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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 885

A P P E N D I X 57.1

CLINICAL PHARMACOLOGY OF ALKYLATING AGENTS

MECHLORETHAMINE (MUSTARGEN) parent compound is not active. The drug is metabolized by the
hepatic cytochrome P450 (CYP) system, which ultimately generates
Chemistry: Mechlorethamine, also called nitrogen mustard, is a at least two active compounds, phosphoramide mustard and acrolein.
water-soluble and alcohol-soluble analog of sulfur mustard gas. It is The latter appears to be responsible for cyclophosphamide’s bladder
a bifunctional chloroethylating agent that alkylates DNA, RNA, and toxicities. The plasma half-life of cyclophosphamide varies from 4 to
protein. 6.5 hours. Approximately 15% of the drug is excreted unchanged in
the urine. Dose reduction should be considered in patients with
Absorption, Fate, and Excretion: The parent compound is severe renal failure.
highly reactive and has a biologic half-life of approximately 15
minutes. The principal route of degradation is spontaneous hydroly- Preparation and Administration: Cyclophosphamide is sup-
sis, but some enzymatic demethylation also occurs. plied as 25- and 50-mg tablets and as a powder for parenteral
administration in 100-, 200-, and 500-mg and 1- and 2-g vials. It is
Preparation and Administration: Mechlorethamine is supplied dissolved by adding 5 mL of preservative-free sterile water for every
in vials of 10 mg with 100 mg of sodium chloride and is reconstituted 100 mg of drug. Cyclophosphamide is chemically stable for 24 hours
with 10 mL of sterile water to yield a 1-mg/mL solution, ideally at room temperature and for 6 days if refrigerated.
prepared immediately before use. However, the manufacturer consid-
ers the drug expired 1 hour after reconstitution. The drug is injected Toxic Effects: Bone marrow suppression is the major side effect.
over a few minutes through tubing as a freely running intravenous The myeloid series is primarily affected, although thrombocytopenia
(IV) infusion. For topical application (e.g., in mycosis fungoides), also occurs at high doses and alopecia is common. Nausea and vomit-
10 mg of drug is dissolved in 60 mL of tap water. Alternatively, a ing can be severe and are usually delayed, occurring 6–8 hours after
10 mg% ointment has been used by dissolving the drug in 95% ethyl administration. Hemorrhagic cystitis occurs in 10% of patients
alcohol and petrolatum (Aquaphor). Mechlorethamine is a powerful receiving nontransplant doses and is apparently caused by the forma-
vesicant. In the event of extravasation, vigorous irrigation followed tion of the urotoxin acrolein. Because of this potential side effect,
by 0.25% sodium thiosulfate injection at the site of extravasation patients should be well hydrated. Mesna disulfide (sodium
should be attempted. Ice packs may be placed for 6–12 hours to 2-mercaptoethanesulfonate disulfide) has also been used on a weight-
minimize the local reaction. equivalent basis to ameliorate cyclophosphamide-induced bladder
toxicity. Other potential toxic effects include stomatitis, skin and nail
Toxic Effects: Myelosuppression is the dose-limiting systemic side hyperpigmentation, interstitial pulmonary fibrosis, and the syndrome
effect. This worsens with each additive cycle. Severe nausea and of inappropriate secretion of antidiuretic hormone. Rare episodes of
vomiting, infertility, alopecia, and pain at the site of injection, which acute congestive heart failure have been reported. After bone marrow
can sometimes spread to involve the venous system (tracking), are transplant doses, hemorrhagic cystitis is common, and cardiac toxic-
also common. Occasionally, a macular papular rash is observed, but ity (cardiomyopathy) may be seen. Late sequelae include bladder
this does not appear to be allergic in nature and does not contrain- fibrosis (more common with daily [oral] therapy), bladder cancer,
dicate continuation of therapy. Infertility is common but may be leukemogenesis, and infertility.
reversible. Infrequent adverse effects include alopecia, anorexia, weak-
ness, and diarrhea. The drug has also been shown to induce chromo- Potential Drug Interactions: Corticosteroids may increase P450
somal abnormalities and may contribute to the development of enzyme–induced metabolism and is often avoided in high-dose
secondary leukemias, as seen in patients treated with this agent as therapy. When combined with doxorubicin, it may increase cardiac
part of the MOPP (mechlorethamine, vincristine [Oncovin], procar- toxicity. This may be prevented by amifostine. In animal studies,
bazine, prednisone) regimen. conflicting results were reported when the P450 enzyme inducer
phenobarbital was given with cyclophosphamide. Most investigators,
Potential Drug Interactions: None reported. however, have observed a reduction in the amounts of active
metabolites. Conversely, when cimetidine (but not ranitidine) was
Therapeutic Indications in Hematology: Mechlorethamine is administered in leukemia-bearing mice before treatment with cyclo-
incorporated in many chemotherapy combinations used in the treat- phosphamide, a significant prolongation of their survival and higher
ment of Hodgkin lymphoma (MOPP and MOPP/ABV [Adriamycin, plasma concentrations of alkylating metabolites were observed.
bleomycin, and vinblastine] hybrid) and in some non-Hodgkin Although one should remain alert for these potential drug interac-
lymphomas (NHLs; prednisone, etoposide, methotrexate, doxorubi- tions, none has been demonstrated in humans. Cyclophosphamide
cin [Adriamycin], cyclophosphamide, Leucovorin [PROMACE]/ reduces serum pseudocholinesterase levels, which may prolong the
MOPP). However, its use has largely been supplanted by other neuromuscular blocking effects if given simultaneously. Caution
agents. must be exercised when administering high doses of these two drugs
to critically ill patients. Life-threatening hyponatremia may develop
Cyclophosphamide (Cytoxan) when used in conjunction with indomethacin, although the precise
incidence is unknown.
Chemistry: Cyclophosphamide is a cyclic phosphamide ester of
mechlorethamine. After being metabolically activated, it alkylates Therapeutic Indications in Hematology: Cyclophosphamide
DNA, forming cross-links. is a key drug in the treatment of lymphomas and myeloma. It is
incorporated in many chemotherapy regimens, including CHOP,
Absorption, Fate, and Excretion: The drug is relatively well MACOP-B, PROMACE/CYTABOM, CVP, and VMCP (see Chap-
absorbed orally, with approximately 75% oral bioavailability. The ters 81 and 85 for details). In addition, cyclophosphamide is the drug