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

1694 four doses, alternating with leucovorin (0.1 mg/kg every other day).
Courses are repeated at 3-week intervals, toxicity permitting, and
urinary β-human chorionic gonadotropin titers are used as a guide
for persistence of disease.
Beneficial effects also are observed in the combination therapy
of Burkitt’s and other non-Hodgkin’s lymphomas. Methotrexate
is a component of regimens for carcinomas of the breast, head and
neck, ovary, and bladder. High-dose methotrexate with leucovorin
rescue (HDM-L) is a standard agent for adjuvant therapy of osteosarcoma
and produces a high complete response rate in CNS lymphomas.
The administration of HDM-L has the potential for renal
toxicity, probably related to the precipitation of the drug, a weak
acid, in the acidic tubular fluid. Thus, vigorous hydration and alkalinization
of urine pH are required prior to drug administration.
HDM-L should be performed only by experienced clinicians who
are familiar with hydration regimens and who have access to laboratories
that monitor concentrations of methotrexate in plasma. If
methotrexate values measured 48 hours after drug administration are
1 μM or higher, higher doses (100 mg/m 2 ) of leucovorin must be
given until the plasma concentration of methotrexate falls to <50 nM
(Stoller et al., 1977). With appropriate hydration and urine alkalinization,
and in patients with normal renal function, the incidence of
nephrotoxicity following HDM-L is <2%. In patients who become
oliguric, intermittent hemodialysis is ineffective in reducing
methotrexate levels. Continuous-flow hemodialysis can eliminate
methotrexate at ~50% of the clearance rate in patients with intact
renal function (Wall et al., 1996). Alternatively, a methotrexatecleaving
enzyme, carboxypeptidase G2, can be obtained from the
Cancer Therapy Evaluation Program at the National Cancer Institute.
When administered intravenously, it rapidly clears the drug
(DeAngelis et al., 1996). Methotrexate concentrations in plasma fall
by ≥99% within 5-15 minutes following enzyme administration,
with insignificant rebound. Systemically administered carboxypeptidase
G2 has little effect on methotrexate levels in the CSF.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Clinical Toxicities. As previously stated, the primary toxicities
of antifolates affect the bone marrow and the intestinal
epithelium and correct within 10-14 days.
Myelosuppressed patients may be at risk for spontaneous
hemorrhage or life-threatening infection, and they may
require prophylactic transfusion of platelets and broadspectrum
antibiotics if febrile. Side effects usually reverse
completely within 2 weeks, but prolonged myelosuppression
may occur in patients with compromised renal function
who have delayed excretion of the drug. The dosage
of methotrexate (and likely pemetrexed) must be reduced
in proportion to any reduction in CrCl.
Additional toxicities of methotrexate include alopecia, dermatitis,
an allergic interstitial pneumonitis, nephrotoxicity (after
high-dose therapy), defective oogenesis or spermatogenesis, abortion,
and teratogenesis. Low-dose methotrexate may lead to cirrhosis
after long-term continuous treatment, as in patients with
psoriasis. Intrathecal administration of methotrexate often causes
meningismus and an inflammatory response in the CSF. Seizures,
coma, and death may occur rarely. Leucovorin does not reverse
neurotoxicity.
A toxicity of particular significance in chronic administration
to patients with psoriasis or rheumatoid arthritis is hepatic
fibrosis and cirrhosis. Increased hepatic portal fibrosis is detected
with higher frequency than in control patients after ≥6 months of
continuous oral methotrexate treatment of psoriasis. Its presence
mandates discontinuation of methotrexate. High-dose administration
regularly causes acute elevation of hepatic transaminases, but
these changes rapidly reverse and are not associated with permanent
liver damage.
Folic acid antagonists are toxic to developing embryos.
Methotrexate is highly effective when used with the prostaglandin
analog misoprostol in inducing abortion in first-trimester pregnancy
(Hausknecht, 1995).
Pemetrexed toxicity mirrors that of methotrexate, with the
additional feature of a prominent erythematous and pruritic rash in
40% of patients. Dexamethasone, 4 mg twice daily on days –1, 0, and
+1, markedly diminishes this toxicity. Unpredictably severe myelosuppression
with pemetrexed, seen especially in patients with preexisting
homocystinemia and possibly reflecting folate deficiency,
largely is eliminated by concurrent administration of low dosages of
folic acid, 350-1000 mg/day, beginning 1-2 weeks prior to pemetrexed
and continuing while the drug is administered. Patients should
receive intramuscular vitamin B 12
(1 mg) with the first dose of pemetrexed
to correct possible B 12
deficiency. These small doses of folate
and B 12
do not compromise the therapeutic effect.
PYRIMIDINE ANALOGS
The antimetabolites as a class encompass a diverse
group of drugs that inhibit RNA and DNA function.
The fluoropyrimidines and certain purine analogs
(6-mercaptopurine and 6-thioguanine) inhibit the synthesis
of essential precursors of DNA. Others, such as
the cytidine and adenosine nucleoside analogs, become
incorporated into DNA and block its further elongation
and function. Other inhibitory effects of these analogs
may contribute to their cytotoxicity and even their ability
to induce differentiation.
To understand the role of these drugs, it is useful to review the
nomenclature of the DNA bases and their metabolic intermediates.
Four bases, shown in Figure 61–7, form DNA; these are two pyrimidines,
thymine and cytosine, and two purines, guanine and adenine.
Some bases (guanine) are found in mammalian cells as free bases,
while others (the pyrimidines) are present in their active form only
as nucleosides (a base attached to a ribose or deoxyribose). These
precursor forms then are converted to a nucleoside triphosphate
(base, sugar, and 5′-phosphate, also known as a nucleotide).
Mammalian cells lack the ability to utilize cytosine, thymine, and
adenine as bases, and so these bases are found in the bloodstream as
nucleosides and in cells as nucleosides or nucleotides. The various
purine and pyrimidine triphosphates form the intracellular pool of
precursors for both RNA (with ribose sugars) and DNA (with
deoxyribose sugars). The composition of RNA also differs from
DNA in that RNA incorporates uracil instead of thymine as one of
its bases.