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

1716 compromised renal function, dosage should be reduced in proportion
to the reduction in CrCl (Arbuck et al., 1986). In patients with
advanced liver disease, increased toxicity may result from a low
serum albumin (decreased drug binding) and elevated bilirubin
(which displaces etoposide from albumin). However, guidelines for
dose reduction in this circumstance have not been defined. Drug concentrations
in the CSF average 1-10% of those in plasma.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Therapeutic Uses. The intravenous dose of etoposide (VEPESID, others)
for testicular cancer in combination therapy is 50-100 mg/m 2
for 5 days, or 100 mg/m 2 on alternate days for three doses. For small
cell carcinoma of the lung, the dosage in combination therapy is
35 mg/m 2 /day intravenously for 4 days or 50 mg/m 2 /day intravenously
for 5 days. The oral dose for small cell lung cancer is twice
the IV dose. Cycles of therapy usually are repeated every 3-4 weeks.
When given intravenously, the drug should be administered slowly
over a 30- to 60-minute period to avoid hypotension and bronchospasm,
which likely result from the additives used to dissolve
etoposide, a relatively insoluble compound.
A disturbing complication of etoposide therapy has emerged
in long-term follow-up of patients with childhood acute lymphoblastic
leukemia, who develop an unusual form of acute nonlymphocytic
leukemia with a translocation in chromosome 11q23. At this locus is
a gene (the MLL gene) that regulates the proliferation of pluripotent
stem cells. The leukemic cells have the cytological appearance of
acute monocytic or monomyelocytic leukemia but may express lymphoid
surface markers. Another distinguishing feature of etoposiderelated
leukemia is the short time interval between the end of
treatment and the onset of leukemia (1-3 years), compared to the
4- to 5-year interval for secondary leukemias related to alkylating
agents, and the absence of a myelodysplastic period preceding
leukemia (Pui et al., 1995). Patients receiving weekly or twice-weekly
doses of etoposide, with cumulative doses >2000 mg/m 2 , seem to be
at higher risk of leukemia.
Etoposide primarily is used for treatment of testicular tumors,
in combination with bleomycin and cisplatin, and in combination
with cisplatin and ifosfamide for small cell carcinoma of the lung. It
also is active against non-Hodgkin’s lymphomas, acute nonlymphocytic
leukemia, and Kaposi sarcoma associated with acquired
immunodeficiency syndrome (AIDS). Etoposide has a favorable toxicity
profile for dose escalation in that its primary acute toxicity is
myelosuppression. In combination with ifosfamide and carboplatin,
it frequently is used for high-dose chemotherapy in total doses of
1500-2000 mg/m 2 (Josting et al., 2000).
Clinical Toxicities. The dose-limiting toxicity of etoposide is
leukopenia, with a nadir at 10-14 days and recovery by 3 weeks.
Thrombocytopenia occurs less often and usually is not severe.
Nausea, vomiting, stomatitis, and diarrhea complicate treatment in
~15% of patients. Alopecia is a common but reversible adverse
effect. Hepatic toxicity is particularly evident after high-dose treatment.
For both etoposide and teniposide, toxicity increases in
patients with decreased serum albumin, an effect related to decreased
protein binding of the drug.
Teniposide
Teniposide (VUMON) is administered intravenously. It has a multiphasic
pattern of clearance from plasma; after distribution, a t 1/2
of 4 hours
and another t 1/2
of 10-40 hours are observed. Approximately 45% of
the drug is excreted in the urine, but in contrast to etoposide, as much
as 80% is recovered as metabolites. Anticonvulsants such as phenytoin
increase the hepatic metabolism of teniposide and reduce systemic
exposure (Baker et al., 1992). Dosage need not be reduced for patients
with impaired renal function. Less than 1% of the drug crosses the
blood-brain barrier. Teniposide is available for treatment of refractory
ALL in children and is synergistic with cytarabine. It is administered
by intravenous infusion in dosages that range from 50 mg/m 2 /day
for 5 days to 165 mg/m 2 /day twice weekly. The drug has limited utility
and primarily is given for acute leukemia in children and monocytic
leukemia in infants, as well as glioblastoma, neuroblastoma, and brain
metastases from small cell carcinomas of the lung. Myelosuppression,
nausea, and vomiting are its primary toxic effects.
DRUGS OF DIVERSE MECHANISM
OF ACTION
Bleomycin
The bleomycins, a unique group of DNA-cleaving antibiotics,
were discovered by Umezawa and colleagues as
fermentation products of Streptomyces verticillus. The
drug currently employed clinically is a mixture of the
two copper-chelating peptides, bleomycins A 2
and B 2
.
The various bleomycins differ only in their terminal
amino acid (Figure 61–14).
Bleomycins have attracted interest because of
their significant antitumor activity against both
Hodgkin’s lymphoma and testicular tumors. They are
minimally myelo- and immunosuppressive but cause
unusual cutaneous side effects and pulmonary fibrosis.
Because their toxicities do not overlap with those of
other cytotoxic drugs, and because of their unique mechanism
of action, bleomycin maintains an important role
in treating Hodgkin’s disease and testicular cancer.
Chemistry. The bleomycins are water-soluble, basic glycopeptides
(Figure 61–14). The core of the bleomycin molecule assumes a metalbinding
cage consisting of a pyrimidine chromophore linked to propionamide,
a β-aminoalanine amide side chain, and the sugars, l-gulose
and 3-O-carbamoyl-d-mannose. Bound in this complex are either Fe 2+
or Cu 2+ . Attached to the metal ion binding core are a tripeptide chain
and a terminal, DNA-binding bithiazole carboxylic acid.
Mechanism of Action. Bleomycin’s cytotoxicity results from its
ability to cause oxidative damage to the deoxyribose of thymidylate
and other nucleotides, leading to single- and double-stranded breaks
in DNA. Studies in vitro indicate that bleomycin causes accumulation
of cells in the G 2
phase of the cell cycle, and many of these cells
display chromosomal aberrations, including chromatid breaks, gaps,
and fragments, as well as translocations (Twentyman, 1983).
Bleomycin cleaves DNA by generating free radicals. In the
presence of O 2
and a reducing agent, such as dithiothreitol, the
metal–drug complex becomes activated and functions as a ferrous
oxidase, transferring electrons from Fe 2+ to molecular oxygen to