DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

dUMP
FdUMP
thymidylate
synthase
N5-10methylene
FH 4 Glu n
TMP
FH 2 Glu n
Other actions of 5-FU nucleotides:
• Inhibition of RNA processing
• Incorporation into DNA
TTP
Figure 61–10. Site of action of 5-fluoro-2’-deoxyuridine-5’-
phosphate (5-FdUMP). 5-FU, 5-fluorouracil; dUMP, deoxyuridine
monophosphate; TMP, thymidine monophosphate; TTP,
thymidine triphosphate; FdUMP, fluorodeoxyuridine monophosphate;
FH 2
Glu n
, dihydrofolate polyglutamate; FH 4
Glu n
, tetrahydrofolate
polyglutamate.
deoxyuridylate and/or fluorodeoxyuridylate into DNA would call
into action the excision-repair process. This process may result in
DNA strand breakage because DNA repair requires TTP, but this
substrate is lacking as a result of TS inhibition. 5-FU incorporation
into RNA also causes toxicity as the result of major effects on both
the processing and functions of RNA.
Resistance to the cytotoxic effects of 5-FU or FUdR has been
ascribed to loss or decreased activity of the enzymes necessary for
activation of 5-FU, amplification of TS (Washtein, 1982), mutation
of TS to a form that is not inhibited by FdUMP (Barbour et al.,
1990), and high levels of the degradative enzymes dihydrouracil
dehydrogenase and thymidine phosphorylase (Van Triest et al.,
2000). TS levels are finely controlled by an autoregulatory feedback
mechanism wherein the unbound enzyme interacts with and inhibits
the translational efficiency of its own mRNA, which provides for the
rapid TS modulation needed for cellular division. When TS is bound
to FdUMP, inhibition of translation is relieved, and levels of free TS
rise, restoring thymidylate synthesis. Thus, TS autoregulation may
be an important mechanism by which malignant cells become insensitive
to the effects of 5-FU (Chu et al., 1991).
Some malignant cells appear to have insufficient concentrations
of 5,10-methylenetetrahydrofolate, and thus cannot form maximal
levels of the inhibited ternary complex with TS. Addition of
exogenous folate in the form of N 5 -formyl FH 4
(leucovorin)
increases formation of the complex and enhances responses to 5-FU
in clinical trials (Grogan et al., 1993).
In addition to leucovorin, a number of other agents have been
combined with 5-FU in attempts to enhance the cytotoxic activity
through biochemical modulation. Methotrexate, by inhibiting purine
synthesis and increasing cellular pools of PRPP, enhances the activation
of 5-FU and increases antitumor activity of 5-FU when given
prior to but not following 5-FU. In clinical trials, the combination of
cisplatin and 5-FU has yielded impressive responses in tumors of
the upper aerodigestive tract, but the molecular basis of their interaction
is not well understood. Oxaliplatin, which downregulates TS
expression, is commonly used with 5-FU and leucovorin for treating
metastatic colorectal cancer. Perhaps the most important interaction
is the enhancement of irradiation by fluoropyrimidines, the basis for
which is unclear. 5-FU with simultaneous irradiation cures anal cancer
and enhances local tumor control in head and neck, cervical, rectal,
gastroesophageal, and pancreatic cancer.
Absorption, Fate, and Excretion. 5-FU is administered parenterally,
because absorption after oral ingestion of the drug is unpredictable
and incomplete. Metabolic degradation occurs in many
tissues, particularly the liver. 5-FU is inactivated by reduction of the
pyrimidine ring in a reaction carried out by dihydropyrimidine dehydrogenase
(DPD), which is found in liver, intestinal mucosa, tumor
cells, and other tissues. Inherited deficiency of this enzyme leads to
greatly increased sensitivity to the drug (Milano et al., 1999). The
rare individual who totally lacks this enzyme may experience profound
drug toxicity following conventional doses of the drug. DPD
deficiency can be detected either by enzymatic or molecular assays
using peripheral white blood cells or by determining the plasma ratio
of 5-FU to its metabolite, 5-fluoro-5,6-dihydrouracil.
Intravenous administration of 5-FU produces peak plasma
concentrations of 0.1-0.5 mM; plasma clearance is rapid (with a t 1/2
of 10-20 minutes). Only 5-10% of a single intravenous dose of 5-
FU is excreted intact in the urine. Although the liver contains high
concentrations of DPD, the dose does not have to be modified in
patients with hepatic dysfunction, presumably because of degradation
of the drug at extrahepatic sites. Given by continuous intravenous
infusion for 24-120 hours, 5-FU achieves steady-state plasma
concentrations in the range of 0.5-0.8 μM. 5-FU enters the CSF in
minimal amounts.
Therapeutic Uses
5-Fluorouracil. 5-FU produces partial responses in
10-20% of patients with metastatic colon carcinomas,
upper GI tract carcinomas, and breast carcinomas but
rarely is used as a single agent. 5-FU in combination
with leucovorin and oxaliplatin or irinotecan in the
adjuvant setting is associated with a survival advantage
for patients with colorectal cancers.
For average-risk patients in good nutritional status with adequate
hematopoietic function, the weekly dosage regimen employs
500-600 mg/m 2 with leucovorin once each week for 6 of 8 weeks.
Other regimens use daily doses of 500 mg/m 2 for 5 days, repeated in
monthly cycles. When used with leucovorin, doses of daily 5-FU for
5 days must be reduced to 375-425 mg/m 2 because of mucositis and
diarrhea. 5-FU increasingly is used as a biweekly infusion, in which
a loading dose is followed by a 48-hour continuous infusion, a schedule
that has less overall toxicity as well as superior response rates and
progression-free survival for patients with metastatic colon cancer
(De Gramont et al., 1998).
Floxuridine (FUdR). FUdR (fluorodeoxyuridine; FUDR,
others) is used primarily by continuous infusion into
the hepatic artery for treatment of metastatic carcinoma
of the colon or following resection of hepatic metastases
(Kemeny et al., 1999); the response rate to such
infusion is 40-50%, or double that observed with intravenous
administration.
1697
CHAPTER 61
CYTOTOXIC AGENTS