD/FC therapy and in tumor-bearing
19 19
mice after L6-CD/13B/FC therapy with F MRS and F
chemical shift imaging [381].
4.2. FU Prodrugs for β-Glucuronidase
Targeting β-glucuronidase (EC 3.2.1.31) is attractive
since the enzyme is normally found only in lysosomes or
microsomes, suggesting that human forms of the enzyme
Malet-Martino, et al.
might be exploited avoiding the problem of an immune
response to the conjugate [382]. Moreover, the concentration
of β-glucuronidase is high in necrotic cells allowing the
activation of prodrugs in this part of the tumor. Of three
glucuronide-based FU prodrugs recently synthesized (Fig.
(9A)) [383], the conversion of compound 1 into FU was
followed in Lovo-bearing mice by 19F MRS [384].
5. Some Recent Data on the Chemistry of Fu Prodrugs
Recent studies have shown that hypoxia in human
tumors is associated with poor prognosis. Tumor hypoxia is
not only a problem for radiation therapy and chemotherapy,
but also appears to accelerate malignant progression and
increase metastasis. Various strategies have been developed
to overcome the problem of hypoxia. One approach is the
use of prodrugs that are activated by hypoxic irradiation.
Indeed, radiation is intended to be applied to tumor sites
only, and in addition, hypoxic cells are thought to be present
only in tumors. Therefore, this type of prodrug appeared
promising in terms of selective tumor treatment. Mori et al.
[385] have found a series of compounds with side chains of
2-oxoalkyl structures at the N1 position of FU that are
converted efficiently to FU following hypoxic irradiation
(Fig. (9B)). Among them, OFU001 (Fig. (9B)) is the
prototype compound in terms of the simplest side-chain
structure. The proposed mechanism of FU release by hypoxic
irradiation is shown in Fig. (9B). Hydrated electrons (eaq )
-
produced by hypoxic irradiation are thought to be
incorporated into the compound to form the corresponding
π* anion radical, which is thermally activated to the σ*
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 297

anion radical with weakened C1’-N1 bond [386].
Subsequently, hydrolytic dissociation of the C1’-N1 bond
occurs, releasing FU. After i.p. administration of OFU001 to
mice bearing subcutaneous SCCVII tumor and a local
irradiation with 15 or 30 Gy, FU was actually released in the
tumor, but no significant therapeutic effects were seen [387].
However, the concept of hypoxic radiation activation seems
interesting and the authors have synthesized several prodrugs
of FdUrd having this type of side-chain.
Differentiation therapy is an attractive approach to cancer
treatment, which assumes that neoplastic transformation
reveals the inability of a cell population to couple
proliferation and differentiation signals. Induced
differentiation modulates the cell program by transforming
malignant cells into mature cells with no proliferative
potential. Therefore, the addition of differentiation treatment
to chemotherapy greatly improves the chance of long-term
survival [388]. Campos et al. [389] synthesized a novel class
of FU-containing acyclonucleosides. The antitumor activity
of these FU O,N-acetals was assessed against HEp human
cells showing that compound 4 (Fig. (9C)) is 4-fold more
active than FU. Moreover, compound 5 has a lower toxicity
than FU and is able to induce myogenic differentiation in

O O
A H F H
F
N N

N O N O

HN HN
R
O2N
O O O O
O
O
OH
O HOOC
OH
HOOC HO HO

HO HO
1 R=H 3

2 R = COOH

B
O

F H
N

N O
CH3
O O O O
O
F H F H F H F
N N e aq - N H+ NH

N OO N O N O N O
CH3 H
O CH3
n( ) F H
O N O
n = 0-4, 9 OFU001 σ* anion radical FU
N O
CH3

π* anion radical
298 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 Malet-Martino, et al.

(Fig. 9) contd….

C
O O O O
F H F H F H H F
N N N N

N O N O N O O N
HO H HO H

CpO O O
iPrO
O O
L
CH3O N N OCH3
H H
4 5

Cp = cyclopentyl iPr = isopropyl L= (CH2) 2 6a

6b

6c

Fig. (9). Some novel FU prodrugs.

rhabdomyosarcoma cells, suggesting that this drug might be
useful for differentiation therapy in this type of tumor. They
also prepared some bis(FU-O,N-acetals) (compounds 6a-c;
Fig. (9C)) with interesting antineoplastic activity against the
HT-29 cell line.
prodrugs with respect to conventional treatment regimens
should continue to be proved in future clinical trials.
ABBREVIATIONS

FU = 5-Fluorouracil
CONCLUSION
FdUMP = 5-Fluoro-2'-deoxyuridine-5'-monophosphate
FU is one of the most widely used cytotoxic drugs. It is
usually administered by i.v. bolus or by continuous i.v. TP = Thymidine phosphorylase
infusion. Although the latter route is the most efficient and
least toxic, it is costly and inconvenient. Treatment is now FdUrd = 5-Fluoro-2'-deoxyuridine
increasingly governed by concern for patient quality of life as
well as for efficacy. I.v. infusion requires attendance in a TS = Thymidylate synthase
hospital or clinic, which is not without psychological impact
FUMP = 5-Fluorouridine-5'-monophosphate
on the patient, and has a non-negligible risk of
complications from catheterization. An oral formulation of OPRT = Orotate phosphoribosyl transferase
FU would be considerable advance in the treatment of cancer.
Unfortunately due to the activity of DPD, the drug on its PRPP = 5’-Phosphoribosyl-1-pyrophosphate
own is poorly absorbed and tissue levels are highly variable.
FUrd = 5-Fluorouridine
The development of new agents that block the catabolism
of FU by inhibiting DPD, or that increase its anabolism FUDP = 5-Fluorouridine-5'-diphosphate
have given new impetus to therapeutic strategies using
fluoropyrimidines. Oral FU prodrugs will undoubtedly join FUTP = 5-Fluorouridine-5'-triphosphate
the list of chemotherapeutic agents as they appear to be as
active, less toxic and more convenient than the parent UTP = Uridine-5’-triphosphate
compound FU. A potential problem with oral chemotherapy
is the reliability of patient compliance with treatment, FUDP-
especially in the adjuvant therapy. Nevertheless, combining sugars = FU-nucleotide sugars
oral fluoropyrimidines with drugs such as CPT-11 and
oxaliplatin is an exciting prospect. The advantages of FU FdUDP = 5-Fluoro-2'-deoxyuridine-5'-diphosphate
The Prodrugs of 5-Fluorouracil Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 2 299

FdUTP = 5-Fluoro-2'-deoxyuridine-5'-triphosphate MTX = Methotrexate

DPD = Dihydropyrimidine dehydrogenase U = Uracil

NADPH = Reduced form of Nicotinamide adenine AUC = Area under the curve
dinucleotide phosphate
MMC = Mitomycin C
FUH2 = 5,6-Dihydro-5-fluorouracil
PMC = Pharmacokinetic modulating chemotherapy
FUPA = α-Fluoro-β-ureidopropionic acid
RT = Radiotherapy
FBAL = α-Fluoro- β-alanine
ER = Estrogen receptor
F- = Fluoride ion
CDHP = 5-Chloro-2,4-dihydroxypyridine
CFBAL = N-carboxy-α-fluoro-β-alanine
OXO = Potassium oxonate
FHPA = 2-Fluoro-3-hydroxypropanoic acid
GDEPT = Gene directed enzyme-prodrug therapy
FAC = Fluoroacetate
CD = Cytosine deaminase
MeTHF = 5,10-Methylene tetrahydrofolate
FC = 5-Fluorocytosine
dUMP = 2’-Deoxyuridine-5’-monophosphate
GM-CSF = Granulocyte-macrophage colony-stimulating
dTMP = Thymidine-5'-monophosphate factor
dTTP = Thymidine-5'-triphosphate HSV TK = Herpes simplex virus thymidine kinase
dUTP = 2’-Deoxyuridine-5’-triphosphate GCV = Ganciclovir
i.v. = Intravenous UPRT = Uracil phosphoribosyltransferase
19
vs = Versus F MRS = Fluorine-19 magnetic resonance spectroscopy
MST = Median survival time TK = Thymidine kinase
HFS = Hand-foot syndrome ADEPT = Antibody directed enzyme-prodrug therapy
LV = Leucovorin
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