First introduced in 1957, the fluoropyrimidine fluorouracil (5-FU)
remains a major chemotherapeutic agent for the treatment of
gastrointestinal, breast, and head and neck cancers. Although
response rates of advanced cancers to 5-FU remain in the 15% to 20%
range, the complexity and variability of the drugs metabolism
offer an opportunity to optimize fluoropyrimidine chemotherapy. This
can be done by selecting tumors most likely to respond to the drug,
altering drug scheduling, inhibiting 5-FU catabolism, modifying
pharmacokinetics by administering 5-FU prodrugs, or screening
individuals for genetic polymorphisms that may increase the risks of
5-FU toxicity. Capecitabine (Xeloda) is a new, orally available,
tumor-selective fluoropyrimidine carbamate prodrug activated by a
three-enzyme process to provide high levels of 5-FU in tumor
This article will briefly review the metabolism of 5-FU, the
determinants of sensitivity to fluoropyrimidines, and strategies to
optimize fluoropyrimidine therapy. It will then describe the
preclinical and clinical pharmacology of capecitabine.
As shown in Figure 1, 5-FU
undergoes a series of anabolic and catabolic reactions. The
cytotoxicity of 5-FU appears to result from the inhibitory activity
of 5-fluoro-2´-deoxyuridine-5´-monophosphate (FdUMP) on
thymidylate synthase and the incorporation of fluoropyrimidines into
ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).[3,4] Although
the incorporation of fluorouridine into RNA can produce toxicity as a
result of major effects on RNA processing and function, the effects
of 5-fluoro-2´-deoxyuridine-5´-triphosphate (FdUTP)
incorporation into DNA are less clear. Presumably, its presence
activates the excision repair process. However, since DNA repair
requires the presence of thymidine triphosphate, a substrate depleted
in 5-FUtreated cells, DNA strand breakage is likely to occur.
Ribonucleotide SynthesisFluorouracil follows the
same pathways as uracil in pyrimidine biosynthesis. Uridine
phosphorylase and uridine kinase sequentially convert 5-FU to
5-fluorouridine and then to 5-fluorouridine-5´-monophosphate
(FUMP). Alternatively, FUMP can be formed by a direct reaction of
5-FU with 5-phosphoribosyl-1-pyrophosphate (PRPP) catalyzed by the
enzyme orotate phosphoribosyl transferase. Cellular kinases
subsequently phosphorylate FUMP to its diphosphate (FUDP) and
triphosphate (FUTP) forms, with FUTP subsequently incorporated into
several forms of RNA by RNA polymerase.
Deoxyribonucleotide SynthesisThe formation of
FdUMP is critical to the antineoplastic activity of 5-FU. FdUMP can
be formed by one of two pathways: (1) conversion of FUDP to
5-fluoro-2´-deoxyuridine-5´-diphosphate (FdUDP) by
enzymatic activity of ribonucleotide reductase, or (2) direct
conversion of 5-FU to 5-fluorouracil deoxyriboside (5-FUdR) by
thymidine phosphorylase. Both are subsequently phosphorylated or
dephosphorylated to FdUMP by thymidine kinase.
FdUMP appears to be responsible for much of the cytotoxicity of 5-FU.
As a potent inhibitor of thymidylate synthase, it prevents the
formation of thymidine monophosphate and thereby inhibits DNA
synthesis.[3,4] Inhibition of thymidylate synthase by FdUMP depletes
cellular stores of thymidine triphosphate, an important precursor of
DNA. This results when FdUMP and 5,10-methylenetetrahydrofolate form
a covalent ternary complex with thymidylate synthase. The stability
of the fluorine-carbon bond blocks the transfer of the methylene
group and the two hydrogen atoms from folate to dUMP and produces
sustained inhibition of the enzymatic activity of thymidylate synthase.
The amount of 5-FU available for antineoplastic activity is directly
regulated by its catabolism.[5,6] The initial and rate-limiting step
in 5-FU catabolism is the reduction of the pyrimidine ring to
5-fluoroureidopropionic acid (FUPA) by hepatic dihydropyrimidine
dehydrogenase (DPD). This enzyme is also found in the intestinal
mucosa and other tissues. FUPA is subsequently converted to
fluoro-beta-alanine by beta-alanine synthase. Following
administration of an intravenous dose of 5-FU, the drug is rapidly
catabolized by the liver, with the majority (60% to 90%) excreted in
the urine as inactive metabolites. Biliary excretion accounts for
2% to 3% of the total. Deficiency of DPD has been estimated to occur
in 2% to 5% of the population and has the potential to dramatically
increase the risk of 5-FU toxicity due to impaired clearance of the drug.[7,8]
A number of clinical and metabolic factors determine the efficacy of
the fluoropyrimidines. These include the sensitivity of the tumor,
drug scheduling, cellular factors (eg, activity of the anabolic and
catabolic enzymes, the presence of a pool of nucleotide precursors,
folate and other cofactors, intact apoptotic pathways), and the
particular formulation of 5-FU.
Pivotal Role of Thymidine Phosphorylase
Thymidine phosphorylase is a key enzyme in DNA synthesis and is
responsible for the reversible conversion of thymidine to thymine.
Thymidine phosphorylase is also a potent angiogenic growth factor and
is identical to platelet-derived endothelial cell growth factor.
Since thymidine phosphorylase can directly activate 5-FU by
converting it to 5-FUdR, levels of thymidine phosphorylase are
critical in the efficacy of fluoropyrimidines. Levels of thymidine
phosphorylase are higher in a wide variety of solid tumors than in
the adjacent nonneoplastic tissue. For these reasons, thymidine
phosphorylase represents an attractive target for fluoropyrimidine
therapy. Since the last step of capecitabine activation is by
intratumoral thymidine phosphorylase, this selectivity can increase
tumor cytotoxicity and decrease systemic exposure to the effects of 5-FU.
Intrinsic Mechanisms of Resistance
Some tumors are inherently more sensitive than others to the
metabolic actions of 5-FU. For example, although gastrointestinal,
breast, and head and neck cancers are relatively sensitive to 5-FU,
the drug has little or no activity against malignant melanomas. In
addition, resistance may develop during the course of disease.
Mechanisms of resistance include insufficient delivery of drug to the
target tissue, decreased anabolism of 5-FU to the nucleotide form,
increased clearance of 5-FU nucleotides, alterations in the kinetics
of thymidylate synthase, depletion of folate cofactors, and/or the
level of the competing substrate, deoxyuridine monophosphate (dUMP).
Strategies to Optimize 5-FU Therapy
Knowledge of 5-FU pharmacokinetics, cellular factors that contribute
to resistance, and 5-FU metabolism provides an opportunity to modify
drug scheduling, as well as to rationally design drugs that can
increase the intrinsic efficacy of 5-FU.
PharmacokineticsFluorouracil shows significant
and unpredictable differences in absorption following administration
of an oral dose. Consequently, the drug is not routinely
administered by the oral route. However, it also shows significant
variations in plasma concentrationtime profiles after both
intravenous bolus and infusion administration. At higher doses,
the nonlinear pharmacokinetics make it difficult to predict plasma
levels and toxicity.
At least some of this pharmacokinetic variability may be due to
individual differences in DPD enzymatic activity. Coadministration of
5-FU with DPD inhibitors such as eniluracil has the potential to
minimize the variability of 5-FU pharmacokinetics between patients,
decrease the circadian variation in 5-FU levels during continuous
infusion therapy, and improve the therapeutic index of the drug.[3,12]
SchedulingThe schedule of administration can have
a significant effect on the efficacy and toxicity of 5-FU.
Fluorouracil has been administered by oral, intravenous bolus, and
continuous infusion techniques. Continuous infusion schedules are
associated with a lower incidence of bone marrow and gastrointestinal
toxicity. Although the therapeutic index of continuous infusion 5-FU
vs bolus administration appears to be improved in patients with
colorectal cancer, no improvement has been observed in survival
Scheduling may also influence the method of cell death following 5-FU
therapy. Preclinical studies suggest that bolus administration may
result in cell death that is more likely mediated by the disruption
of RNA metabolism than by a thymidylate synthaserelated
Cellular FactorsA variety of cellular factors
influence the efficacy of 5-FU therapy (Table
1). The level and activity of thymidylate synthase, as well
as intracellular folate pools, are critical factors in 5-FU activity.
For example, in a series of patients with gastric cancer treated with
5-FU, the level of thymidylate synthase in the primary tumor was
related to tumor response and survival. In a group of patients
with advanced colorectal cancer, intratumoral thymidylate synthase
expression detected by immunohistochemistry was inversely correlated
with tumor response to 5-FU chemotherapy (P = .0001).
Intratumoral folate levels are also an important variable in
determining response to 5-FU therapy. In a group of patients with
head and neck cancers, all patients who responded to 5-FU therapy had
intratumoral reduced folate levels above the median for the entire
population. Overexpression of DPD in tumor cells also appears to
be an important factor in resistance to 5-FU in some patients.
Indeed, the combination of high thymidylate synthase and high DPD
levels in tumor cells appears to account for most cases of clinical
resistance to 5-FU.
As discussed below, the effectiveness of capecitabine is critically
dependent upon the intratumoral level of thymidine phosphorylase, the
enzyme necessary for its intracellular activation.
5-FU Prodrugs5-FU prodrugs offer the opportunity
to alter the scheduling of the drug, improve pharmacokinetics,
increase tumor specificity, and potentially improve the therapeutic
index. Available and investigational 5-FU prodrugs include
capecitabine, tegafur, UFT (a fixed 1:4 ratio of tegafur and uracil),
S-1, and BOF-A2 (see Table 2).[3,19,20]
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