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

is reversible at usual doses, but opportunistic infections
such as Pneumocystis jiroveci pneumonia, or fungal
infections, may occur with extended treatment, and reactivation
of hepatitis B has been described, prompting
some authors to advocate antiviral prophylaxis in hepatitis
B carriers undergoing intensive alkylating agent
chemotherapy (Grewal et al., 2007).
Mucosal Toxicity
Alkylating agents are highly toxic to dividing mucosal
cells and to hair follicles, leading to oral mucosal ulceration,
intestinal denudation, and alopecia.
The mucosal effects are particularly damaging in high-dose
chemotherapy protocols associated with bone marrow reconstitution,
as they predispose to bacterial sepsis arising from the GI tract.
In these protocols, cyclophosphamide, melphalan, and thiotepa have
the advantage of causing less mucosal damage than the other agents.
In high-dose protocols, however, other toxicities become limiting,
as delineated in Table 61–1.
Neurotoxicity
Nausea and vomiting commonly follow agent administration
of nitrogen mustard or BCNU. Ifosfamide is
the most neurotoxic agent of this class and may produce
altered mental status, coma, generalized seizures,
and cerebellar ataxia. These side effects result from the
release of chloroacetaldehyde from the phosphatelinked
chloroethyl side chain of ifosfamide. High-dose
busulfan can cause seizures; in addition, it accelerates
the clearance of phenytoin, an anti-seizure medication.
Other Organ Toxicities. Although mucosal and bone marrow toxicities
occur predictably and acutely with conventional doses of these drugs,
other organ toxicities may supervene after prolonged or high-dose use;
these effects can appear after months or years and may be irreversible
and even lethal. All alkylating agents, including temozolomide, have
caused pulmonary fibrosis, usually several months after treatment. In
high-dose regimens, particularly those employing busulfan or BCNU,
vascular endothelial damage may precipitate veno-occlusive disease
(VOD) of the liver, an often fatal side effect that is successfully
reversed by the investigational drug defibrotide (Richardson et al.,
2003). The nitrosoureas and ifosfamide, after multiple cycles of therapy,
may lead to renal failure. Cyclophosphamide and ifosfamide
release a nephrotoxic and urotoxic metabolite, acrolein, which causes
a severe hemorrhagic cystitis in high-dose regimens. This adverse
effect can be prevented by co-administration of 2-mercaptoethanesulfonate
(mesna; MESNEX), which conjugates acrolein in urine.
Ifosfamide in high doses for transplant causes a chronic, and often
irreversible, renal toxicity. Proximal and, less commonly, distal tubules
may be affected, leading to defective Ca 2+ and Mg 2+ reabsorption, glycosuria,
and renal tubular acidosis. Nephrotoxicity correlates with the
total dose of drug received and increases in frequency in children <5
years of age. The syndrome may be due to chloroacetaldehyde and/or
acrolein excreted in the urine.
The more unstable alkylating agents (particularly
mechlorethamine and the nitrosoureas) have strong vesicant properties,
damage veins with repeated use and, if extravasated, produce
ulceration.
Finally, all alkylating agents have toxic effects on the male
and female reproductive systems, causing an often permanent amenorrhea,
particularly in perimenopausal women, and an irreversible
azoospermia in men.
Leukemogenesis. As a class of drugs, the alkylating agents are highly
leukemogenic. Acute nonlymphocytic leukemia, often associated with
partial or total deletions of chromosome 5 or 7, peaks in incidence ~4
years after therapy and may affect up to 5% of patients treated on regimens
containing alkylating drugs. Leukemia often is preceded by a
period of neutropenia or anemia and by bone marrow morphology
consistent with myelodysplasia. Melphalan, the nitrosoureas, and the
methylating agent procarbazine have the greatest propensity to cause
leukemia, while it is less common after cyclophosphamide.
Table 61–1
Dose-Limiting Extramedullary Toxicities of Single Alkylating Agents
FOLD INCREASE OVER
DRUG MTD, a mg/m 2 STANDARD DOSE MAJOR ORGAN TOXICITIES
Cyclophosphamide 7000 7 Cardiac, hepatic VOD
Ifosfamide 16,000 2.7 Renal, CNS, hepatic VOD
Thiotepa 1000 18 GI, CNS, hepatic VOD
Melphalan 180 5.6 GI, hepatic VOD
Busulfan 640 9 GI, hepatic VOD
Carmustine (BCNU) 1050 5.3 Lung, hepatic VOD
Cisplatin 200 2 PN, renal
Carboplatin 2000 5 Renal, PN, hepatic VOD
a
Maximum tolerated dose (MTD; cumulative) in treatment protocols.
CNS, central nervous system; GI, gastrointestinal; PN, peripheral neuropathy; VOD, veno-occlusive disease.