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

difluorodeoxyuridine (dFdU). Although dFdU has modest toxicity at
the usual concentrations found in plasma, in patients with significant
renal dysfunction, dFdU and its triphosphate accumulate to high
and potentially toxic levels (Koolen et al., 2009). Gemcitabine has a
short plasma t 1/2
of ~15 minutes, with women and elderly patients
clearing the drug more slowly (Abbruzzese et al., 1991). Peak levels
reach 20-60 μM with doses of 1000 mg/m 2 given over 30 minutes
intravenously. Clearance can vary widely among individuals but
is not affected by renal failure.
Similar to that of cytarabine, conversion of gemcitabine to
dFdCMP by deoxycytidine kinase is saturated at infusion rates of
~10 mg/m 2 /min, which produce plasma drug concentrations of
~10-20 μM. In an attempt to increase dFdCTP formation, the duration
of infusion at this maximum concentration has been extended
to 100-150 minutes at a fixed rate of 10 mg/min. The 150-minute
infusion produces a higher level of dFdCTP within peripheral
blood mononuclear cells and increases the degree of myelosuppression
but does not improve antitumor activity (Gandhi, 2007).
The inhibition of DNA repair by gemcitabine may increase cytotoxicity
of other agents, particularly platinum compounds, and with
radiation therapy. Preclinical studies of tumor cell lines show that
gemcitabine enhances formation of cisplatin-DNA adducts, presumably
through suppression of nuclear excision repair.
Therapeutic Uses. The standard dosing schedule for gemcitabine
(GEMZAR) is a 30-minute intravenous infusion of 1-1.25 g/m 2 on days
1, 8, and 15 of each 21- to 28-day cycle, depending on the indication.
Clinical Toxicities. The principal toxicity of gemcitabine is myelosuppression.
Longer-duration infusions lead to greater myelosuppression
and hepatic toxicity. Nonhematological toxicities include a
flu-like syndrome, asthenia, and rarely a posterior leukoencephalopathy
syndrome. Mild elevation in liver transaminases may
occur in ≥40% of patients and are reversible. Interstitial pneumonitis,
at times progressing to acute respiratory distress syndrome
(ARDS), may occur within the first two cycles of treatment and usually
responds to corticosteroids. Rarely, patients on gemcitabine
treatment for many months may develop a slowly progressive
hemolytic uremic syndrome, necessitating drug discontinuation
(Humphreys et al., 2004). Gemcitabine is a very potent radiosensitizer,
likely the result of its inhibition of RNR, depletion of dATP,
and inhibition of DNA repair (Flanagan et al., 2007) and should not
be used with radiotherapy except in closely monitored clinical trials.
PURINE ANALOGS
The pioneering studies of Hitchings and Elion begun in
1942 who identified analogs of naturally occurring
purine bases with antileukemic and immunosuppressant
properties. Their work led to the development of
drugs not only for treatment of malignant diseases
(mercaptopurine, thioguanine) but also for immunosuppression
in auto-immune disease and organ transplantation
(azathioprine) and antiviral chemotherapy
(acyclovir, ganciclovir, vidarabine, zidovudine) (Figure
61–11). The hypoxanthine analog allopurinol, a potent
inhibitor of xanthine oxidase, is an important byproduct
of this effort (see Chapter 34). Other purine analogs
have valuable roles in cancer therapy. These include
pentostatin (2′-deoxycoformycin), the first effective
agent against hairy cell leukemia, cladribine (standard
therapy for hairy cell leukemia), fludarabine phosphate
(standard treatment for CLL) nelarabine (pediatric
ALL), and clofarabine (T-cell leukemia/lymphoma).
The apparent preferential activity of these agents in lymphoid
malignancies may relate to their effective uptake,
activation, and apoptotic effects in lymphoid tissue.
6-Thiopurine Analogs
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG)
are approved agents for human leukemias and function
as analogs of the natural purines, hypoxanthine and
guanine. The substitution of sulfur for oxygen on C6 of
the purine ring creates compounds that are readily
transported into cells, including activated malignant
cells. Nucleotides formed from 6-MP and 6-TG inhibit
S
H N
N
CH
N N
H
MERCAPTOPURINE
H
HO
N
H
H 2 C
N
OH
OH
O
N
N
HO
PENTOSTATIN
(2 -DEOXYCOFORMYCIN)
N
NH 2
N
H 2 C
OH
O
ADENOSINE
N
N
OH
H
N
S
N
C
H 2 N N N
H
THIOGUANINE
H 3 C
NO 2
AZATHIOPRINE
Figure 61–11. Structural formulas of adenosine and various
purine analogs.
N
N
N
S
N
H
N
N
1701
CHAPTER 61
CYTOTOXIC AGENTS