Cyclophosphamide

Cyclophosphamide belongs to the class of alkylating agents and is used for the treatment of cancers (particularly within polychemotherapeutic regimens) and immune-mediated diseases.

CHEMICAL STRUCTURE AND PHARMACOKINETIC PROPERTIES

Cyclophosphamide is a pro-drug that is bio-transformed, mainly in the liver by the microsomal system, into the active alkylating metabolite (phosphamide mustard) which interferes with the growth of the susceptible, rapidly proliferating neoplastic cells. The same reaction also yields acrolein, which is toxic to the urothelium. Orally administered cyclophosphamide is well absorbed and has a bioavailability of about 75%. Following intravenous administration the peak blood level of the metabolites is reached in about 3 hours. Twenty percent of the drug is bound to plasma proteins. Cyclophosphamide is eliminated mainly through the kidneys in the form of metabolites; 5-25% is excreted unmodified.

MECHANISM OF ACTION

Cyclophosphamide (a bifunctional alkylating agent) has two alkyl groups which form two cross-links between two chains of DNA or within the same chain (position N7 of guanine), causing a complete break in the DNA or a block of transcription and protein synthesis. Cyclophosphamide acts independently of the phase of the cell cycle.

MECHANISM OF RESISTANCE

The main mechanism of resistance to cyclophosphamide involves removal of the alkylated nucleotides from the DNA chains by 6-alkylguanine-transferase.

CLINICAL INDICATIONS AND DOSE

Although potentially effective as monotherapy in sensitive malignancies, cyclophosphamide is normally administered in the context of a polychemotherapeutic regimen for the treatment oflymphomas and carcinomas, usually at a dose of 50-75 mg/m2/die per os for 2 or 4 consecutive days or 200-300 mg/m2 intravenously every 3 weeks. A ‘metronomic’ strategy, using a dose of 10 mg/m2 per os every 24-48 hours, has been employed in the treatment of carcinomas and sarcomas.

TOXICITY

Cyclophosphamide can have side effects on various organs and systems:

• bone marrow: reversible bone marrow suppression   (in particular neutropenia and lymphocytopenia), since stem cells contain high levels of aldehyde dehydrogenase which inactivates 4-hydroxycyclophosphamide (the first metabolite deriving from the degradation of cyclophosphamide).

• immune system: immunosuppression through depletion of B lymphocytes and suppression of the activity of T lymphocytes.
  
  
• gastrointestinal system: possible effects include nausea, vomiting, loss of appetite up to anorexia, particularly following oral administration of the drug.
  
  
• urothelium: haemorrhagic cystitis caused by acrolein, particularly following intravenous administration of the drug (Fig. 1).
  
  
• heart: doxorubicin-induced cardiac toxicity may be exacerbated.

Suggested readings

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