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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

Alkylating Agents: Nitrogen Mustards

Mechlorethamine (nitrogen mustard; Mustargen), a de-rivative of the war gas sulfur mustard, is considered to be the first modern anticancer drug.

Nitrogen Mustards



Mechlorethamine (nitrogen mustard; Mustargen), a de-rivative of the war gas sulfur mustard, is considered to be the first modern anticancer drug. In the early 1940s it was discovered to be effective in the treatment of hu-man lymphomas.


Mechlorethamine in aqueous solution loses a chlo-ride atom and forms a cyclic ethylenimmonium ion. This carbonium ion interacts with nucleophilic groups, such as the N7 and O6 of guanine, and leads to an interstrand cross-linking of DNA. Although there is great variation among normal and tumor tissues in their sensitivity to mechlorethamine, the drug is generally more toxic to proliferating cells than to resting or plateau cells. Mechlorethamine has a chemical and biological half-life in plasma of less than 10 minutes after intravenous in-jection. Little or no intact drug is excreted in urine.


The major indication for mechlorethamine is Hodgkin’s disease; the drug is given in the MOPP regi-men (mechlorethamine, vincristine, procarbazine, pred-nisone;). Other less reactive nitrogen mustards are now preferred for the treatment of non-Hodgkin’s lymphomas, leukemias, and various solid tumors.

The dose-limiting toxicity of mechlorethamine is myelosuppression; maximal leukopenia and thrombocy-topenia occur 10 to 14 days after drug administration, and recovery is generally complete at 21 to 28 days. Lymphopenia and immunosuppression may lead to ac-tivation of latent herpes zoster infections, especially in patients with lymphomas. Mechlorethamine will affect rapidly proliferating normal tissues and cause alopecia, diarrhea, and oral ulcerations. Nausea and vomiting may occur 1 to 2 hours after injection and can last up to 24 hours. Since mechlorethamine is a potent blistering agent, care should be taken to avoid extravasation into subcutaneous tissues or even spillage onto the skin. Reproductive toxicity includes amenorrhea and inhibi-tion of oogenesis and spermatogenesis. About half of premenopausal women and almost all men treated for 6 months with MOPP chemotherapy become perma-nently infertile. The drug is teratogenic and carcino-genic in experimental animals.




Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mus-tards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabolically by microsomal en-zymes of the cytochrome P450 system before ioniza-tion of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide.


Cyclophosphamide can be given orally, intramuscu-larly, or intravenously. The plasma half-life of intact cy-clophosphamide is 6.5 hours. Only 10 to 15% of the cir-culating parent drug is protein bound, whereas 50% of the alkylating metabolites are bound to plasma pro-teins. Since cyclophosphamide and its metabolites are eliminated primarily by the kidneys, renal failure will greatly prolong their retention.


Cyclophosphamide has a wide spectrum of antitu-mor activity. In lymphomas, it is frequently used in com-bination with vincristine and prednisone (CVP [or COP] regimen) or as a substitute for mechlorethamine in the MOPP regimen (C-MOPP). High dosages of in-travenously administered cyclophosphamide are often curative in Burkitt’s lymphoma, a childhood malignancy with a very fast growth rate. Oral daily dosages are use-ful for less aggressive tumors, such as nodular lym-phomas, myeloma, and chronic leukemias.

Cyclophosphamide is a component of CMF (cy-clophosphamide, methotrexate, 5-fluorouracil) and other drug combinations used in the treatment of breast cancer. Cyclophosphamide in combination may pro-duce complete remissions in some patients with ovarian cancer and oat cell (small cell) lung cancer. Other tu-mors in which beneficial results have been reported in-clude non–oat cell lung cancers, various sarcomas, neu-roblastoma, and carcinomas of the testes, cervix, and bladder. Cyclophosphamide also can be employed as an alternative to azathioprine in suppressing immunologi-cal rejection of transplant organs.


Bone marrow suppression that affects white blood cells more than platelets is the major dose-limiting tox-icity. Maximal suppression of blood cell count occurs 10 to 14 days after drug administration; recovery is gener-ally seen 21 to 28 days after injection. Cyclophos-phamide reduces the number of circulating lympho-cytes and impairs the function of both humoral and cellular (i.e., B and T cell) aspects of the immune sys-tem. Chronic therapy increases the risk of infections. Nausea may occur a few hours after administration. Alopecia is more common than with other mustards.


A toxicity that is unique to cyclophosphamide and ifosfamide is cystitis. Dysuria and decreased urinary fre-quency are the most common symptoms. Rarely, fibro-sis and a permanently decreased bladder capacity may ensue. The risk of development of carcinoma of the bladder also is increased. Large intravenous doses have resulted in impairment of renal water excretion, hy-ponatremia, and increased urine osmolarity and have been associated with hemorrhagic subendocardial necrosis, arrhythmias, and congestive heart failure. Interstitial pulmonary fibrosis may also result from chronic treatment. Other effects of chronic drug treat-ment include infertility, amenorrhea, and possible mu-tagenesis and carcinogenesis.





Ifosfamide (Ifex) is an analogue of cyclophosphamide that requires metabolic activation to form 4-hydroxy-ifosfamide. In general, the metabolism, serum half-life, and excretion of ifosfamide are similar to those of cy-clophosphamide.


Ifosfamide is active against a broad spectrum of tu-mors, including germ cell cancers of the testis, lym-phomas, sarcomas, and carcinomas of the lung, breast, and ovary. It is thought to be more active than cy-clophosphamide in germ cell cancers and sarcomas.


Ifosfamide is less myelosuppressive than cyclophos-phamide but is more toxic to the bladder. It also may produce alopecia, nausea, vomiting, infertility, and sec-ond tumors, particularly acute leukemias. Neurological symptoms including confusion, somnolence, and hallu-cinations have also been reported. It is recommended that ifosfamide be coadministered with the thiol com-pound mesna (Mesnex) to avoid hemorrhagic cystitis.




Melphalan (Alkeran) is an amino acid derivative of mechlorethamine that possesses the same general spec-trum of antitumor activity as do the other nitrogen mus-tards. However, the bioavailability of the oral prepara-tion is quite variable (25–90%) from one patient to another.


The major indications for melphalan are in the pal-liative therapy of multiple myeloma and cancers of the breast or ovary. Because it does not produce alopecia, melphalan is occasionally substituted for cyclophos-phamide in the CMF regimen for breast cancer.


Melphalan produces less nausea and vomiting than does cyclophosphamide; however, its bone marrow sup-pression tends to be more prolonged and affects both white cells and platelets. Peak suppression of blood counts occurs 14 to 21 days after a 5-day course of drug therapy; recovery is generally complete within 3 to 5 weeks.





Chlorambucil (Leukeran) is an aromatic nitrogen mus-tard that is intermediate in chemical reactivity between mechlorethamine and melphalan. Its mechanisms of ac-tion and range of antitumor activity are similar to theirs. It is well absorbed orally, but detailed information con-cerning its metabolic fate in humans is lacking.


Chlorambucil is used primarily as daily palliative therapy for chronic lymphocytic leukemia, Walden-ströom’s macroglobulinemia, myeloma, and other lym-phomas.


Bone marrow toxicity is the major side effect of chlorambucil. Nausea is uncommon or mild, and hair loss does not occur. Chlorambucil shares the immuno-suppressive, teratogenic, and carcinogenic properties of the nitrogen mustards.


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