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

1712 The recommended dosing regimen of topotecan for ovarian
cancer and small cell lung cancer is a 30-minute infusion of
1.5 mg/m 2 /day for 5 consecutive days every 3 weeks. For cervical
cancer in conjunction with cisplatin, the dose of topotecan is
0.75 mg/m 2 on days 1, 2, and 3, repeated every 21 days. Because
a significant fraction of the topotecan administered is excreted in
the urine, patients with decreased CrCl may experience increased
toxicity (O’Reilly et al., 1996). Therefore, the dose of topotecan
should be reduced to 0.75 mg/m 2 /day in patients with moderate
renal dysfunction (CrCl of 20-40 mL/min), and topotecan should
not be administered to patients with severe renal impairment (CrCl
<20 mL/min). Hepatic dysfunction does not alter topotecan clearance
and toxicity. A baseline neutrophil count >1500 cells/mm3 and
a platelet count >100,000 is necessary prior to topotecan administration.
For small cell lung cancer, oral therapy can be used at a dosage
of 2.3 mg/m2/day for 5 consecutive days repeated every 21 days.
The oral dose is reduced to 1.8 mg/m2 for patients with a CrCl of
30-49 mL/min.
Irinotecan. Approved single-agent dosage schedules of irinotecan
(CAMPTOSAR, others) in the U.S. include 125 mg/m 2 as a 90-minute
infusion administered weekly (on days 1, 8, 15, and 22) for 4 out of 6
weeks, and 350 mg/m 2 given every 3 weeks. In patients with advanced
colorectal cancer, irinotecan is used as first-line therapy in combination
with fluoropyrimidines or as a single agent or in combination with
cetuximab following failure of a 5-FU/oxaliplatin regimen.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Clinical Toxicities
Topotecan. The dose-limiting toxicity with all dosing schedules is
neutropenia, with or without thrombocytopenia. The incidence of
severe neutropenia at the recommended phase II dose of 1.5 mg/m 2
daily for 5 days every 3 weeks may be as high as 81%, with a 26%
incidence of febrile neutropenia. In patients with hematological
malignancies, GI side effects such as mucositis and diarrhea become
dose limiting. Other less common and generally mild topotecanrelated
toxicities include nausea and vomiting, elevated liver
transaminases, fever, fatigue, and rash.
Irinotecan. The dose-limiting toxicity with all dosing schedules is
delayed diarrhea, with or without neutropenia. In the initial studies,
up to 35% of patients experienced severe diarrhea. Adoption of an
intensive regimen of loperamide (4 mg of loperamide starting at the
onset of any loose stool beginning more than a few hours after
receiving therapy, followed by 2 mg every 2 hours) (see Chapter 47)
has effectively reduced this incidence by more than half. However,
once severe diarrhea occurs, standard doses of antidiarrheal agents
tend to be ineffective. Diarrhea generally resolves within a week and,
unless associated with fever and neutropenia, rarely is fatal.
The second most common irinotecan-associated toxicity is
myelosuppression. Severe neutropenia occurs in 14-47% of the
patients treated with the every-3-weeks schedule and is less frequently
encountered among patients treated with the weekly schedule. Febrile
neutropenia is observed in 3% of patients and may be fatal, particularly
when associated with concomitant diarrhea. A cholinergic syndrome
resulting from the inhibition of acetylcholinesterase activity by irinotecan
may occur within the first 24 hours after irinotecan administration.
Symptoms include acute diarrhea, diaphoresis, hypersalivation,
abdominal cramps, visual accommodation disturbances, lacrimation,
rhinorrhea, and less often, asymptomatic bradycardia. These effects
are short lasting and respond within minutes to atropine. Atropine may
be prophylactically administered to patients who have previously
experienced a cholinergic reaction. Other common and generally manageable
toxicities include nausea and vomiting, fatigue, vasodilation
or skin flushing, mucositis, elevation in liver transaminases, and alopecia.
Finally, there have been case reports of dyspnea and interstitial
pneumonitis associated with irinotecan therapy in Japanese patients
with lung cancer (Fukuoka et al., 1992).
ANTIBIOTICS
Dactinomycin (Actinomycin D)
The first anticancer antibiotics were the series of actinomycins
discovered by Waksman and colleagues in
1940. The most important of these, actinomycin D, has
beneficial effects in the treatment of solid tumors in
children and choriocarcinoma in adult women.
Chemistry and Structure-Activity Relationships. The actinomycins
are chromopeptides. Most contain the same chromophore,
the planar phenoxazone actinosin, which is responsible for their
yellow-red color. The differences among naturally occurring actinomycins
are confined to variations in the structure of the amino acids
of the peptide side chains.
Mechanism of Action. The capacity of actinomycins to bind with
double-helical DNA is responsible for their biological activity and
cytotoxicity. X-ray studies of a crystalline complex between dactinomycin
and deoxyguanosine permitted formulation of a model that
explains the binding of the drug to DNA (Sobell, 1973). The planar
phenoxazone ring intercalates between adjacent guanine–cytosine
base pairs of DNA, while the polypeptide chains extend along the
minor groove of the helix. The summation of these interactions provides
great stability to the dactinomycin-DNA complex, and as a
result of the binding of dactinomycin, the transcription of DNA by
RNA polymerase is blocked. The DNA-dependent RNA polymerases
are much more sensitive to the effects of dactinomycin than
are the DNA polymerases. In addition, dactinomycin causes singlestrand
breaks in DNA, possibly through a free-radical intermediate
or as a result of the action of topoisomerase II.
Cytotoxic Action. Dactinomycin inhibits rapidly proliferating cells
of normal and neoplastic origin and, on a molar basis, is among the