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

1698 Intrahepatic arterial infusion for 14-21 days causes minimal
systemic toxicity; however, there is a significant risk of biliary sclerosis
if this route is used for multiple cycles of therapy. Treatment
should be discontinued at the earliest manifestation of toxicity (usually
stomatitis or diarrhea) because the maximal effects of bone marrow
suppression and gut toxicity will not be evident until days 7-14.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Capecitabine (XELODA). Capecitabine, an orally administered
prodrug of 5-FU, is approved for the treatment of 1)
metastatic breast cancer in patients who have not
responded to a regimen of paclitaxel and an anthracycline
antibiotic; 2) metastatic breast cancer when used
in combination with docetaxel in patients who have had
a prior anthracycline-containing regimen; and 3)
metastatic colorectal cancer.
The recommended dosage is 2500 mg/m 2 /day, given in two
divided doses with food, for 2 weeks, followed by a rest period of 1
week. Capecitabine is well absorbed orally. It is rapidly de-esterified
and deaminated, yielding high plasma concentrations of an inactive
prodrug 5′-deoxyfluorodeoxyuridine (5′-dFdU), which disappears
with a t 1/2
of ~1 hour. The conversion of 5′-dFdU to 5-FU by thymidine
phosphorylase occurs in liver tissues, peripheral tissues, and
tumors. 5-FU levels are <10% of those of 5′-dFdU, reaching a maximum
of 0.3 mg/L or 1 μM at 2 hours. Liver dysfunction delays the
conversion of the parent compound to 5′-dFdU and 5-FU, but there is
no consistent effect on toxicity (Twelves et al., 1999).
Combination Therapy. Higher response rates are seen
when 5-FU or capecitabine is used in combination with
other agents (e.g., with cisplatin in head and neck cancer,
with oxaliplatin or irinotecan in colon cancer).
The combination of 5-FU and oxaliplatin or irinotecan has
become the standard first-line treatment for patients with metastatic
colorectal cancer, although equivalent results are reported for
capecitabine and oxaliplatin. 5-FU in combination regimens has
improved survival in the adjuvant treatment for breast cancer and,
with oxaliplatin and leucovorin, for colorectal cancer. 5-FU also is
a potent radiation sensitizer. Beneficial effects also have been
reported when combined with irradiation as primary treatment for
locally advanced cancers of the esophagus, stomach, pancreas,
cervix, anus, and head and neck. 5-FU produces very favorable
results for the topical treatment of premalignant keratoses of the skin
and multiple superficial basal cell carcinomas.
Clinical Toxicities. The clinical manifestations of toxicity caused
by 5-FU and floxuridine are similar. The earliest untoward symptoms
during a course of therapy are anorexia and nausea, followed
by stomatitis and diarrhea, which constitute reliable warning signs
that a sufficient dose has been administered. Mucosal ulcerations
occur throughout the GI tract and may lead to fulminant diarrhea,
shock, and death, particularly in patients who are DPD deficient.
The major toxic effects of bolus-dose regimens result from the
myelosuppressive action of 5-FU. The nadir of leukopenia usually is
between days 9 and 14 after the first injection of drug.
Thrombocytopenia and anemia also may occur. Loss of hair, occasionally
progressing to total alopecia, nail changes, dermatitis, and
increased pigmentation and atrophy of the skin may be encountered.
Hand-foot syndrome, a particularly prominent adverse effect of
capecitabine, consists of erythema, desquamation, pain, and sensitivity
to touch of the palms and soles. Acute chest pain with evidence
of ischemia in the electrocardiogram may result from coronary artery
vasospasms during or shortly after 5-FU infusion. In general, myelosuppression,
mucositis, and diarrhea occur less often with infusional
regimens than with bolus regimens, while hand-foot syndrome
occurs more often with infusional regimens than with bolus regimens.
The significant risk of toxicity with fluoropyrimidines emphasizes
the need for very skillful supervision by physicians familiar
with the action and possible hazards.
Capecitabine causes much the same spectrum of toxicities as
5-FU (diarrhea, myelosuppression), but the hand-foot syndrome
occurs more frequently and may require dose reduction or cessation
of therapy.
CYTIDINE ANALOGS
Cytarabine (Cytosine Arabinoside; Ara-C)
Cytarabine (1-β-D-arabinofuranosylcytosine; Ara-C) is
the most important antimetabolite used in the therapy of
AML. It is the single most effective agent for induction
of remission in this disease.
Mechanism of Action. Ara-C is an analog of 2′-deoxycytidine
with the 2′-hydroxyl in a position trans to the
3′-hydroxyl of the sugar (Figure 61–7). The 2′-hydroxyl
hinders rotation of the pyrimidine base around the
nucleoside bond and interferes with base pairing. The
drug enters cells via a nucleoside transporter and is
converted to its active form, the 5′-monophosphate
ribonucleotide, by deoxycytidine kinase (CdK), an
enzyme that shows polymorphic expression among
patients, as detailed in the following paragraphs.
Ara-C penetrates cells by a carrier-mediated process shared
by physiological nucleosides. Several candidate carriers bring nucleosides
into cells, but the hENT1 transporter appears to be the primary
mediator of Ara-C influx. In infants and adults with ALL and
t(4;11) mixed-lineage leukemia (MLL) translocation, high-dose Ara-
C is particularly effective; in these patients, the nucleoside transporter,
hENT1, is highly expressed (Pui et al., 2004), and its
expression correlates with sensitivity to Ara-C. A single-point mutation
in hENT1 conferred Ara-C resistance in a leukemic cell line
(Cai et al., 2008). At extracellular drug concentrations >10 μM (levels
achievable with high-dose Ara-C), the nucleoside transporter no
longer limits drug accumulation, and intracellular metabolism to a
triphosphate becomes rate limiting.
Ara-C must be “activated” by conversion to the 5′-monophosphate
nucleotide (Ara-CMP), a reaction catalyzed by CdK.
Polymorphisms of CdK may influence the rate of activation in individual
patients (Lamba et al., 2007). Ara-CMP then reacts with
appropriate deoxynucleotide kinases to form diphosphate and
triphosphates (Ara-CDP and Ara-CTP). Ara-CTP competes with the
physiological substrate deoxycytidine 5′-triphosphate (dCTP) for